2,6-substuted-4-monosubstituted amino-pyrimidines as prostaglandin d2 receptor antagonists

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

 

The technical FIELD

The present invention relates to pyrimidine compounds, their receipt, containing these compounds, pharmaceutical compositions and their pharmaceutical use in the treatment of pathological conditions which can be influenced by inhibition of the receptor for prostaglandin D2.

It is shown that local stimulation of allergen in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis leads to a rapid rise in the level of prostaglandin D2 (PGD2) in nasal and bronchial wash fluid, tears and skin abdominal fluid. PGD2 can have a variety of inflammatory action, for example to increase the permeability of blood vessels in the conjunctiva and the skin, to increase the resistance of the Airways of the nose, narrowing the respiratory tract and the infiltration of eosinophils into the conjunctiva and trachea.

PGD2 is the major product of effects of cyclooxygenase on arachidonic acid produced by mastocytoma immunological stimulation [Lewis R.A., Soter, N.A., Diamond P.T., Austen K.F., J.A. Oates, L.J. Roberts II, prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982]. Activated Metacity is one of the main sources of PGD2 - play a key role in allergic reactions under such conditions as asthma, allergic rhinitis, allergic conjunctiva is t, allergic dermatitis and other diseases [C.E. Brightling, Bradding p, Pavord I.D., A.J. Wardlaw, New Insights into the role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556, 2003].

Many of the effects of PGD2 mediated by its action at the receptor prostaglandin D (DP) - receptor-associated G-protein, expressed on the epithelium and smooth muscle.

In asthma respiratory epithelium has long been considered the main source of inflammatory cytokines and chemokines, which determine the development of the disease [Holgate, S., Lackie, P., Wilson, S., Roche, W., Davies D., Bronchial Epithelium as a Key Regulator of Airway Allergen Sensisitzation and Remodelling in Asthma, Am. J. Respir. Crit. Care Med. 162, 113-117, 2000]. In experimental models of asthma mice upon stimulation with antigen is a sharp activation of the DP receptor in the epithelium of the respiratory tract [Matsuoka, T., Hirata M., Tanaka H., Takahashi Y., Murata, T., Kabashima K., Sugimoto y, Kobayashi t, Ushikubi f, Aze y, Eguchi n, Urade Y., Yoshida N., Kimura K, Mizoguchi, A., Honda Y., Nagai H., Narumiya, S., Prostaglandin D2 as a mediator of allergic asthma, Science 287, 2013-2017, 2000]. In knockout mice with a null DP receptor is markedly reduced Hyper-reactivity of the Airways and chronic inflammation [Matsuoka, T., Hirata M., Tanaka H., Takahashi Y., Murata, T., Kabashima K., Sugimoto y, Kobayashi t, Ushikubi f, Aze y, Eguchi n, Urade Y., Yoshida N., Kimura K, Mizoguchi, A., Honda Y., Nagai H., Narumiya, S., Prostaglandin D2 as a mediator of allergic asthma, Science 287, 2013-2017, 2000] two of the most important characteristic of asthma people.

It is also believed that the DP receptor is involved in allergic rhinitis human common Allergy is Eskom disorder, characterized by symptoms such as sneezing, itching, rhinorrhea, and nasal congestion. Local application of PGD2 in the nose causes a dose-dependent increase in nasal congestion [Doyle WJ, Boehm s, Skoner D.P., Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy, J. Allergy Clin. Immunol. 86(6 Pt 1), 924-35, 1990].

PUBLISHED RESULTS

It was shown that the DP receptor antagonists reduce airway inflammation in experimental models of asthma Guinea pigs [Arimura, A., Yasui K., Kishino j, Asanuma F., Hasegawa h, Kakudo s, Ohtani M., Arita H. (2001), Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751, J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001]. Thus, PGD2, apparently, acts on the DP receptor and plays an important role in the manifestation of the main features of allergic asthma.

It has been shown that antagonists of DP can effectively reduce the symptoms of allergic rhinitis in many species, in particular, it was shown that they can suppress induced antigens nasal congestion is the most obvious symptom of allergic rhinitis [Jones, T.R., Savoie, C., Robichaud, A., Sturino, C., Scheigetz, J., Lachance, N., Roy, B., Boyd, M., Abraham, W., Studies with a DP receptor antagonist in sheep and guinea pig models of allergic rhinitis, Am. J. Resp. Crit. Care Med. 167, A218, 2003; Arimura, A., Yasui K., Kishino j, Asanuma F., Hasegawa h, Kakudo s, Ohtani M., Arita H. Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001].

The DP antagonists are also effective in experimental the different models of allergic conjunctivitis and allergic dermatitis [Arimura A., Yasui K., Kishino j, Asanuma F., Hasegawa h, Kakudo s, Ohtani M., Arita H. (2001), Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751, J. Pharmacol. Exp. Ther. 298(2), 411-9, 2001; and Torisu K., Kobayashi K., Iwahashi M., Nakai Y., Onoda, T., Nagase, T., Sugimoto I., Okada Y., Matsumoto R., Nanbu F., Ohuchida s, Nakai H., Toda M., Discovery of a new class of potent, selective, and orally active prostaglandin D2receptor antagonists, Bioorg. & Med. Chem. 12, 5361-5378, 2004].

In this document, the applicants describe a new connection 2,6-substituted-4-monosubstituted amino-pyrimidine, having valuable pharmaceutical properties, in particular the ability to communicate with the DP receptor and regulate its function.

The INVENTION

The present invention is devoted to the connection 2,6-substituted-4-monosubstituted amino-pyrimidine of the formula (I)

where

(A) Cy1- cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl, heteroaryl, aryl or polycyclic alkaryl, each of which optionally has from one to three identical or different substitute groups Cy1which are

acyl, cyano, halogen, nitro, carboxy, hydroxy, alkylthio, alkylsulfonyl, alkylsulfanyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, polycyclic alkaryl, aroyl, arylethoxysilanes, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonyl, aaltio, heteroaromatic, heteroarylboronic, N-m is oxysulfate, R2-C(=N-OR3), Y1Y2N, Y1Y2NC(=O)-, Y1Y2NC(=O)-O-, Y1Y2NSO2-, alkyl-O-C(=O)-(C2-C6-alkylen-Z1-, Y1Y2N-C(=O)-(C1-C6-alkylen-Z1-, Y1Y2N-(C2-C6)alkylene-Z1-, alkyl-C(=O)-N(R5)-SO2-, alkyl-O-C(=O)-N(R5)-, alkyl-O-C(=O)-N(R5)-SO2-, alkyl-O-N(R5)-SO2-, alkyl-O-N(R5)-C(=O)-, alkyl-SO2-N(R5)-C(=O)-, aryl-SO2-N(R5)-C(=O)-, alkyl-SO2-N(R5)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-;

alkenyl, which is optionally substituted by alkoxy or hydroxy;

alkoxycarbonyl, which is optionally substituted by Y1Y2N;

quinil, which is optionally substituted by alkoxy or hydroxy;

alkyl, which optionally contains from one to three identical or different substituents which are halogen, carboxy, cyano, hydroxy, Y1Y2N, Y1Y2N-C(=O)-, H2N-C(=NH)-NH-O-, R6-C(=O)-N(R5)-, alkyl-O-C(=O)-N(R5)-, alkyl-SO2-N(R5)-, R8-SO2-N(R5)-C(=O)-, aryl-N(R5)-C(=O)-, heteroaryl-N(R5)-C(=O)-, heterocyclyl-N(R5)-C(=O)-, alkoxycarbonyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, polycyclic alkaryl; alkoxy, optionally substituted carboxy, aryl or heteroa the scrap; or alkoxycarbonyl, which is optionally substituted by Y1Y2N-; and

alkoxy, which optionally has one to three identical or different substituents, represents carboxy, alkoxycarbonyl, cyano, halogen, -NY1Y2, Y1Y2N-C(=O)-, cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or polycyclic alkaryl;

where

aryl or heteroaryl fragments in the replacement group Cy1optional independently have substituents, represents hydroxy, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;

and where

cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl or polycyclic alkaline fragments in the replacement group Cy1optional independently have substituents, represents hydroxy, amino, alkyl, alkoxy, oxo, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;

and besides, if Cy1is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl or polycyclic alkaryl, each of which may be independently substituted by oxo;

(B) Cy2- cycloalkenyl, heterocyclyl, aryl, heteroaryl or polycyclic alkaryl, each of which is independently optionally has from one d the three identical or different substituents, represents alkoxy, (C1-C3)-alkyl, hydroxy, cyano, halogen, halogenoalkane, halogenated, nitro, Y1Y2N, Y1Y2N-SO2-, aryl or heteroaryl, where aryl optionally substituted by alkyl or hydroxyalkyl, and heteroaryl optionally substituted by alkyl;

(C) L1- alkylen with a linear or branched chain containing from 1 to about 6 carbon atoms, optionally substituted by carboxy or hydroxy; or

L1- -CH2-(C1-C5)halogenation, or

L1- cycloalkyl containing from 1 to about 7 carbon atoms and optionally substituted by hydroxy; or

L1and Cy2together form aristically or cycloalkenyl;

(D) R1- (C1-C4)-alkylthio, Y4Y5N-; (C1-C4)-alkoxy, which optionally has one to three substituents as halogen; or (C1-C4)-alkyl, which optionally has one to three substituents as halogen, hydroxy or alkoxy;

(E) L2- bond, -O - or-CH2-O-;

and where

R2, R3, R4and R5each independently represent H or alkyl,

R6- alkyl, which optionally is hydroxy or alkoxysubstituted;

R7- H or alkyl;

R8is alkyl, aryl, arylalkyl, heteroaryl, heteroaryl is alkyl, where aryl or heteroaryl fragment optionally substituted with halogen;

Y1and Y2each independently represent hydrogen or alkyl, which optionally has one to three identical or different substituents, represents carboxy, alkoxycarbonyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aryl, heteroaryl or polycyclic alkaryl; where the aryl or heteroaryl independently optionally substituted by hydroxy, amino, alkyl or alkoxy, and where cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl and polycyclic alkaryl independently optionally substituted by hydroxy, amino, alkyl, alkoxy or oxo; or

Y1and Y2together with the nitrogen atom to which they are bound, form a nitrogen-containing saturated three-semicolony heterocyclyl, which optionally contain another heteroatom selected from O, S or NY3where Y3is hydrogen or alkyl, and where heterocyclyl optionally has from one to three identical or different substituents, represents carboxy, hydroxy, hydroxyalkyl, oxo, amino, alkylamino or dialkylamino;

Y4and Y5each independently represent H or (C1-C4)-alkyl;

Z1- C(=O)-N(R4), NR4or S(O)n; and

n is 0, 1 is 2;

provided that if R1- methoxy, L1- -CH2-CH2-L2communication and Cy2is 2,4-dichlorophenyl, Cy1is not 1-methyl-2-ethoxycarbonylmethyl-5-yl;

or its N-oxide, or prodrug in the form of ester or its pharmaceutically acceptable salt, hydrate or MES.

Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds of the formula (I) in a mixture with a pharmaceutically acceptable carrier.

Another aspect of the present invention is a method of treating a patient suffering from a disorder mediated by PGD2, including, in particular, allergic disorders (e.g., allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itch (such as atopic dermatitis and urticaria), diseases (such as cataract, retinal detachment, inflammation, infection, and sleep disorders), which arise as a secondary diseases are the result of behavior accompanied by itch (such as reccesive the I and rubbing), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebral circulation disorders, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and similar diseases, through the introduction of the patient pharmaceutically effective amount of the compounds of formula (I).

FULL description of the INVENTION

Used above and throughout the description of the invention, the following terms, unless otherwise indicated, have adopted the following values.

"Acyl" means an H-CO - or (aliphatic or cyclic residue)-CO-. For your preferred atilov are lower alkanoyl that contains the lowest alkali. Examples atilov are formyl, acetyl, propanol, 2-methylpropanol, butanol, Palmitoyl, acryloyl, propanol and cyclohexylcarbonyl.

"Aliphatic residue" means alkyl, alkenyl or quinil.

"Alkenyl" means a linear or branched aliphatic hydrocarbon group with a double carbon-carbon bond, having from 2 to about 15 carbon atoms. Preferred alkenyl includes from 2 to about 12 carbon atoms. More preferred alkenyl includes from 2 to about 4 carbon atoms. "Branched" means that linear alkenylphenol chain attached to one or more lower alkyl what's groups, such as methyl, ethyl or propyl. "Lower alkenyl" means from 2 to about 4 carbon atoms in the chain, which may be linear or branched. Examples of alkenyl are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylmethanol and decenyl.

"Alkoxy" means alkyl-O-. Examples of alkoxygroup are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptox.

"Alkoxyalkyl" means alkyl-O-alkylene. Examples of alkoxyalkyl are methoxymethyl and ethoxymethylene.

"Alkoxycarbonyl" means alkyl-O-CO-. Examples of alkoxycarbonyl are methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl.

"Alkyl" means a linear or branched aliphatic hydrocarbon having from 1 to about 20 carbon atoms. Preferred alkyl contains from 1 to about 12 carbon atoms. More preferred is lower alkyl. "Branched" means that linear alkyl chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. "Lower alkyl" means from 1 to about 4 carbon atoms in the alkyl chain, which may be linear or branched.

"Alkylamino" means alkyl-NH-. The preferred alkylaminocarbonyl is (C1-C6)-alkylamino. Examples of Ala is aminogroup are methylaminopropyl and atramentaria.

"Alkylene" means a linear or branched bivalent hydrocarbon having from 1 to about 15 carbon atoms. The preferred alkylene is lower alkylen with the number of carbon atoms from 1 to about 6. Examples of alkylene are methylene, ethylene, propylene and butylene.

"Alkylsulfonyl" means alkyl-SO-. The preferred alkylsulfonyl is (C1-C6-alkylsulfonyl. Example alkylsulfonyl group is CH3-SO-.

"Alkylsulfonyl" means an alkyl-SO2-. The preferred alkylsulfonyl is (C1-C6)-alkylsulfonyl. Examples of alkylsulfonyl are CH3-SO2and CH3CH2-SO2-.

"Alkylthio" means alkyl-S-. An example of ancilliary is CH3S.

"Quinil" means a linear or branched aliphatic hydrocarbon with a triple carbon-carbon bond, having from 2 to about 15 carbon atoms. Preferred quinil has from 2 to about 12 carbon atoms. More preferred quinil has from 2 to about 6 carbon atoms. "Branched" means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. "Lower quinil" means from 2 to about 4 carbon atoms in alkenylphenol chain, which can be LINEST is th or branched. Examples of alkinyl are ethinyl, PROPYNYL, n-butynyl, 2-butynyl, 3-methylbutyl, n-pentenyl, heptenyl, octenyl and decenyl.

"Aroyl" means an aryl-CO-. Examples rolnych groups are benzoyl and 1 - and 2-naphtol.

"Aryl" means an aromatic monocyclic or polycyclic ring system having from 6 to about 14 carbon atoms. Preferred aryl has from 6 to about 10 carbon atoms. Examples of arilou are phenyl and naphthyl.

"Arylalkyl" means an aryl-alkyl-. Preferred arylalkyl contains (C1-C6)-alkyl fragment. Examples of arylalkyl are benzyl, 2-phenethyl and naphthalenethiol.

"Allakaket" means arylalkyl-O-. Examples arylalkyl groups are benzyloxy and 1 - or 2-naphthalenyloxy.

"Arylethoxysilanes" means arylalkyl-O-CO-. Examples allamoxicillinpills groups are phenoxycarbonyl and mattoxicator.

"Arylalkyl" means arylalkyl-S-. An example of arylalkylamine is menzilcioglu.

"Arylchloroalkanes" means a condensed aryl and cycloalkenyl. The preferred arylcycloalkylamine is one in which the aryl is phenyl, and cycloalkenyl ring has from about 5 to about 7 atoms. Arylchloroalkanes connected through any of the atoms cycloalkenyl fragment tolerance is a first such communication. Examples of arylcyclohexylamines are 1,2-dihydronaphthalene and inden.

"Aristically" means a condensed aryl and cycloalkyl. The preferred arylcyclohexylamine is one in which the aryl is phenyl, and cycloalkyl ring has from about 5 to about 6 atoms. Aristically connected through any of the atoms cycloalkyl fragment, allowing such communication. An example of killglance is 1,2,3,4-tetrahydronaphthalen.

"Arylheteroacetic" means a condensed aryl and heterocyclyl. The preferred arylheteroacetic is one in which the aryl is phenyl, and heterocyclyl ring has from about 5 to about 6 atoms. Arylheteroacetic connected through any of the atoms heterocyclyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part arylheteroacetic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom arylheteroacetic may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part arylheteroacetic can also be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of arylheteroacetic are 3H-indolinyl, 1H-2-oxoindole, 2H-1-ACS is ethanolic, 1,2-dihydroquinoline, 3,4-dihydroquinoline, 1,2-dihydroisoquinolines and 3,4-dihydroisoquinolines.

"Arylheteroacetic" means a condensed aryl and heterocyclyl. The preferred arylheteroacetic is one in which the aryl is phenyl and the heterocyclic ring has from about 5 to about 6 atoms. Arylheteroacetic connected through any of the atoms heterocyclyl fragment, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part allheterocou mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom allheterocou may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part allheterocou may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples allheterocou are indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroindol-2-yl, 2,3-dihydrobenzo[f]isoindole-2-yl and 1,2,3,4-tetrahydrobenzo[g]-isoquinoline-2-yl.

"Aryloxy" means aryl-O-. Examples of aryloxy are fenoxaprop and naftussya.

"Aryloxyalkyl" means aryl-O-CO-. Examples of aryloxyalkyl are phenoxycarbonyl and mattoxicator.

"Arylsulfonyl the means aryl-SO-. Examples of arylsulfonyl are phenylsulfinyl and naphthylmethyl.

"Arylsulfonyl" means aryl-SO2-. Examples of arylsulfonyl are phenylsulfonyl and naphthylmethyl.

"Aristeo" means an aryl-S-. Examples of aricioglu are phenylthio and naphthylthiourea.

"Compounds of the present invention" and similar expressions include the above-described herein the compounds of formula (I), including ester prodrug, pharmaceutically acceptable salt and solvate, e.g. hydrates, where permitted by the context. Similarly, the reference to intermediate compounds, regardless of whether they are themselves the subject of this invention extends to their salts and solvate, where permitted by the context.

"Cycloalkenyl" means a non-aromatic mono - or polycyclic ring system having from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, which has at least one double carbon-carbon bond. Preferred ring ring systems contain from about 5 to about 6 atoms in the ring; these rings are the preferred size is also referred to as "lower". Examples of monocyclic cycloalkenyl are cyclopentenyl, cyclohexenyl and cycloheptenyl. An example of politicly the definition cycloalkenyl is norbornadiene.

"Cycloalkenyl" means a condensed aryl and cycloalkenyl. The preferred cycloalkylation is one in which the aryl is phenyl, and cycloalkenyl ring has from about 5 to about 6 atoms. Cycloalkenyl connected through any of the atoms of the aryl fragment, allowing such communication. Examples of cycloalkylation are 1,2-dihydronaphthalene and inden.

"Cycloalkylcarbonyl" means a condensed heteroaryl and cycloalkenyl. It is preferable to cycloalkylcarbonyl in which heteroaryl has from about 5 to about 6 atoms in the ring and cycloalkenyl has from about 5 to about 6 atoms in the ring. Cycloalkylcarbonyl connected through any of the atoms of the heteroaryl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of cycloalkylcarbonyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of cycloalkylcarbonyl may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of cycloalkylcarbonyl can also be oxidized to the corresponding N-oxide. Examples of cycloalkylcarbonyl are 5,6-dihydrohelenalin, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxaline, 5,6-dihydroxy zainil, 4,5-dihydro-1H-benzimidazolyl and 4.5-dihydroisoxazole.

"Cycloalkyl" means a non-aromatic mono - or polycyclic saturated ring system having from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred ring systems contain from about 5 to about 7 atoms in the ring; these rings are the preferred size is also referred to as "lower". Examples of monocyclic cycloalkyl are cyclopentyl, cyclohexyl and cycloheptyl. Examples of polycyclic cycloalkyl are 1-decalin, norbornyl and adamant-(1 - or 2-)yl.

"Cycloalkenyl" means a condensed aryl and cycloalkyl. The preferred cycloalkylation is one in which the aryl is phenyl, and cycloalkyl ring has from about 5 to about 6 atoms. Cycloalkenyl connected through any of the atoms cycloalkyl fragment, allowing such communication. An example of cycloalkenyl is 1,2,3,4-tetrahydronaphthalen.

"Cycloalkyl" means a bivalent cycloalkyl group having from about 4 to about 8 carbon atoms. Preferred cycloalkyl contains from about 5 to about 7 atoms in the ring; these rings are the preferred size is also referred to as "lower". The nature of the binding cycloalkanones group predusmatriva is no formation of 1,1-, 1,2-, 1,3 - or 1,4-structures, and, where applicable, the stereochemical configuration of points education links can be CIS or TRANS. Examples of monocyclic cycloalkanes are (1,1-, 1,2 - or 1,3-)cyclohexene and (1,1 - or 1,2-)cyclopentyl.

"Cycloalkylcarbonyl" means a condensed heteroaryl and cycloalkyl. It is preferable to cycloalkylcarbonyl in which heteroaryl has from about 5 to about 6 atoms in the ring and cycloalkyl has from about 5 to about 6 atoms in the ring. Cycloalkylcarbonyl connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of the condensed cycloalkylcarbonyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of cycloalkylcarbonyl may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of cycloalkylcarbonyl can also be oxidized to the corresponding N-oxide. Examples of cycloalkylcarbonyl are 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 5,6,7,8-tetrahydroquinazolin, 4,5,6,7-tetrahydro-1H-benzimidazolyl and 4,5,6,7-tetrahydrooxazolo.

"Cilil" means cycloalkyl, cycloalkenyl, heterotic the sludge or heterocyclyl.

"Dialkylamino" means (alkyl)2-N. The preferred dialkylamino is (C1-C6alkyl)2-N. Examples of dialkylamino are dimethylamino, diethylamino and methylaminopropyl.

"Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Halogenoalkane" means the CNS group having from one to three halogen groups as substituents. Preferred are lower CNS group having from one to three halogen as substituents. Most preferred are lower CNS group, substituted with one halogen.

"Halogenated" means an alkyl group having from one to three halogen groups as substituents. Preferred are lower alkyl groups having from one to three halogen as substituents. Most preferred are lower alkyl groups substituted with one halogen.

"Halogenation" means alkylene having from one to three halogen groups as substituents. Preferred are lower alkylene with one to three Halogens as substituents. Most preferred are lower alkyl groups substituted with one halogen. Examples of halogenosilanes are-CHF-, -CF2, -CH2-CHF - and-CH2-CF2-.

"Heteroaryl" means heteroaryl-CO-. Examples of heteroaryl are thiophenol, nicotinoyl, pyrrol-2-ylcarbonyl, 1 - and 2-naphtol and pyridinoyl.

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system having from about 5 to about 14 carbon atoms, in which one or more carbon atoms of the ring system are heteroatoms other than carbon, for example nitrogen, oxygen or sulfur. Preferred aromatic ring system has from about 5 to about 10 carbon atoms and from 1 to 3 heteroatoms. The most preferred ring system size from about 5 to about 6 atoms. Indicate "Aza", "oxa" or "thio" as a prefix in the name of heteroaryl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heteroaryl can be basic nitrogen atom and may be optionally oxidized to the corresponding N-oxide. If heteroaryl substituted hydroxyl group, it also includes the appropriate tautomer, if it is possible for this heteroaryl. Examples of heteroaryl are pyrazinyl, thienyl, isothiazolin, oxazolyl, pyrazolyl, furutani, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, hee shall oxalyl, phthalazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, isoindolyl, benzimidazolyl, benzothiazyl, cyanopyridyl, thienopyrimidine, pyrrolopyridine, imidazopyridine, benzoxazinones, 1,2,4-triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, ethenolysis, isothiazolin, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, hintline, chinoline, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl.

"Heteroaromatic" means heteroaryl-alkyl-. Preferred heteroaromatic contains C1-4the alkyl fragment. An example of heteroallyl is tetrazol-5-ylmethyl.

"Heteroaromatics" means heteroaryl-alkyl-O-.

"Heteroarylboronic" means heteroallyl-O-CO-.

"Heteroalicyclic" means a condensed heteroaryl and cycloalkenyl. It is preferable heteroarylboronic in which heteroaryl has from about 5 to about 6 atoms in the ring and cycloalkenyl has from about 5 to about 6 atoms in the ring. Heteroarylboronic connected through any of the atoms cycloalkenyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part heteroarylboronic mean that at least one of the atoms of the ring at outstay the nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heteroarylboronic may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion heteroarylboronic may also be optionally oxidized to the corresponding N-oxide. Examples of heteroarylboronic are 5,6-dihydrohelenalin, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxaline, 5,6-dihydroquinazolin, 4,5-dihydro-1H-benzimidazolyl and 4.5-dihydroisoxazole.

"Heteroalicyclic" means a condensed heteroaryl and cycloalkyl. It is preferable to heteroalicyclic in which heteroaryl has from about 5 to about 6 atoms in the ring and cycloalkyl has from about 5 to about 6 atoms in the ring. Heteroalicyclic connected through any of the atoms cycloalkyl group, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl part of the condensed heteroalicyclic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heteroalicyclic may be the basic nitrogen atom. The nitrogen atom of the heteroaryl portion of heteroalicyclic may also be optionally oxidized to the corresponding N-oxide. Examples of heteroalicyclic are 5,6,7,8-tetrahydroquinolin is l, 5,6,7,8-tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 5,6,7,8-tetrahydroquinazolin, 4,5,6,7-tetrahydro-1H-benzimidazolyl and 4,5,6,7-tetrahydrooxazolo.

"Heteroalicyclic" means a condensed heteroaryl and heterocyclyl. It is preferable heterooligomerization in which heteroaryl has from about 5 to about 6 atoms in the ring and heterocyclyl has from about 5 to about 6 atoms in the ring. Heterooligomerization connected through any of the atoms heterocyclyl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part heterooligomerization mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterooligomerization may be the basic nitrogen atom. The nitrogen atom or sulfur heteroaryl part heteroalicyclic may also be optionally oxidized to the corresponding N-oxide. The nitrogen atom or sulfur or heteroaryl heterocyclyl part heteroalicyclic may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterooligomerization are 7,8-dihydro[1,7]naphthyridine, 1,2-dihydro[2,7]-naphthyridines, 6,7-dihydro-3H-imides the[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridine, 1,2-dihydro-1,6-naphthyridine, 1,2-dihydro-1,7-naphthyridine, 1,2-dihydro-1,8-naphthyridine and 1,2-dihydro-2,6-naphthyridine.

"Heteroalicyclic" means a condensed heteroaryl and heterocyclyl. It is preferable heteroalicyclic in which heteroaryl has from about 5 to about 6 atoms in the ring and heterocyclyl has from about 5 to about 6 atoms in the ring. Heteroalicyclic connected through any of the atoms heterocyclyl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part heteroalicyclic mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom condensed heteroalicyclic may be the basic nitrogen atom. The nitrogen atom or sulfur heteroaryl part heteroalicyclic may also be optionally oxidized to the corresponding N-oxide. The nitrogen atom or sulfur or heteroaryl heterocyclyl part heteroalicyclic may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples heterooligomerization are 2,3-dihydro-lH-pyrrol[3,4-b]quinoline-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,7]naphthiridine-2-yl, 1,2,3,4-Tetra grabens[b][1,6]naphthiridine-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydrothieno[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepine[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepine[4,5-b]indole-2-yl, 5,6,7,8-tetrahydro[1,7]naphthyridin, 1,2,3,4-tetrahydro[2,7]naphthyridin, 2,3-dihydro[1,4]like[2,3-b]pyridyl, 2,3-dihydro[1,4]like[2,3-b]pyridyl, 3,4-dihydro-2H-1-oxa[4,6]diazonaphthalene, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazonaphthalene, 1,2,3,4-tetrahydro[1,5]-naphthyridine, 1,2,3,4-tetrahydro[1,6]naphthyridine, 1,2,3,4-tetrahydro[1,7]naphthyridine, 1,2,3,4-tetrahydro[1,8]naphthyridine and 1,2,3,4-tetrahydro[2,6]naphthyridine.

"Heteroaromatic" means heteroaryl-O-. Example heteroarylboronic group is peridiocally group.

"Heterocyclyl" means a non-aromatic monocyclic or polycyclic hydrocarbon ring system having from about 3 to about 10 carbon atoms, in which one or more carbon atoms of the ring system is(are) the heteroatom(s), excellent(and) from carbon, for example nitrogen, oxygen or sulfur, and which contains at least one double carbon-carbon bond or a double carbon-nitrogen bond. Preferred non-aromatic ring system has from about 5 to about 10 carbon atoms and from 1 to 3 heteroatoms. PR is doctitle ring ring systems contain from about 5 to about 6 atoms in the ring; these rings are the preferred size is also referred to as "lower". Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterocyclyl may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic azaheterocycles are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridin, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl and 2-pyrazolines. Examples of oksytetracyclin are 3,4-dihydro-2H-Piran, dihydrofuran and fordevelopment. An example of a polycyclic exegetically is 7-oxabicyclo[2.2.1]heptenyl. Examples of monocyclic togetherdoctoral are dihydrothiophene and dihydrothiophene.

"Heterocultural" means a condensed aryl and heterocyclyl. The preferred heterocyclisation is one in which the aryl is phenyl, and heterocyclyl ring has from about 5 to about 6 atoms. Heterocultural connected through any of the atoms of aryl, allowing such communication. The designation of Aza, the oxa" or "thio" as a prefix in the name heterocyclyl part of the condensed heterocultural mean, that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heterocultural may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part of heterocultural may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterocyclization are 3H-indolinyl, 1H-2-oxoindole, 2H-1-occaisonaly, 1,2-dihydroquinoline, 3,4-dihydroquinoline, 1,2-dihydroisoquinolines and 3,4-dihydroisoquinolines.

"Heterocyclisation" means a condensed heteroaryl and heterocyclyl. It is preferable to heterocyclisation in which heteroaryl has from about 5 to about 6 atoms in the ring and heterocyclyl has from about 5 to about 6 atoms in the ring. Heterocyclisation connected through any of the atoms heteroaryl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part of geterotsiklicheskikh mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of azaheterocyclic may be the basic nitrogen atom. The nitrogen atom or sulfur heteroaryl part of geterotsiklicheskikh mo the et also be optionally oxidized to the corresponding N-oxide. The nitrogen atom or sulfur or heteroaryl heterocyclyl part of geterotsiklicheskikh may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of geterotsiklicheskikh are 7,8-dihydro[1,7]naphthyridine, 1,2-dihydro[2,7]-naphthyridines, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridine, 1,2-dihydro-1,6-naphthyridine, 1,2-dihydro-1,7-naphthyridine, 1,2-dihydro-1,8-naphthyridine and 1,2-dihydro-2,6-naphthyridine.

"Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system having from about 3 to about 10 carbon atoms, in which one or more carbon atoms of the ring system is(are) the heteroatom(s), excellent(and) from carbon, for example nitrogen, oxygen or sulfur. Preferred ring systems have from about 5 to about 10 carbon atoms and from 1 to 3 heteroatoms. Preferred ring ring systems contain from about 5 to about 6 atoms in the ring; these rings are the preferred size is also referred to as "lower". Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom heterocyclyl can be a major at the IOM nitrogen. The nitrogen atom or sulfur heterocyclyl may also be optionally oxidized to a corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic heterocyclyl are piperidinyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,3-DIOXOLANYL, 1,4-dioxane, tetrahydrofuranyl, tetrahydrothiophene and tetrahydrothiopyran.

"Heterocyclisation" means a condensed aryl and heterocyclyl. The preferred heterocyclisation is one in which the aryl is phenyl, and heterocyclyl ring has from about 5 to about 6 atoms. Heterocyclisation connected through any of the atoms of the aryl fragment, allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heterocyclyl part of heterocyclisation mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of heterocyclisation may be the basic nitrogen atom. The nitrogen atom or sulfur heterocyclyl part of heterocyclisation may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of heterocyclisation are indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroindol-2-yl, 2,3-dihydrobenzo[f]isoindole-2-yl and 1,2,3,4-tetrahydrobenzo[g]-and chinolin-2-yl.

"Heterocyclisation" means a condensed heteroaryl and heterocyclyl. It is preferable to heterocyclisation in which heteroaryl has from about 5 to about 6 atoms in the ring and heterocyclyl has from about 5 to about 6 atoms in the ring. Heterocyclisation connected through any of the atoms heterocyclyl allowing such communication. Indicate "Aza", "oxa" or "thio" as a prefix in the name heteroaryl or heterocyclyl part of geterotsiklicheskikh mean that at least one of the ring atoms is a nitrogen atom, oxygen or sulfur, respectively. The nitrogen atom of geterotsiklicheskikh may be the basic nitrogen atom. The nitrogen atom or sulfur heteroaryl part of geterotsiklicheskikh may also be optionally oxidized to the corresponding N-oxide. The nitrogen atom or sulfur or heteroaryl heterocyclyl part of geterotsiklicheskikh may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of geterotsiklicheskikh are 2,3-dihydro-1H-pyrrole[3,4-b]quinoline-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,7]naphthiridine-2-yl, 1,2,3,4-tetrahydrobenzo[b][1,6]naphthiridine-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl, 2,3-dihydro-1H-pyrrolo[3,4-b]indole-2-yl, 1H-2,3,4,5-tetrahydro sepino[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepine[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepine[4,5-b]indol-2-yl, 5,6,7,8-tetrahydro[1,7]naphthyridin, 1,2,3,4-tetrahydro[2,7]naphthyridin, 2,3-dihydro[1,4]like[2,3-b]pyridyl, 2,3-dihydro-[1,4]like[2,3-b]pyridyl, 3,4-dihydro-2H-1-oxa[4,6]diazonaphthalene, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazonaphthalene, 1,2,3,4-tetrahydro[1,5]-naphthyridine, 1,2,3,4-tetrahydro[1,6]naphthyridine, 1,2,3,4-tetrahydro[1,7]naphthyridine, 1,2,3,4-tetrahydro[1,8]naphthyridine and 1,2,3,4-tetrahydro[2,6]naphthyridine.

"Hydroxyalkyl" means the HO-alkylene-. Examples of hydroxyalkyl are HO-CH2and HO-CH2-CH2-.

"Polycyclic alkaryl" means polycyclic ring system having at least one aromatic ring condensed with at least one non-aromatic ring which may be saturated or unsaturated, and may contain in the ring one or more heteroatoms, such as nitrogen, oxygen or sulfur. Examples of polycyclic alcario are arylchloroalkanes, aristically, arylheteroacetic, arylheteroacetic, cycloalkenyl, cycloalkenyl, cycloalkylcarbonyl, cycloalkylcarbonyl, heteroalicyclic, heteroalicyclic, heteroalicyclic, heteroalicyclic, heterocultural, heterocyclization, heterocyclyl the l and heterocyclisation. Preferred polycyclic alkalline groups are bicyclic system consisting of one aromatic ring fused with one non-aromatic ring which can contain in the ring one or more heteroatoms, such as nitrogen, oxygen or sulphur.

"Patient" means humans and other mammals.

Used herein, the term "pharmaceutically acceptable prodrug" means prodrugs of the compounds of the present invention, which by competent medical opinion are suitable for use in contact with the tissues of patients with unwanted toxicity, irritation, allergic reaction are within a reasonable relationship between benefits and risks, and are effective for their intended uses of the compounds according to the invention. The term "prodrug" means compounds that are transformed in vivo into the parent compound according to the invention, for example, by hydrolysis in blood. Functional groups that can undergo rapid transformations through metabolic decay in vivo, form a class of groups that can react with a carboxyl group of the compounds according to the invention. These include, in particular, groups such as alkanoyl (for example, acetyl, propanol, butano and similar), unsubstituted or substituted aroyl (for example, benzoyl or substituted benzoyl), alkoxycarbonyl (for example, etoxycarbonyl), trialkylsilyl (for example, trimethyl - or triethylsilyl) and complex monetary formed with dicarboxylic acids (for example, succinyl). Due to the ease with which the affected metabolic decomposition group of compounds according to the invention are oxidized in vivo, compounds with such groups act as prodrugs. Connection with the subject of metabolic decomposition groups have the advantage that they may show an increased bioavailability as a result of higher solubility and/or rate of absorption of the parent compound due to the presence of exposed metabolic disintegration of the group. A detailed discussion can be found in Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al., Ed., Academic Press,42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bandaged, ed., Chapter 5; "Design and Applications of Prodrugs" 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard,8, 1-38, (1992); J. Pharm. Sci.,77, 285 (1988); Chem. Pharm. Bull., N. Nakeya et al., 32, 692 (1984); Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella,14A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, E.B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which, through references to them are included in this document.

"Ester prodrug" means a compound that can be transformed in vivo during metabolic the definition of processes (for example, by hydrolysis) to a compound of formula (I). For example, ester compounds of formula (I)containing a hydroxyl group by hydrolysis to develop in the body in the original molecule. Alternatively an ester of the compounds of formula (I)containing a carboxyl group in the hydrolysis process can be transformed in vivo into the original molecule. Examples of ester prodrugs are

1-ethoxycarbonylmethyl ester 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid and its enantiomers;

1-ethoxycarbonylmethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid and its enantiomers;

2-dimethylaminoethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acids;

methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid.

"Pharmaceutically acceptable salts" means non-toxic, inorganic and organic salts of the compounds according to the invention is formed by attaching the acid or base. These salts can be obtained in situ during the final phase of isolation and purification of compounds.

Example N-oxide is

[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine.

"MES" means the connection according to the invention, are physically associated with one or more solvent molecules. To the physical linking applies, in particular, the formation of hydrogen bond. In certain cases, the MES can be identified, for example, when one or more solvent molecules included in the crystal lattice of a solid crystalline substance. The term "MES" applies to both the solution phase and on the isolated solvate. Typical solvate is a hydrate, ethanolate and methanolate.

Suitable esters of compounds of formula (I)containing a hydroxyl group include, for example, acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isethionate, di-para-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, para-toluensulfonate, cyclohexylsulfamate and hinata.

Suitable esters of compounds of formula (I)containing a carboxyl group are, for example, described in F.J. Leinweber, Drug Metab. Res., 1987,18, page 379.

A particularly useful class of esters of compounds of formula (I)containing the guide is auxillou group, can be formed from acid fragments as described in the work Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)benzoate, such as dialkylaminomethyl, in which the two alkyl groups may be combined and/or separated by an oxygen atom or a nitrogen atom optionally Deputy, for example alkilirovanii a nitrogen atom, especially (morpholinomethyl)benzoate, for example 3 - or 4-(morpholinomethyl)benzoate, and (4-alkylpiperazine-1-yl)benzoate, for example 3 - or 4-(4-alkylpiperazine-1-yl)benzoate.

Some of the compounds according to the invention are basic, and such compounds are applicable in the form of free bases or in the form of their pharmaceutically acceptable salts, formed by adding acid.

Salts formed by attaching acids, are more convenient to use the form, and in practice the use of the compounds in salt form is essentially equivalent to its use in free base form. Acids that can be used to obtain the salts formed by adding acid, preferably are such that when mixed with the free base form of pharmaceutically acceptable salts, i.e. salts, the anions of which are non-toxic to the patient in pharmaceutical doses of such salts, so that beneficial ingibiruet what their effects, inherent in the free base are not suppressed side effects typical of anions. Although preferred are pharmaceutically acceptable salts of the mentioned basic compounds, all salts formed by attaching acid, can be used as sources of compounds in the free base form even if the particular salt itself is desired only as an intermediate product, for example when the salt is formed only for purification and identification, or when it is used as an intermediate connection when receiving a pharmaceutically acceptable salt by ion exchange. In particular, the salts formed by the addition of acids, can be obtained by the independent reaction of the purified compound in free base form with a suitable organic or inorganic acid and allocation thus obtained salt. Pharmaceutically acceptable salts according to the invention include salts formed from mineral and organic acids. Examples of salts of addition of acid are hydrobromide, hydrochloride, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valerate, oleates, palmitate, hinata, stearates, laurate, borate, benzoate, lactates, phosphates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, naphthalate, mesylates, glycopep the courses, lactobionate, sulfamate, malonate, salicylates, propionate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-para-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, para-toluensulfonate, cyclohexylsulfamate and laurylsulphate. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977), included in this description by reference.

If the connection according to the invention substituted acid fragment may be salts formed by addition of bases, which are simply a more convenient form of application, and in practice the use of the salt form is essentially equivalent to its use in the form of the free acid. The bases that can be used for the preparation of salts formed by adding a base, preferably are such that when mixed with the free acid form pharmaceutically acceptable salts, i.e. salts, the cations of which are non-toxic to the patient in pharmaceutical doses of such salts, and useful inhibiting effects inherent in the free base are not suppressed side effects attributed to cations. Salts formed by attaching a substrate can also be obtained independently by the reaction of purified compound in its acid form with a suitable organic or neorganic the sky Foundation formed from the salts of alkali or alkaline earth metals, and the allocation thus obtained salt. The salts formed by the addition of bases include pharmaceutically acceptable metal salts and amines. Suitable metal salts include salts of sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Preferred are the sodium and potassium salts. Suitable inorganic salts formed during the addition of base, obtained from the grounds of the metals, which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine salts formed by addition of a base, derived from amines, basicity of which is sufficient for the formation of a stable salt, and preferably from amines commonly used in medicinal chemistry because of their low toxicity and suitability for use in medical purposes. Ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, diethylamine, piperazine, Tris(hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium, triethylamine, dibenzylamine, fenamin, dehydroabietylamine, N-ethylpiperidine, benzylamine, Tetramethylammonium, tetraethylammonium, m is tillin, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and dicyclohexylamine.

Being useful in themselves as active compounds, salts of the compounds according to the invention is useful for cleaning compounds, for example, by using the difference in solubility of the salts and the parent compounds, by-products and/or raw materials by means known in the art methods.

It is obvious that the compounds according to the invention may contain asymmetric centers. These asymmetric centers can independently be in the R - or S-configuration. For professionals in the field it is obvious that certain compounds according to the invention can also exhibit geometric isomerism. It should be understood that the present invention applies to the individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures of compounds of the above formula (I). Such isomers can be distinguished from mixtures by known methods or their modifications. One means of separating mixtures of isomers are the methods of chiral chromatography. As an alternative means of separating mixtures of isomers is possible to use the methods of chiral recrystallization. Individual isomeric compounds can also be obtained by using, when possible, chiral predestin is of IKI.

As for a more detailed description of preferred compounds according to the invention, one of the private embodiments of the present invention is a compound of formula (I), where R1- amino, dimethylamino, methoxy, ethoxy, ethyl, methylthio, methylamino or 2,2,2-triptoreline; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1- phenyl, benzimidazolyl, benzo[1,3]dioxole, benzothiazolyl, benzo[b]thiophenyl, 1H-benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxane, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, furanyl, imidazolyl, 1H-indazole, indolinyl, indolyl, ethenolysis, isoxazolyl, oxadiazolyl, oxazolyl, 2-oxo-1H-pyridinyl, phenyl, pyrazolyl, pyridyl, thiazolyl, chinoline, thienyl or piperidinyl, each of which is optionally independently has from one to three identical or different substitute groups Cy1; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1- phenyl, benzimidazole-2-yl, benzimidazole-5-yl, benzo[1,3]dioxol-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzo is resol-6-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, 2-oxo-1H-pyridine-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-silt or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups Cy1; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- phenyl, cyclohexenyl, benzo[1,3]dioxole, benzofuranyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[b]thiophenyl, imidazolyl, indolyl, Isopropenyl, phenyl, naphthalenyl, pyridyl or thienyl, each of which optionally has from one to three identical or different substituents, which are alkoxy, (C1-C3)-alkyl, hydroxy, cyano, halogen, halogenoalkane, halogenated, nitro, Y1Y2N, Y1Y2N-SO2-, aryl or heteroaryl, where aryl optionally substituted by alkyl or hydroxyalkyl and where heteroaryl it is certainly substituted by alkyl; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- phenyl, cyclohex-1-enyl, benzo[1,3]dioxol-5-yl, benzofuran-6-yl, 2,3-dihydrobenzofuran-2-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-2-yl, benzo[b]thiophene-2-yl, imidazol-4-yl, 1H-indol-3-yl, 1H-indol-5-yl, naphthalene-2-yl, isochroman-1-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl or Tien-2-yl, each of which optionally has from one to three identical or different substituents, which are alkoxy, (C1-C3)-alkyl, hydroxy, cyano, halogen, halogenoalkane, halogenated, nitro, Y1Y2N, Y1Y2N-SO2-, aryl or heteroaryl, where aryl optionally substituted by alkyl or hydroxyalkyl and where heteroaryl optionally substituted alkyl; or an N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where: L1- -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH(CH3)-, -CH2-C(CH3)2-, -CH(CH3)-CH2-, -CH2-CH(OH)-, -CH(CO2H)-CH2-, -CH2-CF2-, oror its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where L1and Cy2together form indan-1-yl or indan-2-yl, or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where L1- -CH2-CH2-; or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where L1- -CH2-CF2-; or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1is unsubstituted phenyl or phenyl having from one to three identical or different substitute groups, which are :

acyl, alkylsulfonyl, alkylsulfonyl, carboxy, cyano, halogen, heteroaryl, heterocyclyl, hydroxy, nitro, R2-C(=N-OR3), Y1Y2N, Y1Y2NC(=O)-, Y1Y2 NC(=O)-O-, Y1Y2NSO2-,

Y1Y2N-C(=O)-(C1-C6-alkylen-Z1-, alkyl-C(=O)-N(R5)-SO2-, alkyl-O-C(=O)-N(R5)-, alkyl-O-C(=O)-N(R5)-SO2-, alkyl-O-N(R5)-C(=O)-, alkyl-O-N(R5)-SO2-, alkyl-SO2-N(R5)-C(=O)-, aryl-SO2-N(R5)-C(=O)-, alkyl-SO2-N(R5)-, R6-C(=O)-N(R5)-, alkyl-NH-C(=O)-NH-;

alkoxy, which optionally have one to three identical or different substituents, which are the carboxyl group or heteroaryl; or

alkyl, which optionally has one to three identical or different substituents which are halogen, carboxy, aryl, heteroaryl, polycyclic aryl, cyano, hydroxy, Y1Y2N-, H2N-C(=NH)-NH-O-, R6-C(=O)-N(R5)-, R6-N(R5)-C=O)-, alkyl-O-C(=O)-N(R5)-, alkyl-SO2-N(R5)-, R8-SO2-N(R5)-C(=O)-, H2N-C(=NH)-NH-O-; or CNS group, which is optionally substituted by carboxyl group or heteroaryl;

where

aryl or heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;

and where

heterocyclyl or polycyclic alkaline fragments in the replacement group optional is positive independently have substituents, which are hydroxy, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl, R8-SO2-N(R5)-C(=O) -, or oxo;

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzo[1,3]dioxol-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, 2-oxo-1H-pyridine-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups, which are the lowest alkanoyl, lower alkoxy, carboxy, cyano, halogen, R2-C(=N-OR3), Y1Y2N, Y1Y2NC(=O)-, heteroaryl or lower alkyl, optionally substituted by one to three identical or different groups including halogen, carboxy, heteroaryl, hydroxy or Y1Y2/sup> N-; where the heteroaryl fragments in foster optional groups independently have substituents in the form of hydroxyl, amino, alkyl or CNS group; or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzo[1,3]dioxol-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, 2-oxo-1H-pyridine-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups are formyl, acetyl, methoxy, carboxy, cyano, chlorine, methyl, -CHF2-oxazol-5-yl, tetrazol-5-yl, HO2C-CH2-, HOCH2-, HO-CH(CH3)-, H-C(=N-OH)-, H-C(=N-OCH3)- ,- CH3-C(=N-OH) -, - CH3-C(=N-OCH3)-, H2N-CH2-, CH3NHCH2-, CH3OCH2C 2NHCH2-, CH3NH-C(=O)-,oror its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy1is phenyl or phenyl having from one to three identical or different substitute groups are formyl, acetyl, methoxy, chlorine, fluorine, hydroxy, nitro, cyano, carboxy, CH3O-CH=CH-, CH3-SO -, - CH3SO2-, CH3CH2SO2-, HO2C-CH2-O-, HO2C-C(CH3)2-O-,5-amino-[1,3,4]oxadiazol-2-yl, 3-methylisoxazol-5-yl, 3-methyl-[1,2,4]oxadiazol-5-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 2-methyl-2H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 5-methyl-2H-[1,2,4]triazole-3-yl, 3H-[1,3,4]oxadiazol-2-it, oxazol-5-Il, tetrazol-5-yl, 1H-tetrazol-5-ylmethyl, 1-methyl-1-(1H-tetrazol-5-yl)ethyl,3H-[1,3,4]oxadiazol-2-he, H-C(=N-OH) -, - CH3-C(=N-OH)-, H2N - (CH3)2N-,CH3OCH2CH2NH-,HOCH2CH2NH-, HO2C-CF2-, CH3CH2SO2NHC(=O)-C(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-, H2N-C(=O) -, - CH3NHC(=O)-, (CH3)2NC(=O)-, (CH3)2NCH2CH2NH-C(=O)-, HO2CCH2NH-C(=O)-, HO2CCH(CH3)NH-C(=O)-, HO2CCH(CH{CH3}2)NH-C(=O)-, HO2CCH(CH2CH{CH3}2)NH-C(=O)-,CH3CH2NH-C(=O)-O-, H2N-SO2-, CH3NHSO2-, CH3CH2NHSO2-, (CH3)2CHNH-SO2-, CH3CH2NH-C(=O)-CH2-O-, (CH3)2CHNH-C(=O)-CH2-O-, (CH3)2NCH2CH2NH-C(=O)-C(CH3)2-O-CH3-C(=O)-NH-SO2-, CH3CH2-O-C(=O)-NH-, CH3-O-C(=O)-NH-SO2-, CH3-O-N(CH3)-C(=O) -, - CH3-O-NH-SO2-, CH3-SO2-NH-C(=O) -, - CH3-SO2-N(CH3)-C(=O)-,CH3-SO2-NH-CH3-C(=O)-NH-, CH3O-CH2-C(=O)-NH-, CH3CH2NH-C(=O)-NH-, HO2C-CH2CH2-, HO2C-CH(CH3)-, HO2C-C(CH3)2-, HO2C-CH2-O-CH2-, benzyl, NC-CH2-, HOCH2-, HOCH2CH2-, HO-CH(CH3)-, HO-C(CH3)2-, H2NCH2-, (CH3)2NCH2CH2NHCH2-, HO2C-CH(CH2Ph)-NHCH2-, HO2C-CH(CH2OH)-NHCH2-,H2N-C(=NH)-NH-O-CH2-, CH3OCH2-C(=O)-NH-CH2-, HOCH2-NH-C(=O)-CH2-, CH3-C(=O)-NH-CH2-, CH3-C(=O)-NH-CH2CH2-, HOCH2CH2-NH-C(=O)-CH2CH2-, CH3-O-C(=O)-NH-CH2-, CH3SO2-NH-CH2-, H2N-C(=NH)-NH-O-CH2-,or; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- cyclohex-1-enyl; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- naphthyl or phenyl, each of which optionally has from one to three identical or different substituents, which are alkoxy, (C1-C3)-alkyl, hydroxy, cyano, halogen, halogenoalkane, halogenated, nitro, Y1Y2N, Y1Y2N-SO2-, aryl or heteroaryl, where aryl optionally substituted by alkyl or hydroxyalkyl and where heteroaryl optionally substituted alkyl; or an N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- naphthyl or phenyl, each of which optionally has from one to three identical or different substituents, which are the methoxy, ethoxy methyl, ethyl, bromine, chlorine, fluorine, F2HCO-, F3CO-, F3C, amino, H2N-SO2-, cyano, hydroxy, nitro or 5-methyl[1,3,4]oxadiazol-2-yl, or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I), where Cy2- benzo[1,3]dioxol-5-yl, 1H-indol-3-yl, 1H-indol-5-yl, imidazol-4-yl, 1H-indol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl or Tien-2-yl, each of which optionally has from one to three identical or different substituents, which are alkoxy, halogen or hydroxy; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES

Another private embodiment of the present invention is a compound of formula (I), where L2connection.

Another private embodiment of the present invention is a compound of formula (II)

where Cy1and Cy2described above, or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1is unsubstituted phenyl or phenyl having from one to three identical or different substitute groups, which are:

acyl, alkylsulfonyl, carboxy, cyano, halogen, heteroaryl, hydroxy, heterocyclyl, R2-C(=N-OR3), Y1Y2N, Y1Y2NC(=O)-, Y1Y2NC(=O)-O-, Y1Y2N-SO2-, Y1Y2N-C(=O)-(C1-C6-alkylen-Z1-, alkyl-C(=O)-N(R5)-SO2-, alkyl-O-C(=O)-N(R5)-SO2-, alkyl-O-N(R5)-SO2-, alkyl-SO2-N(R5)-C(=O)-, alkyl-SO2-N(R5)-, R6-C(=O)-N(R5)-, alkyl-NH-C(=O)-NH-;

alkenyl, which is optionally substituted CNS group;

CNS group, which is optionally substituted by carboxyl group or heteroaryl; or

alkyl, which is optionally substituted with halogen, carboxy, cyano, heteroaryl, hydroxy, R6-C(=O-N(R 5)-, R8-SO2-N(R5)-C(=O)-; or CNS group, which is optionally substituted by carboxyl group;

where

heterocyclic fragments in foster optional groups independently have the substituents are hydroxy, amino, alkyl, alkoxy, oxo, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and

heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1is unsubstituted phenyl or phenyl having from one to three identical or different substitute groups are formyl, acetyl, cyano, methoxy, chlorine, fluorine, hydroxy, carboxy, 5-amino-[1,3,4]oxadiazol-2-yl, 3-methyl-isoxazol-5-yl, 3-methyl-[1,2,4]oxadiazol-5-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 2-methyl-2H-tetrazol-5-yl, 5-methyl-2H-[1,2,4]triazole-3-yl, oxazol-5-yl, tetrazol-5-yl, 1H-tetrazol-5-ylmethyl, 1-methyl-1-(1H-tetrazol-5-yl)ethyl, H2N-CH3-NHC(=O) -, - CH3CH2NH-C(=O)-O-CH3O-CH=CH-, CH3SO2-, CH3CH2SO2-, HO2C-CH2-O, HO2C-C(CH3)2-O-, H-C(=N-OH) -, - CH3-C(=N-OH) -, - CH3OCH2CH2NH-, H2N-SO2-, CH3NHSO2-, CH3CH2NHSO2-, (CH3)2CHNH-SO2-, CH3CH2NH-C(=O)-CH2-O-, (CH3)2CHNH-C(=O)-CH2-O-CH3-C(=O)-NH-SO2-, CH3-O-C(=O)-NH-SO2-, CH3-O-NH-SO2-, CH3-SO2-NH-C(=O) -, - CH3-SO2-N(CH3)-C(=O) -, - CH3-SO2-NH-CH3-C(=O)-NH-, CH3O-CH2-C(=O)-NH-, CH3CH2NH-C(=O)-NH-, HO2C-CH2CH2-, HO2C-CH(CH3)-, HO2C-C(CH3)2-, HO2C-CH2-O-CH2-, HOCH2-, HO-CH(CH3)-, HO-C(CH3)2-, NC-CH2-, CH3OCH2-C(=O)-NH-CH2-,HO2C-CF2-, CH3CH2SO2NHC(=O)-C(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-,oror its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is with the unity of formula (II), where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzo[1,3]dioxol-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, 2-oxo-1H-pyridine-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups, which are:

acyl, carboxy, heteroaryl, R2-C(=N-OR3), Y1Y2NC(=O)-; or

alkyl, which is optionally substituted by carboxyl group, heteroaryl or a hydroxyl group;

where

heteroaryl fragments in substituting groups may be optionally independently substituted hydroxy, amino, alkyl or alkoxy,

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzo[1,3]dioxol-5-yl, benzothiazol the-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, 2-oxo-1H-pyridine-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, the quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups are formyl, acetyl, methyl, methoxy, carboxy, oxazol-5-yl, tetrazol-5-yl, HO2C-CH2-, HOCH2-, HO-CH(CH3)-H-C(=N-OH)-, H-C(=N-OCH3)- ,- CH3-C(=N-OH) -, - CH3-C(=N-OCH3)- ,- CH3NH-C(=O)-,or; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy2- naphthyl or phenyl, each of which optionally has from one to three identical or different substituents, which are alkoxy, (C1-C3)-alkyl, hydroxy, cyano, halogen, halogenoalkane, halogenated, nitro, Y1Y2N-, 1Y2N-SO2-, aryl or heteroaryl, where aryl optionally substituted by alkyl or hydroxyalkyl and where heteroaryl optionally substituted alkyl; or an N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy2- naphthyl or phenyl, each of which optionally has from one to three identical or different substituents, which are the methoxy, methyl, ethyl, cyano, bromine, chlorine, fluorine, F2HCO-, F3CO-, F3C-, nitro-or 5-methyl-[1,3,4]oxadiazol-2-yl, or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy2- cyclohex-1-enyl, benzo[1,3]dioxol-5-yl, benzofuran-6-yl, 2,3-dihydrobenzofuran-2-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-2-yl, benzo[b]thiophene-2-yl, imidazol-4-yl, 1H-indol-3-yl, 1H-indol-5-yl, naphthalene-2-yl, isochroman-1-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl or Tien-2-yl, or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy2- benzo[1,3]dioxol-5-yl, 2,difterent[1,3]dioxol-5-yl, pyridine-4-yl or Tien-2-yl, or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1is phenyl, which optionally has from one to three identical or different substitute groups, which are:

acyl, carboxy, cyano, halogen, heteroaryl, heterocyclyl, hydroxy, R2-C(=N-OR3), Y1Y2NC(=O)-, Y1Y2NC(=O)-O-, alkyl-O-C(=O)-N(R5)-SO2-, alkyl-SO2-N(R5)-C(=O)-;

CNS group, which is optionally substituted by carboxyl group or heteroaryl; or

alkyl, which is optionally substituted with halogen, carboxy, heteroaryl, hydroxy, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-; or CNS group, which is optionally substituted by carboxyl group;

where

heterocyclic fragments in foster optional groups independently have the substituents are hydroxy, amino, alkyl, alkoxy, oxo, carboxy, alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;

heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, amino, alkyl, alkoxy, carboxy, alkoxycarbonyl or R8-SO2-N(R5-C(=O)-;

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1is phenyl, which optionally has from one to three identical or different substitute groups are formyl, methoxy, carboxy, chlorine, fluorine, cyano, tetrazol-5-yl, 1H-tetrazol-5-ylmethyl, HO2C-CH2-O-, HO2C-C(CH3)2-O-, H-C(=N-OH) -, - CH3NHC(=O) -, - CH3CH2NH-C(=O)-O-CH3-O-C(=O)-NH-SO2-, CH3-SO2-NH-C(=O)-, HO2C-CH(CH3)-, HO2C-C(CH3)2-, HO2C-CH2-O-CH2-, HOCH2-,HO2C-CF2-, CH3CH2SO2NHC(=O)-C(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-,oror its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1represents a

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1- 1H-benzotriazol-6-yl, 1H-indazol-6-yl, indol-5-yl, indol-6-yl, 2-oxo-1H-pyridine-5-yl, quinoline-6-yl, quinoline-3-yl, Tien-2-yl, Tien-3-yl or 1-piperidine-1-yl, each of which optionally has from one to three identical or different substituents, which are acyl, carboxy, tetrazol-5-yl; R2-C(=N-OR3), Y1Y2NC(=O)-; or alkyl, which is optionally substituted by carboxyl or hydroxyl group; or N-oxide or ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy1- 1H-benzotriazol-6-yl, 1H-indazol-6-yl, indol-5-yl, indol-6-yl, 2-oxo-1H-pyridine-5-yl, quinoline-6-yl, quinoline-3-yl, Tien-2-yl, Tien-3-yl or 1-piperidine-1-yl, each of which optionally has from one to three identical or different substituents, which are the formyl, carboxy, tetrazol-5-yl, H-C(=N-OH) -, - CH3-C(=N-OH) -, - CH3-NH-C(=O)-, HO2C-CH2- or H-CH 2-.

Another private embodiment of the present invention is a compound of formula (II), where Cy1represents a

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (II), where Cy2- 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-differenl, 2-fluoro-6-chlorophenyl, 3-fluoro-4-methoxyphenyl, 4-forfinal, 2-fluoro-4-triptoreline, 4-methoxyphenyl, 4-nitrophenyl, 2,2-debtorrent[1,3]dioxol-5-yl or 4-trifloromethyl; or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I)represents:

3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile,

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide,

N-ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,

p> N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine,

N-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)acetamide", she

N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetamide", she

ethyl ester of (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid,

3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,

4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,

[6-(3,5-dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-yl)pyrimidine-4-yl]amine,

(6-isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,

(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol,

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol,

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanol,

(3-{6-[2-(2-chloro-6-forfinal)is thylamino]-2-methoxypyridine-4-yl}phenyl)methanol,

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine,

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine,

[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

N-(2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide,

4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide,

[2-methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

(6-benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,

1-(4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon,

[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[6-(2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[6-(4-dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

2,2'-dimethoxy-N*6*,N*6'*-bis-[2-(4-methoxyphenyl)ethyl]-[4,4']bipyridinyl-6,6'-diamine,

[2-methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[6-(5-deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmatieteen-2-yl)pyrimidine-4-yl]AMI is,

6-{4-fluoro-3-[(2-methoxyethylamine)methyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,

4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol,

N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N',N'-dimethylated-1,2-diamine,

[6-(1H-benzimidazole-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3H-benzoxazol-2-it,

[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methylsulfonylamino-4-yl]amine,

3-{6-[2-(3,4-acid), ethylamino]-2-methylsulfonylamino-4-yl}benzoic acid,

[2-(4-methoxyphenyl)ethyl]-[6-(3-methoxyphenyl)-2-methylsulfonylamino-4-yl]amine,

[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-yl]amine,

[6-(3,4-acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine,

[2-ethyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

6-(3-methoxyphenyl)-N*4*-[2-(4-methoxyphenyl)ethyl]-N*2*,N*2*-dimethylpyrimidin-2,4-diamine,

2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzo is you acid,

[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]amine,

ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid,

methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid,

methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid,

methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile,

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile,

2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid,

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid,

(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid,

2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,

[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine,

[2-(4-methoxyphenethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine,

{2-methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,

N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide,

3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamid,

the reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

the reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,

the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone,

the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,

[6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-methylpropyl]Amin,

[2-(2-chloro-6-forfinal)ethyl]-[6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino-4-yl]amine,

5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methylsulfonylamino-4-yl}-1H-pyridine-2-it,

5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-it,

5-{6-[2-(2-chloro-6-forfinal)is thylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-it,

3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-he,

3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-he,

3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-he,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,

3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid,

[2-(3,4-acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl)amine,

[2-(3,4-acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl)amine,

(6-biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine,

3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide,

1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon,

3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol,

2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,

1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone,

3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}be soyou acid,

[2-methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol,

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-6-Yeremey-4-yl)amine,

2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol,

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile,

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde,

3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

[2-methoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,

ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,

{2-methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,

{2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,

{2-methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,

{2-methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,

[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)who enyl]pyrimidine-4-yl}amine,

1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea,

ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid,

[2-(4-chlorophenyl)-1-methylethyl]-[6-(3,4-acid)-2-methoxypyridine-4-yl]amine,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine,

[2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-ileti]Amin,

3-{2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol,

[2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

[2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)amine,

[2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

(4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)amine,

[2-(1H-imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,

(2S)-2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid,

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

[2 methods the si-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

(2-methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, example 45;

3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine,

N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetamide", she

[2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine,

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol,

[2-(2,4-dichlorophenyl)ethyl]-(2-methyl-6-{3-[1-methyl-1-(1H-tetrazol-5-yl)ethyl]phenyl}pyrimidine-4-yl)amine,

[2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

1-ethoxycarbonylmethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

2-dimethylaminoethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid,

[6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium,

[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-IU is oxiranyl)ethyl]amine,

3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile,

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid,

ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid,

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,

methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,

methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid,

N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate,

N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]acetamide", she

[2-(2-fluoro-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]amine,

2-{3-[6-(2,2-debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,

2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionate the acid,

5-(3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]triazole-3-one,

2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{2-methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{6-[(benzo[b]thiophene-2-ylmethyl)amino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionic acid,

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-3-carboxylic acid,

1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarbonyl acid,

2-morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

2-(4-methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol,

(3'-chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol,

methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,

N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamine is]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide,

ethyl ester of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)deferoxamine econsultancy,

ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile,

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital,

[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine,

2-{3-[6-(indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,

2-{3-[6-(indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,

N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide,

methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-ethoxymethyleneamino-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-hydroxyethylpyrrolidine-4-yl}phenyl)-2-methylpropionic acid,

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methods dipyrimidine-4-yl}thiophene-2-carboxylic acid,

5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid,

2,3-dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{6-[(2,3-dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{6-[(isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,

2-(3-{6-[(benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,

N-(6-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)acetamide", she

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid,

N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-C-phenylmethanesulfonyl,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide,

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide,

[2-(2,4-dichlorophenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)Piperi the Jn-1-yl]pyrimidine-4-yl}amine,

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid,

2-(2-chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol or

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid,

or its N-oxide, or its ester prodrug, or pharmaceutically acceptable salt, hydrate or MES.

Another private embodiment of the present invention is a compound of formula (I) or its pharmaceutically acceptable salt, which represent:

3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile, example 1;

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 2;

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide, example 3;

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide, example 4(a);

N-ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide, example 4(b);

N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide, example 4(c);

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine, example 5;

N-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide, example 6(a);

N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)atilim is but]pyrimidine-4-yl}phenyl)acetamide", she example 6(b);

ethyl ester of (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid, example (6c);

3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 7;

triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, example 8(a);

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 8(b);

4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 8(c);

[6-(3,5-dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 8(d);

[2-methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 8(e);

[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-Yeremey-4-yl]amine, example 8(f);

(6-isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, example 8(g);

(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol from example 9(a);

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol from example 9(b);

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanol, example 9(c);

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol, example 9(d);

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine, example 10(a);

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-Hino is in 3-Yeremey-4-yl)amine, example 10(b);

[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(c);

N-(2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide, example 10(d);

4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide, example 10(e);

[2-methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(f);

(6-benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, example 10(g);

1-(4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon, example 10(h);

[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(i);

[6-(2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(j);

[2-methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(k);

[6-(4-dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(l);

2,2'-dimethoxy-N*6*,N*6'*-bis-[2-(4-methoxyphenyl)ethyl]-[4,4']bipyridinyl-6,6'-diamine, example 10(m);

[2-methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 11(a);

[2-methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 11(b);

[6-(5-deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 12;

[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmenite the Hairdryer-2-yl)pyrimidine-4-yl]amine, example 13(a);

the hydrochloride of 6-{4-fluoro-3-[(2-methoxyethylamine)methyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, example 13(b);

hydrochloride 4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol, example 13(c);

the hydrochloride of N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N',N'-dimethylated-1,2-diamine, example 13(d);

[6-(1H-benzoimidazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 14(a);

[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 14(b);

6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3H-benzoxazol-2, example 14(c);

hydrochloride 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol, example 15(a);

hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 15(b);

hydrochloride 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 15(c);

hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 15(d);

[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methylsulfonylamino-4-yl]amine, example 16(a);

3-{6-[2-(3,4-acid), ethylamino]-2-methylsulfonylamino-4-yl}benzoic acid, example 16(b);

[2-(4-methoxyphenyl)ethyl]-[6-(3-methoxyphenyl)-2-methylsulfonylamino-4-and the]amine, example 16(c);

[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-yl]amine, example 17(a);

[6-(3,4-acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine, example 17(b);

[2-ethyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 18;

the hydrochloride of 6-(3-methoxyphenyl)-N*4*-[2-(4-methoxyphenyl)ethyl]-N*2*,N*2*-dimethylpyrimidin-2,4-diamine, example 19;

2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 20(a);

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 20(b);

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 20(c);

[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 21(a);

[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]amine, example 21(b);

ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid, example 22(a);

methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid example 22(b);

methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid example 22(c);

methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid example 22();

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile, example 22(e);

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile, example 22(f);

2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid, example 23(a);

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid example 23(b);

(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid example 23(c);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid; example 23(d);

cleaners containing hydrochloride salt of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 23(e);

[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine, example 24(a);

hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine, example 24(b);

{2-methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine, example 24(c);

N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide, example 25(a);

3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamide, example 25(b);

the reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, etc which measures 26(a);

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 26(b);

the reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 26(c);

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 26(d);

the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone, example 26(e);

the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 26(f);

hydrochloride [6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 27;

the hydrochloride of N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate, example 28;

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-methylpropyl]amine, example 29;

[2-(2-chloro-6-forfinal)ethyl]-[6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino-4-yl]amine, example 30;

5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methylsulfonylamino-4-yl}-1H-pyridine-2-it, example 31;

5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-it, example 32;

5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-it, example 33;

hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-she primer(a);

hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-it, example 34(b);

hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it, example 34(c);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 35(a);

3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 35(b);

[2-(3,4-acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl]amine, example 35(c);

[2-(3,4-acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl]amine, example 35(d);

(6-biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine, example 35(e);

hydrochloride 3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(f);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide, example 35(g);

1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon, example 35(h);

3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol, example 35(i);

2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 35(j);

3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(k);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 35(l);

1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)e is ylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone, example 35(m);

hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(n);

[2-methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 35(o);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol, example 35(p);

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-4-Yeremey-4-yl]amine, example 35(q);

2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol, example 35(r);

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile, example 35(s);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile, example 35(t);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 35(u);

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde, example 35(v);

3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(w);

[2-methoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 35(x);

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 35(y);

ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 35(z);

{2-methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine, example 36;

{2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-label iphenyl)ethyl]amine, example 37;

{2-methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine, example 38;

{2-methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine, example 39;

[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine, example 40;

1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea, example 41;

ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid; example 42;

[2-(4-chlorophenyl)-1-methylethyl]-[6-(3,4-acid)-2-methoxypyridine-4-yl]amine, example 43(a);

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine, example 43(b);

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine, example 43(c);

hydrochloride [2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(d);

hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-ileti]amine, example 43(e);

3-{2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol, example 43(f);

hydrochloride [2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(g);

hydrochloride [2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(h);

hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-p is ridin-3-retil)amine, example 43(i);

hydrochloride [2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(j);

hydrochloride (4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(k);

hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)amine, example 43(l);

[2-(1H-imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine, example 43(m);

(2S)-2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid, example 43(n);

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 43(o);

[2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 44;

(2-methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, example 45;

3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 46(a);

hydrochloride [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine, example 46(b);

the hydrochloride of N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)ndimethylacetamide, example 46(c);

hydrochloride [2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine, example 46(d);

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol, example 46(e);

hydrochloride [2-(2,4-dichlorophenyl)ethyl]-(2-methyl-6-{3-[1-methyl-1-(1H-tetrazol-5-yl)et the l]phenyl}pyrimidine-4-yl)amine, example 47;

hydrochloride [2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 48;

hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid; example 49(a);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 49(b);

hydrochloride of 1-ethoxycarbonylmethylene ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 50;

the dihydrochloride of 2-dimethylaminoethanol ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 51;

(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid, example 52;

triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium, example 53(a);

[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 53(b);

3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 53(c);

sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine, example 54;

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile, example 55;

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid, example 56;

2-(3-{6-[2-2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate sodium; example 57;

ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid, example 58;

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid, example 59;

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid, example 60;

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, example 61;

triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, example 62;

methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid, example 63;

N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate, example 64;

the hydrochloride of N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]ndimethylacetamide, example 65;

[2-(2-fluoro-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]amine, example 66;

2-{3-[6-(2,2-debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid, example 67;

2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionic acid, example 68;

5-(3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]shall resol-3-one, example 69;

2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid, example 70;

2-(3-{2-methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid, example 71;

2-(3-{6-[(benzo[b]thiophene-2-ylmethyl)amino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionic acid, example 72;

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid, example 73;

hydrochloride of 1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarboxylic acid; example 74;

2-morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 75;

2-(4-methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 76;

ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 77;

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol from example 78(a);

(3'-chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol from example 78(b);

methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 79;

4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid; example 80(a);

N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide; example 80(b);

ethyl ester of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid; example 80(c);

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid, example 81(a);

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide econsultancy acid; example 81(b);

ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid, example 81(c);

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile, example 82(a);

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital, example 82(b);

[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine, example 82(c);

2-{3-[6-(indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid, example 83(a);

2-{3-[6-(indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid, example 83(b);

N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide, example 84(a);

methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid; example 84(b);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-ethoxymethyleneamino-4-yl}phenyl)-2-methylpropionic the Yu acid; example 85;

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-hydroxyethylpyrrolidine-4-yl}phenyl)-2-methylpropionic acid; example 86;

5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}thiophene-2-carboxylic acid, example 87;

hydrochloride 5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid, example 88;

2,3-dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 89;

2-(3-{6-[(2,3-dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid, example 90;

2-(3-{6-[(isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid, example 91;

2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid, example 92;

2-(3-{6-[(benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid, example 93;

N-(6-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)ndimethylacetamide, example 94;

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid; example 95(a);

N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-C-phenylmethanesulfonyl; example 95(b);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-label apyrimidine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he; example 95(c);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide; example 95(d);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide; example 95(e);

[2-(2,4-dichlorophenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)piperidine-1-yl]pyrimidine-4-yl}amine, example 96;

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid, example 97;

2-(2-chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol, example 98; or

hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid; example 99.

Another private embodiment of the present invention is a compound of formula (I) or its pharmaceutically acceptable salt, which represent:

N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide, example 4(c);

3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 7;

triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, example 8(a);

5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 8(b);

(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol from example 9(a);

(3-{2-methoxy-6-[2-(4-methoxime the Il)ethylamino]pyrimidine-4-yl}phenyl)methanol example 9(c);

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine, example 10(a);

[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine, example 10(b);

[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 10(c);

[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 14(b);

hydrochloride 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol, example 15(a);

hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 15(b);

hydrochloride 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 15(c);

hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid; example 15(d);

2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 20(a);

3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 20(b);

2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 20(c);

methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid example 22(b);

methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid example 22(c);

(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}is enocsi)acetic acid, example 23(b);

(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid example 23(c);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid; example 23(d);

cleaners containing hydrochloride salt of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 23(e);

[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine, example 24(a);

hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine, example 24(b);

{2-methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine, example 24(c);

N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide, example 25(a);

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 26(b);

the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 26(d);

the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone, example 26(e);

the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 26(f);

hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it, example 34(a);

hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxyphenyl the DIN-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-she example 34(b);

hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it, example 34(c);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid, example 35(a);

hydrochloride 3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(f);

3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol, example 35(i);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde, example 35(l);

hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(n);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile, example 35(t);

3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, example 35(u);

hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 35(w);

[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine, example 40;

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine, example 43(b);

[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 43(o);

hydrochloride [2-(2,4-dichlorophenyl)ethyl]-(2-methyl-6-{3-[1-methyl-1-(1H-tetrazol-5-yl)ethyl]phenyl}pyrimidine-4-yl)amine, example 47;

hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propional the th acid; example 49(a);

(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid, example 52;

triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium, example 53(a);

[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine, example 53(b);

3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, example 53(c);

sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine, example 54;

(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid, example 56;

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid, example 59;

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid, example 60;

triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, example 62;

1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-3-carboxylic acid, example 73;

4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid; example 80(a);

N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide; example 80(b);

(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxide is kidin-4-yl}phenyl)DIPEROXY acid, example 81(a);

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide econsultancy acid; example 81(b);

[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine, example 82(c);

N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide, example 84(a);

[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid; example 95(a);

N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-C-phenylmethanesulfonyl; example 95(b);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he; example 95(c);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide; example 95(d);

2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide; example 95(e); or

[2-(2,4-dichlorophenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)piperidine-1-yl]pyrimidine-4-yl}amine, example 96.

Compounds according to the invention and used to produce intermediate and initial matter, called in accordance with the IUPAC nomenclature, in which the characteristic group in the name have the following priority, in descending order of precedence:acid, esters, amides, etc. Or compounds are named using AutoNom 4 (Beilstein Information Systems, Inc.). For example, the compound of formula (I), where R1- methoxy, L1- ethylene, L2communication, Cy1- 3-(2H-tetrazol-5-yl)phenyl, Cy2- 3-fluoro-4-methoxyphenyl, i.e. the compound having the following structure:

is called [2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}Amin.

However, it is believed that, if for any of the compounds represented by structural formula and nomenclature the name, there is a mismatch between the structural formula and nomenclature name, correct it is necessary to consider the structural formula.

Compounds according to the invention are active as antagonists of the receptor for prostaglandin D2, and can be used as an active pharmacological substances. Accordingly, they are included in the pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.

Compounds covered by the present invention are antagonists of the receptor for prostaglandin D2 according to tests described in the literature and are described in the following section on pharmacological tests, the results of which are considered to be short aliroot with pharmacological activity in humans and other mammals. Thus, in one implementation of the present invention represented by the compounds according to the invention and compositions containing them, which can be used in the treatment of patients suffering from diseases that can facilitate the introduction of PGD2 antagonist, or exposed to such diseases. For example, the compounds according to the invention can be used to treat a variety of disorders mediated by PGD2, including, in particular, allergic disorders (e.g., allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food Allergy), systemic mastocytosis, disorders accompanied by systemic activation of mastocytes, anaphylactic shock, bronchoconstriction, bronchitis, urticaria, eczema, diseases accompanied by itch (such as atopic dermatitis and urticaria), diseases (such as cataract, retinal detachment, inflammation, infection, and sleep disorders), which arise as a secondary diseases the result of behavior accompanied by itch (such as scratching and rubbing), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, disorders of cerebral circulation, chronic rheumatoid arthritis, pleurisy, ulcerative colitis and podobn the diseases.

In addition, the compounds according to the invention can be used for combination therapy with:

(i) antihistamines, such as Fexofenadine, loratadine and cetirizine, for the treatment of allergic rhinitis;

(ii) leukotriene antagonists such as montelukast and zafarulla for the treatment of allergic rhinitis, COPD, allergic dermatitis, allergic conjunctivitis, etc. - accurate information, see WO 01/78697 A2;

(iii) beta-agonists, such as albuterol, salbuterol and terbutalina, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.;

(iv) antihistamines, such as Fexofenadine, loratadine and cetirizine, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.;

(v) inhibitors of PDE4 (phosphodiesterase 4), such as roflumilast and cilomilast, for the treatment of asthma, COPD, allergic dermatitis, allergic conjunctivitis, etc.; or

(vi) antagonists TP (thromboxane A2 receptor or antagonists of CrTh2 (molecules homologous to receptor chemoattractant expressed on Th2 cells), such as ramatroban (BAY u3405), for the treatment of COPD, allergic dermatitis, allergic conjunctivitis, etc.

A particular implementation of therapeutic methods of the invention is the treatment of allergic rhinitis.

Another is a special implementation of therapeutic methods of the invention is the treatment of bronchial asthma.

In accordance with another item of the invention, a method of treatment of a patient (human or animal)suffering from diseases that may be alleviated by the introduction of an antagonist of the receptor for prostaglandin D2, or exposed to such diseases, for example, the conditions described above, comprising the administration to a patient an effective amount of the compounds according to the invention or containing composition. By "effective amount" refers to the number of compounds according to the invention, which is effective as an antagonist of the receptor for prostaglandin D2, and are therefore able to provide the desired therapeutic effect.

Included here are links to treatment apply as a preventive therapy and for treatment of established conditions.

The present invention also extends to pharmaceutical compositions comprising at least one compound according to the invention in a mixture with a pharmaceutically acceptable carrier.

In practice, the compounds according to the invention can be administered in the form of pharmaceutically acceptable dosage forms for humans and other animals by local or systemic administration, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, intestinal, parenteral (including subcutaneous, nutrim the muscle, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. You should take into account that the preferred route of administration may vary, for example, depending on the patient's condition.

"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compounds according to the invention, which include, for example, tablets, pills, powders, elixirs, syrups, liquid formulations, including suspensions, sprays, inhalers, pills, pellets, emulsions, solutions, granules, capsules and suppositories, liquid formulations for injection, including liposomal drugs. A General description of the methods and compositions can be found in the latest edition Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

A special aspect of this invention is the compound according to the invention, which must be entered in the form of pharmaceutical compositions. In accordance with the present invention the pharmaceutical compositions comprise compounds according to the invention and pharmaceutically acceptable carriers.

Pharmaceutically acceptable carriers are composed of at least one of the components, which are pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients or fillers, such as preservatives, fillers, disintegrating agents, matiauda substances, emulsifiers, emulsion stabilizers, suspendresume substances, isotonic agents, sweeteners, flavorings, fragrances, dyes, microbicides, antifungal agents, other therapeutic agents, lubricants, chemicals, slowing down or accelerating the suction and dispensing substances, depending on the characteristics of the route of administration and dosage forms.

Examples suspendida substances are ethoxylated isostearyl alcohols, polyoxyethylenated and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant or mixtures of these substances.

Examples of bactericidal and antifungal substances that prevent the action of microorganisms, are parabens, chlorobutanol, phenol, sorbic acid and similar substances.

Examples of isotonic substances are sugars, sodium chloride and similar substances.

Examples of substances that slow down and prolong the absorption are aluminum monostearate and gelatin.

Examples of substances accelerate and stimulate absorption, are dimethyl sulfoxide and its analogs.

Examples of diluents, solvents, carriers, solubilizing additives, emulsifiers and emulsion stabilizers are water, chloroform, sucrose, ethanol, isoprop Lowy alcohol, ethyl ester of carbonic acid, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butyleneglycol, glycerin, glycols, dimethylformamide, Tween® 60, Span® 60, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate, esters sorbitan and fatty acids, vegetable oils (such as cottonseed oil, peanut oil, wheat germ oil, olive oil, castor oil and sesame oil) and injectable organic esters, such as etiloleat and the like, or suitable mixtures of these compounds.

Examples of formative fillers are lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.

Examples of disintegrating agents include starch, alginic acid and certain complex silicates.

Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene glycols of high molecular weight.

The choice of pharmaceutically acceptable carrier, in General, determined in accordance with the chemical properties of the active compound, such as solubility, mode of administration and precautions that must be observed in pharmaceutical practice.

The pharmaceutical compositions according to the invention, suitable for peroral the CSOs application, can be a dosage form, such as solid dosage forms such as capsules, pills or tablets, each of which contains a certain amount of the active ingredient, or such as powders or granules, or liquid dosage forms such as solutions or suspensions in aqueous or non-aqueous liquid medium, or a liquid emulsion of oil-in-water or water-in-oil. The active ingredient is also not necessarily has the form of a bolus, electuary or paste.

"Solid dosage form" means a dosage form of the compounds according to the invention in the form of solids, for example capsules, tablets, pills, powders, pills, or granules. In such dosage forms, the compound according to the invention is added in at least one traditionally used excipient (or carrier)such as sodium citrate or dicalcium phosphate or (a) fillers or additives, such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum, (c) moisturizing agents, such as, for example, glycerol, (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain complex silicates and Na2CO3, () solutions-moderators, such as, for example, paraffin, (f) absorption accelerators, such as Quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerylmonostearate, (h) adsorbents, such as kaolin or bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) fogging components (k) of the buffer substances and agents, slowly releasing compound(I) according to the invention in a certain part of the intestinal tract.

A tablet may be prepared by compressing or moulding, and optionally has one or more auxiliary components. Molded tablets can be obtained by compressing in a suitable machine the active ingredient in granular form, such as powder or granules, which may not necessarily be mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Can be used such inert fillers as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and leavening agents, such as starch, alginic acid and certain complex silicates, mixed with lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. The mixture powder is Breznik compounds, moistened with an inert liquid diluent, can be molded in a suitable machine to obtain a molded tablets. Tablets do not necessarily have coverage or notches, and does not necessarily have a composition that provide slow or controlled allocation of the contained active ingredient.

Solid compositions may also be used as fillers in gelatin capsules with soft or hard content with the use of such inert excipients as lactose or milk sugar and high molecular weight glycols and similar substances.

If necessary, and for more effective distribution, the compounds may be microencapsulating systems slow or directional release, such as a biocompatible, biodegradable polymeric matrix (e.g., copolymer of d,l-lactide with glycolide), liposomes and microspheres for subcutaneous and intramuscular injection method, called subcutaneous or intramuscular injection, slow absorption, providing a slow release of the compound(s) within 2 weeks or longer. Connections can be sterilized, for example, by filtration through inhibiting bacteria filter or adding sterilizing agents in the form of sterile solid compositions, which can the be dissolved in sterile water or other sterile injectable medium immediately before use.

Liquid dosage form" means a form of active compound that is administered to the patient in liquid form, for example in the form of a pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain commonly used in this field inert diluents, such as solvents, solubilizing agents and emulsifiers.

Aqueous suspensions can contain emulsifying agents or substances promoting the formation of a suspension.

Pharmaceutical compositions suitable for topical application, is the song, allowing for local administration to the patient. The composition need not take the form of ointments for topical application, balms, powders, sprays and inhalers, gels (water or alcohol based), creams, usually used in this field, or to be included in the matrix base for use as a patch that provides a controlled release of compound through the skin barrier. In the form of an ointment, the active ingredients can be used with paraffin or water-soluble bases. Alternatively, the active ingredients can be in the form of a cream with an oil-water basis. Compositions intended for topical application through the eyes represent the eye drops, and in which the active ingredient is dissolved or suspended in a suitable carrier, typically, an aqueous solvent. Compositions intended for topical application through the oral mucosa include tablets, having in its composition the active ingredient in the flavor additive, normally sucrose and gum or tragakant; lozenges, having in its composition the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum; and compositions for rinsing of the mouth, having in its composition the active ingredient in a suitable liquid carrier.

The oil phase of the emulsion pharmaceutical compositions can be obtained in the usual way from the well-known ingredients. This phase is optional is composed of only emulsifier (also known emulsifying substance), however, it is desirable that it also included at least one emulsifier containing fat or oil, or emulsifier-containing fat and oil. In a particular implementation of the invention in the composition is included hydrophilic emulsifier together with a lipophilic emulsifier, which acts as a stabilizer. The emulsifier(s) with stabilizer(s) or without form emulgirujushchie wax together with the oil and fat of form emulgirujushchie materials, which is the oily dispersed phase of the cream formulations.

If necessary, the aqueous phase of the cream base may include, for example, of at least the e 30 wt.%/wt. a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol or polyethylene glycol (including PEG 400) and mixtures thereof. Compositions for topical application may, if necessary, to have a connection, stimulating the absorption or penetration of the active ingredient through the skin or other treated areas.

The choice of suitable oils or fats for use in the composition depends on the desired properties. It is desirable that the cream was lean, necrosadism and washable product with suitable consistency, preventing leakage from tubes or other containers. Can be used linear or branched one or dibasic alkalemia esters, such as diisopropylamide, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixture of esters with branched chain, known as Crodamol CAP. They can be used separately or in mixtures, depending on the desired properties. Alternatively can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin or other mineral oils.

Pharmaceutical compositions for rectal or vaginal introduction are called compositions, the shape of which allows for rectal or vaginal introduction is their patient and which contain at least one compound according to the invention. Suppositories are one of the forms of such compositions, which can be obtained by mixing the compounds according to the invention with suitable non-irritating inert excipients or carriers, for example cocoa butter, polyethylene glycol or wax-based suppository, which are in a solid state at ordinary temperatures, but become liquid at body temperature and therefore melt at rectal or vaginal insertion and release the active ingredient.

The pharmaceutical composition introduced by injection, may be injected intramuscularly, intravenously, intraperitoneally and/or subcutaneously. The composition of the invention is prepared in liquid solutions, in particular in physiologically compatible buffers such as solution Khanka or ringer's solution. In addition, the composition can be prepared in solid form and dissolved or suspended immediately prior to use. It is also possible lyophilized form. The compositions are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions which may contain suspendresume substances, thickeners and anti-oxidants, buffers, bacteriostats and additives that make the composition isotonic, and have the correct pH level corresponding to the indicator of the patient's blood, which will be introduced is repeat.

The pharmaceutical compositions according to the invention, suitable for nasal or inhalation, are compounds which form is suitable for administration to a patient or nasal inhalation. The composition may contain a carrier in powder form with a particle size of, for example, in the range from 1 to 500 microns (including particle sizes in the range from 20 to 500 microns in increments of 5 microns, i.e. with dimensions of 30 microns, 35 microns, etc). Suitable compositions with liquid media for use, for example, as a spray or nasal drops include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration, can be obtained in accordance with conventional methods and to introduce other therapeutic substances. For the introduction of the compositions according to the invention as inhalation therapy can be used dosing inhalers.

The actual dosage of the active ingredient(s) in the compositions according to the invention may vary with the purpose of obtaining the amount of the active ingredient(s)effective to produce a desired therapeutic effect for a particular composition and method of its introduction to the patient. Therefore, the dosage selected for each patient depends on many factors such as the desired therapeutic effect, the route of administration, desire is th the duration of treatment, the etiology and severity of the disease, the patient's condition, weight, sex, diet, and age, the type and effectiveness of each active ingredient, speed of absorption, metabolism and/or selection, and other factors.

Full daily dose of the compounds according to the invention, administered to the patient one or more doses can be, for example, from about 0.001 to about 100 mg/kg of body weight per day, preferably from 0.01 to 10 mg/kg/day. For example, the adult dose usually ranges from about 0.01 to about 100, preferably from about 0.01 to about 10 mg/kg of body weight per day by inhalation, from about 0.01 to about 100, preferably from 0.1 to 70, preferably from 0.5 to 10 mg/kg of body weight per day in oral introduction, and from about 0.01 to about 50, preferably from 0.01 to 10 mg/kg of body weight per day intravenously. The percentage of active ingredient may be different, but it should provide optimum dosage. Dosage forms of compositions may contain fractional unit dose, allowing to obtain the desired daily dose. Obviously, possibly the almost simultaneous introduction of several standard doses. The dose may be as frequent as needed to achieve the desired therapeutic effect. Some patients are able to respond quickly to large or IU is isie dose and it may be adequate low maintenance dose. For other patients may require prolonged treatment with intensity from 1 to 4 doses per day in accordance with the physiological needs of each patient. Needless to say, other patients may require no more than one or two doses per day.

Standard dose compositions can be obtained by any of the conventionally used in the pharmaceutical industry methods. Such methods include the stage of linking the active ingredient with a carrier consisting of one or more accessory ingredients. Typically, the compositions have a homogeneous and irreversible binding of the active ingredient with liquid carriers, or fine solid carriers, or both, with the subsequent formation of the product if necessary.

The composition can be packaged in a single dose or in several doses, for example, in sealed vessels and bubbles with elastic tubes and can be stored in a lyophilized condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Individual injection solutions and suspensions may be prepared from sterile powders, granules or pellets of the above described types.

Compounds according to the invention can b shall be obtained by application or adaptation of known methods, under which refers to the methods previously used or described in the literature, for example as described in R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

The following reactions may be necessary to protect reactive functional groups, for example hydroxyl, amino, imino-, thio -, or carboxyl group, to avoid their unwanted participation in the reactions when they should remain in the final product. Conventional protective groups can be used in accordance with standard procedure, for example, see T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999. Suitable aminosidine groups include sulfonyl (for example, tosyl), acyl (e.g., benzyloxycarbonyl or tert-butoxycarbonyl) and alkylaryl (e.g., benzyl), which can be removed by hydrolysis or hydrogenolysis. Other suitable aminosidine group is TRIFLUOROACETYL [-C(=O)CF3], which can be removed catalyzed by bases, hydrolysis, or solid-phase polymer-bound benzyl group, such as associated with the polymer Merrifield 2,6-dimethoxybenzyl group (linker Almana) or 2,6-dimethoxy-4-[2-(policyrelease)ethoxy]benzyl, which can remove the acid-catalyzed hydrolysis, for example triperoxonane acid.

The compound of formula (I), where R 1Cy1Cy2L1and L2defined above, can be obtained by the reaction of compounds of formula (III), where L2, R1and Cy1defined above, and X1is halogen, preferably chlorine, or triflate group, with an amine of formula (IV), where L1and Cy2defined above.

The reaction is conveniently carried out, for example, in the presence of a suitable base, such as sodium bicarbonate, in an inert solvent, for example 1-methyl-2-pyrrolidinone, at a temperature of about 160°C.

The compound of formula (I), where L2- bond, and R1Cy1Cy2and L1defined above, can also be obtained by the reaction of compounds of formula (V), where R1L1and Cy2defined above, and X2is halogen, preferably chlorine, or triflate group, with Bronevoy acid of formula (VI) or ether of pinacol and Bronevoy acid of the formula (XVII), where Cy1defined above.

The reaction mix is convenient to carry out, for example, in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and Cs2CO3in an inert solvent, such as water dimethyl ether of ethylene glycol, at a temperature of about 100°C. This reaction is also conveniently carried out in a microwave oven at a temperature of about 40°C. The reaction mix can be carried out in the presence of a complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM and Cs2CO3in an inert solvent such as aqueous acetonitrile, at temperatures up to about the boiling point.

The compound of formula (I), where L2- -CH2-O-, and R1Cy1Cy2and L1defined above, can also be obtained by the reaction of compounds of formula (V), where R1L1and Cy2defined above, and X3is halogen, preferably chlorine, or triflate group, with a compound of formula (XIV), where Cy1defined above. The reaction can be done in the presence of sodium hydride in an inert solvent, for example dimethylformamide, at a temperature up to the boiling point.

The compound of formula (I), where L2- -O-, R1- (C1-C4)-alkylthio or (C1-C4)-alkyl, which optionally has one to three identical or different substituents which are halogen, hydroxyl or CNS group, Cy1Cy2and L1defined above, can also be obtained by reaction of compounds of formula (XV), where Cy1defined above, and X4is halogen, preferably chlorine, or triflate group, with a compound of formula (XVI), where Cy1defined above. Rea is a recommendation comfortable to hold, for example, in the presence of a suitable base, such as sodium bicarbonate or Cs2CO3in an inert solvent, such as dimethylformamide, at a temperature up to the boiling point.

The compound of formula (I), where L2- -O-, R1- -NY4Y5or (C1-C4)-alkoxy, which optionally has as substituents of one to three halogen, Cy1Cy2and L1defined above, can also be obtained (i) by oxidation of the corresponding compounds of formula (I), where R1- methylthiourea, oxidant such as 3-chloroperoxybenzoic acid, in an inert solvent, such as DCM, at a temperature of about room temperature and (ii) subsequent reaction with the alkali metal alkoxide such as sodium alkoxide or HN4Y5in an inert solvent.

The compound of formula (I), where L2communication, Cy1- nitrogen-containing heterocyclyl connected to the pyrimidine ring through a nitrogen atom in the ring, where Cy1optionally has from one to three identical or different substitute groups Cy1defined above, and L1Cy2and R1defined above, can be obtained by the reaction of the corresponding compounds of formula (V), where R1L1and Cy2defined above, and X2is halogen, preferably chlorine is, with a corresponding compound of formula (XVIII), where Cy1defined above.

The reaction is conveniently carried out, for example, in the presence of a suitable base, such as sodium bicarbonate or K2CO3in an inert solvent, such as 1-methyl-2-pyrrolidinone, at a temperature of about 140°C.

Compounds according to the invention can also be obtained by conversion of one of the compounds according to the invention in the other.

For example, the compound of formula (I)where the group Cy1substituted carboxyl group, can be obtained by hydrolysis of the corresponding esters. The hydrolysis is conveniently carried out in the form of alkaline hydrolysis using a base such as hydroxide of alkali metal such as lithium hydroxide, or carbonate of an alkali metal such as K2CO3in the presence of a mixture of water and an organic solvent, such as dioxane, THF or methanol, at a temperature from about ambient temperature to about the boiling temperature. Hydrolysis of esters can also be in the form of acid hydrolysis using an inorganic acid such as hydrochloric acid, in the presence of a mixture of water and an inert organic solvent, such as dioxane or THF, at temperatures from about 50°C to 80°C.

Other compounds of formula (I), in which the group Cy1substituted carbon the ilen group, you can get acid-catalyzed removal of tert-butilkoi group corresponding tert-butyl esters under standard reaction conditions, for example reaction with triperoxonane acid at a temperature of about room temperature.

Other compounds of formula (I), in which the group Cy1substituted carboxyl group, can be obtained by hydrogenation of the corresponding benzyl esters. The reaction can be done in the presence of ammonium formate and a suitable metal catalyst, for example palladium deposited on an inert carrier such as carbon, preferably in a solvent such as MeOH or EtOH, at a temperature of about the boiling point. The reaction can be carried out in the presence of a suitable metal catalyst, such as platinum or palladium, which optionally may be deposited on an inert carrier such as carbon, preferably in a solvent such as MeOH or EtOH.

Other compounds of formula (I), in which the group Cy1substituted carboxyl group, can be obtained by oxidation of the corresponding compounds of formula (I), in which the group Cy1substituted formyl group. The reaction can be carried out with the help of the monohydrate of sodium dihydrophosphate and sodium chlorite at a temperature of about room temperature.

Another example of mutual transformation with the of dinani is a compound of formula (I), in which the group Cy1substituted Y1Y2N-C(=O)-group, which can be obtained by the combination of compounds of formula (I), in which the group Cy1substituted carboxyl group, with an amine of the formula Y1Y2NH, to obtain the amide bond by standard methods of binding peptides. Examples include (i) binding in the presence of hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium and triethylamine (or diisopropylethylamine) in THF (or dimethylformamide) at room temperature, (ii) binding in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in the presence of triethylamine, (iii) the processing of 1-hydroxybenzotriazole and a carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, in an inert solvent, such as dimethylformamide, at a temperature of about room temperature. The combination could also be carried out during the reaction of compounds of formula (I), in which the group Cy1substituted carboxyl group, a N-oxide hexaphosphate N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridine-1-yl)methylene}-N-methylmethanamine in the presence of a suitable base, such as diisopropylethylamine, in an inert solvent, such as dimethylformamide, at a temperature of about room temperature, followed by reaction with an amine of the formula Y1Y2NH (to obtain compounds of formula (I), in which the group Cy1 replaced with H2N-C(=O)-group, you can use the ammonium chloride).

Another example of mutual transformation of compounds is a compound of formula (I), in which the group Cy1substituted alkyl-SO2-NH-C(=O)-group, which can be obtained by the combination of compounds of formula (I), in which the group Cy1substituted carboxyl group, alkylsulfonamides formula alkyl-SO2-NH2pick amide bond using standard procedures binding peptides.

Another example of mutual transformation of compounds is a compound of formula (I), in which the group Cy1substituted R6-C(=O)-N(R5)group, which can be obtained by the reaction of compounds of formula (I), in which the group Cy1replaced by HN(R5)-group, with the acid chloride of formula R6-C(=O)-Cl in an inert solvent, such as DCM, in the presence of a suitable base, such as triethylamine, at a temperature of about 0°C.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted Y1Y2NSO2the group, which can be obtained (i) by the reaction of compounds of formula (I), in which the group Cy1replaced with H2N-group, with sodium nitrite in the presence of hydrochloric acid at a temperature of about 0°C followed by treatment education is basaisa diazonium salts with sulfur dioxide in the presence of copper chloride, (ii) subsequent treatment of the resulting compounds of the formula (I), in which the group Cy1substituted Cl-SO2group, an amine of the formula Y1Y2NH at a temperature of about 0°C.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted alkoxy-C(=O)-NH-SO2the group, which can be obtained by the reaction of compounds of formula (I), in which the group Cy1replaced with H2N-SO2group, with alkylchlorosilanes in the presence of sodium hydride in an inert solvent, such as THF, at a temperature of about 0°C.

Another example of mutual transformation of compounds is a compound of formula (I), in which the group Cy1substituted HOCH2the group, which can be obtained by recovering the corresponding compounds of formula (I), in which the group Cy1substituted C1-4alkyla-C(=O)-group. Recovery is convenient to hold in the form of a reaction with lithium aluminum hydride in an inert solvent, such as THF, at a temperature from about room temperature up to about the boiling point.

Another example of mutual transformation of compounds is a compound of formula (I), in which the group Cy1substituted HOCH2the group, which can be obtained by recovering the corresponding compounds of formula (I), in which the group Cy1substituted H-C(=O)-gr is POI. Recovery is convenient to hold in the form of a reaction with sodium borohydride in an inert solvent, such as THF, at a temperature from about 0°C to about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced with F2CH-group, which can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted H-C(=O)-group, with the TRIFLUORIDE diethylaminoethyl in an inert solvent, such as DCM, at boiling point.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted R2-C(=N-OR3)-group, where R2and R3both H, which can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted formyl group, with hydroxylamine hydrochloride in the presence of a suitable base, such as pyridine, at a temperature of about room temperature. The compounds of formula (I), in which the group Cy1substituted R2-C(=N-OR3)-group, where R3Is H and R2- alkyl, can be obtained in a similar manner from compounds of the formula (I), in which the group Cy1substituted alkyl-CO-group.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted R7-NH-C(=O)-NH-group, where R7defined above, which can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted amino group, with an isocyanate of formula R7N=C=O in an inert solvent, such as THF, at a temperature of about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced bythat can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted H-C(=O)-group, with toiletrieschoice in the presence of K2CO3in an inert solvent such as MeOH at a temperature about the boiling point.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced bythat can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted CH3O-C(=O)-CH2group, with hydrazine in an inert solvent such as a mixture of MeOH and DCM, at a temperature of about room, followed by processing the resulting hydrazide 1,1-carbonyl diimidazol in the presence of triethylamine in an inert solvent, such as N-METI pyrrolidin, at room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I)containing the groupthat can be obtained by the reaction of the corresponding compounds of formula (I)containing NC-CH2group by (i) reaction with hydroxylamine hydrochloride in the presence of sodium methoxide in an inert solvent such as a mixture of MeOH and DCM at room temperature; (ii) reaction of the resulting N-hydroxyazetidine with 1,1-carbonyl diimidazol in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene in an inert solvent, such as N-methylpyrrolidone at room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced bywhere Ra- alkyl, which can be obtained by the reaction of the corresponding compounds of formula (I)where the group Cy1substituted carboxyl group, with compounds of formula Ra-C(=NH)-NHOH in the presence of TBTU, followed by processing in a microwave oven at a temperature of about 140°C.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced bywhere Ra- alkyl, which can be obtained from the result R is the action of the corresponding compounds of formula (I), where the group Cy1replaced with H2N-C(=O)-group, with compounds of formula Ra-C(OCH3)2-N(CH3)2at a temperature of about 110°C followed by reaction with hydrazine.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced bywhere Ra- alkyl, which can be obtained by the reaction of the corresponding compounds of formula (I)where the group Cy1substituted CH3-C(=O)-group, with compounds of formula Ra-C(OCH3)2-N(CH3)2at a temperature of about 90°C followed by reaction with hydroxylamine.

Another example of mutual transformation of compounds are the compounds of formula (I)containing sulfoxide communication, which can be obtained by oxidation of corresponding compounds containing-S-. For example, the oxidation is conveniently carry by reaction with peroxyketal, for example 3-chloroperbenzoic acid, preferably in an inert solvent, for example DCM, preferably at a temperature of about room temperature or by reaction with acid peroxomonosulfate potassium in this environment, as water-methanol, brought by means of the buffer to about pH 5, at a temperature from about 0°C to room. The latter method is preferred for compounds containing kislotno-unstable group.

Another example of mutual transformation of compounds are the compounds of formula (I)containing sulfonic communication, which can be obtained by oxidation of corresponding compounds containing-S - or sulfoxide communication. For example, the oxidation is conveniently carry by reaction with peroxyketal, for example 3-chloroperbenzoic acid, preferably in an inert solvent, such as DCM, preferably at a temperature of about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I)containing an N-oxide group, which can be obtained by oxidation of corresponding compounds containing suitable tertiary nitrogen atom. For example, the oxidation is conveniently carry by reaction with peroxyketal, for example 3-chloroperbenzoic acid, preferably in an inert solvent, such as DCM, preferably at a temperature of about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I)containing a cyano, which can be obtained by the reaction of the corresponding compounds of formula (I)containing a-C(=O)-NH2group, with pentachloride phosphorus in the presence of triethylamine. The reaction is conveniently carried out in an inert solvent, such as THF, at a temperature of about the boiling point.

Another example of mutual the th transformation of compounds are the compounds of formula (I), containing tetrazolyl group, which can be obtained by the reaction of the corresponding compounds of formula (I)containing a cyano, usedatabaseyou. The reaction is conveniently carried out in an inert solvent, such as toluene, at a temperature of about the boiling point. Alternatively, the reaction may be carried out with the use of trimethylsilane and oxide dibutylamine in an inert solvent, such as toluene, at a temperature of about 95°C.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted hydroxyl group, which can be obtained by the reaction of the corresponding compounds of formula (I), in which the group Cy1substituted metaxylene group, with a Lewis acid, such as trichromacy boron, in an inert solvent, such as DCM, at a temperature from about 0°C to about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted by a group-ORa(where Ra- alkyl, which optionally has substituents, as cycloalkyl, heterocyclyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl or polycyclic alkaryl), which can be obtained by alkylation of the corresponding compounds of formula (I), in which the group Cy1Zam is established by a hydroxyl group, with compounds of the formula (VII):

Ra-X3(VII)

where Radirectly defined above, X3is a halogen, preferably a bromine atom or Casilina group under standard alkylation conditions. The alkylation can be carried out, for example, in the presence of a base such as a carbonate of an alkali metal (e.g., K2CO3or Cs2CO3), alkali metal alkoxide (for example, tertiary piperonyl potassium) or an alkali metal hydride (e.g. sodium hydride), in dimethylformamide or dimethylsulfoxide at a temperature from about 0°to about 100°C.

Another example of mutual transformation of compounds are the compounds of formula (I)in which Cy1-(where Ra- aryl, polycyclic alkaryl, cycloalkyl, heteroaryl, heterocyclyl or alkyl, which optionally has substituents, as cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aryl, heteroaryl or polycyclic alkaryl), which can be obtained by alkylation of the corresponding compounds of formula (I)in which Cy1-with compounds of the formula (VII), where Radefined immediately above, and X3is halogen, preferably an atom of b is Ohm or Casilina group, in standard alkylation conditions. The alkylation can be carried out, for example, in the presence of a base such as a carbonate of an alkali metal (e.g., K2CO3or Cs2CO3), alkali metal alkoxide (for example, tertiary piperonyl potassium) or an alkali metal hydride (e.g. sodium hydride), in dimethylformamide or dimethylsulfoxide at a temperature from about 0°to about 100°C.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1substituted by a group Y1Y2N-CH2-that can be obtained by reductive amination of the corresponding compounds of formula (I), in which the group Cy1substituted H-C(=O)-group, with an amine of the formula Y1Y2NH in the presence of triacetoxyborohydride sodium and acetic acid in an inert solvent, such as MeOH or 1,2-dichloroethane, at a temperature approximately equal to room temperature. Reductive amination can be carried out in the presence of cyanoborohydride sodium or cyanoborohydride lithium in methanol at a temperature of about room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I), in which the group Cy1replaced with H2N-CH2the group, which can be obtained by recovering the corresponding compounds of formula (I), the cat is where the group Cy 1substituted H-C(=N-OH)-group. Recovery can be performed using zinc in the presence of acetic acid at room temperature.

Another example of mutual transformation of compounds are the compounds of formula (I)in which R1- CNS group, which can be obtained by the reaction of the corresponding compounds of formula (I)in which R1- methanesulfonyl, with a suitable alcohol in the presence of sodium hydride. The reaction is conveniently carried out in an inert solvent, such as dimethylformamide, at a temperature from about 0°to about 20°C.

Another example of mutual transformation of compounds are the compounds of formula (I)in which R1- alkyl, which can be obtained by the reaction of the corresponding compounds of formula (I)in which R1- methanesulfonyl, with a suitable manipolation. The reaction is conveniently carried out in an inert solvent, such as THF, at a temperature of from about -50°C to about 20°C.

Another example of mutual transformation of compounds are the compounds of formula (I)in which R1- dialkylamino, which can be obtained by the reaction of the corresponding compounds of formula (I)in which R1- methanesulfonyl, with a suitable dialkylamino. The reaction is conveniently carried out in a microwave oven at a temperature of about 150°C in an inert dissolve the Le, such as methanol.

It is clear that the compounds according to the invention may contain asymmetric centers. These asymmetric centers can independently be in either the R - or S-configuration. For the person skilled in the art it is obvious that certain compounds according to the invention can also exhibit geometric isomerism. It should be understood that the present invention applies to the individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures of compounds of the above formula (I). Such isomers can be distinguished from their mixtures by known methods or their modifications, e.g. chromatographic methods or methods of recrystallization, or to obtain separately from the corresponding isomers of the intermediate compounds.

Intermediate compounds of formula (II), where Cy1defined above, R1- alkylthio, X1a chlorine atom, can be obtained by the reaction of dichloropyrimidine formula (IX), where R - (C1-C4)-alkyl, Bronevoy acid of formula (VI), where Cy1defined above, in the presence of a complex metal catalyst such as tetrakis(triphenylphosphine)palladium(0) and Cs2CO3using the above conditions.

Intermediate compounds of formula (II), where Cy1as described above, R1- (C1C 4)-alkoxy, and X1a chlorine atom, can be obtained from the corresponding intermediate compounds of formula (II)in which R1- (C1-C4)-alkylthio, as a result of (i) processing meta-chloroperoxybenzoic acid in an inert solvent, such as DCM, at a temperature of about room temperature and (ii) reaction with alkali metal alkoxide such as sodium alkoxide, in an inert solvent, such as dimethyl ether of ethylene glycol.

Intermediate compounds of formula (V), where L1and Cy2defined above, R1- (C1-C4)-alkoxy and X2a chlorine atom, can similarly be obtained from the corresponding intermediate compounds of formula (V)in which R1- (C1-C4)-alkylthio.

Intermediate compounds of formula (V), where L1and Cy2defined above and R1- (C1-C4)-alkylthio or (C1-C4)-alkoxy, can be obtained in the reaction with dichloropyrimidine formula (X), where R is alkyl, with an amine of formula (IV), where L1and Cy2defined above, in the presence of a suitable base, such as sodium bicarbonate, in an inert solvent, such as ethanol, at a temperature up to the boiling point.

A subclass of the intermediate compounds of formula (IV)in which Cy2defined above, and L1- ethylene, i.e. the tick of the compounds of the formula (IV'), you can get as a result of (i) the reaction of aryl - or heteroanalogues formula (XI)in which Cy2defined above, with ammonium acetate in glacial acetic acid at a temperature of about 110°C and (ii) recovering the resulting 2-nitroaniline derivatives of the formula (XII) with lithium aluminum hydride in an inert solvent, such as ether, at a temperature of about 40°C.

Intermediate compounds of formula (IV)in which Cy2defined above, and L1the ethylene can be obtained by restoring acetonitrile formula (XIII) by means of Raney Nickel and ammonia. Recovery is conveniently carried out in water at a temperature of about 50°C in a Parr shaker at a pressure of 50 pounds per square inch (344,7 kPa).

According to another point of the invention is formed by attaching the acid salts of the compounds according to the invention can be obtained by the reaction of the free base with the appropriate acid by known methods or their modifications. For example formed by attaching the acid salts of the compounds according to the invention can be obtained either by dissolving the free base in water or an aqueous solution of alcohol, or other suitable solvents containing the appropriate acid and the release of salt by evaporating the solution, or the reaction of St. the free base and acid in an organic solvent, where salt precipitates from solution or allocate the concentration of the solution.

For example, Kalinovo salt of the compounds of formula (I), in particular compounds described herein, can be obtained as follows.

Into a solution of the compounds of formula (I) (0,283 mmol) in MeOH (10 ml) is added 50% (wt./wt.) an aqueous solution of choline chloride (67 μl) and stirred the mixture at room temperature for several minutes. The mixture is concentrated under vacuum. The residue is dissolved in acetonitrile (2 ml). If necessary, the solution is filtered to remove insoluble solids. The filtrate is concentrated under vacuum until crystals. Add EtOAc (~2 ml) and heat the mixture to 50-60°C, and then cooled to room temperature. The crystals are filtered, washed with EtOAc, and dried under vacuum at room temperature and get the desired Kalinovo Sol connection.

For example, salt of phosphoric acid compounds of the formula (I), in particular compounds described herein, can be obtained as follows.

Phosphoric acid (3,21 ml, 1,49 N. aqueous solution) is added to a solution of the compounds of formula (I) (4,56 mmol) in THF (45 ml). The mixture can be clouded and stirred for 10 minutes. If you dropwise at intervals add water until the mixture becomes a clear solution. The mixture is left for 1.5 hours at room temperature. Mixture conc the shape under vacuum, the residue is recrystallized from acetone and receive the desired salt of phosphoric acid compounds.

For example, sulfur salt of the compounds of formula (I), in particular compounds described herein, can be obtained as follows.

The compound of formula (I) (0,122 mmol) dissolved in acetone (2 ml) under heating. In the standard solution add 1 N. H2SO4(1252 µl). The mixture is heated under stirring and dropwise add water in sufficient quantity to obtain a clear solution when heated. The solution is cooled to room temperature and the solvent is evaporated in a stream of nitrogen. The residue is dried under vacuum overnight at room temperature and get the desired salt of sulfuric acid compounds.

Salts formed by the addition of acid to the compounds according to the invention can be regenerated from the salts by known methods or their modifications. For example, the source compounds according to the invention can be regenerated from the salts formed when attaching acid, by treatment with alkali, for example aqueous sodium bicarbonate solution or aqueous solution of ammonia.

Compounds according to the invention can be regenerated from the salts formed when attaching the base by means of known methods or their modifications. For example, the source compounds according to the invention can be regenerated from them is Olga, formed when attaching the base by treatment with an acid, for example hydrochloric acid.

Compounds according to the invention can easily be obtained or formed in the process according to the invention as a solvate (e.g. hydrate). Hydrates of the compounds according to the invention can be easily obtained by recrystallization from a mixture of water/organic solvent such organic solvents as dioxane, tetrahydrofuran or methanol.

According to another point of the invention formed by joining the base salts of the compounds according to the invention can be obtained by the reaction of the free acid with the appropriate base by known methods or their modifications. For example formed by joining the base salts of the compounds according to the invention can be obtained either by dissolving the free acid in water or an aqueous solution of alcohol, or other suitable solvents containing the appropriate base, and the release of salt by evaporating the solution, or the reaction of the free acids and bases in an organic solvent, where the salt precipitates from solution or allocate the concentration of the solution.

Source or intermediate compounds can be obtained using known methods or their modifications, such as methods, opican the x in the reference examples, or identical chemical methods.

The present invention is further illustrated by, but not limited to, the following examples and intermediate substances.

Experiments on liquid chromatography high pressure and mass spectrometry (GHMC) to determine retention time (RT) and associated mass ions was carried out using one of the following methods.

Method A: The experiments are carried out on the spectrometer Micromass Platform LC with elektrorazpredelenie positive and negative ions and detection using a detector light scattering (ELS)/diode matrix on a column Phenomenex Luna C18(2) 30×4.6 mm with a flow rate of eluent 2 ml per minute. Solvent mixture of 95% solvent A and 5% solvent B within the first 0.5 minute with a gradual change to 5% solvent A and 95% solvent B over the next 4 minutes. The final composition of the solvent remains constant for a further 0.5 minutes.

The spectra of nuclear magnetic resonance (NMR) 400 MHZ1H recorded at ambient temperature on the spectrometer Varian Unity Inova (400 MHz) with 5 mm triple sensor resonance. In the NMR chemical shift (δ) are expressed in ppm relative to tetramethylsilane. The magnitude of the chemical shift is indicated in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard.

Method A note is applied in examples 8(a)-(g), 9(a)-(b), 10(a)-(m), 11(a), 12, 13(a), 14(a)-(c), 26(d)-(f), 35(l)-(m), 61 and 62 to obtain the appropriate analytical data.

Method B: Mass spectra (MS) are recorded on a mass spectrometer Micromass LCT. The method includes the ionization positive elektrorazpredelenie and scan mass m/z 100 to 1000. Liquid chromatography is performed using a binary pump and degasser Hewlett Packard 1100 Series; stationary phase: column Phenomenex Synergi 2µ Hydro-RP 20×4.0 mm, mobile phase: A=0.1% of formic acid (FA) in water, B=0,1% FA in acetonitrile. Injected volume of 5 μl using system CTC Analytical PAL. The flow rate of eluent is 1 ml/min Gradient from 10% B to 90% B over 3 minutes, and from 90% B to 100% B in 2 minutes. Auxiliary detector: UV detector Hewlett Packard 1100 Series, wavelength = 220 nm, evaporative light scattering detector (ELS) Sedere SEDEX 75, temperature = 46°C, the nitrogen pressure = 4 bar.

The spectra of nuclear magnetic resonance (NMR) 300 MHZ1H recorded at ambient temperature on the spectrometer Varian Mercury (300 MHz) with a 5 mm ASW sensor. In the NMR chemical shift (δ) are expressed in ppm relative to tetramethylsilane. The magnitude of the chemical shift is indicated in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard.

Method B is used in other examples to obtain the appropriate analytical data.

In the following examples the Ah and descriptions of the synthesis of the terms used have the following meanings: "kg" - kilograms, "g" for grams, "mg" - milligrams, "μg" - micrograms, "mol" - moles, "mmol" mmol, M - both molarity, "mm" - millionares, "μm" - mikrokosmos, "nm" - nanoelement, "l" - liters, "ml - milliliters, "μl" - Microlitre, "°C" degrees Celsius, "TPL" melting point "as" boiling point, "mm of Hg" - pressure in millimeters of mercury, "cm" - centimeters, "nm - nanometers, "abs." absolute, "conc." - concentrated, "c" is the concentration in g/ml, "K.T." room temperature, "TLC" - thin layer chromatography, "HPLC" is a high - performance liquid chromatography, "I.P. Pavlova." - IPR, "i.v." intravenous, C - singlet, d - doublet; t - triplet; "kV" Quartet; m - multiplet, "DD" is doublet of doublets; "ush." broadened, "LC" - liquid chromatography, "MS" - mass spectrometry, ESI/MS = ionization in electrospray/mass spectrometry, "RT" = retention time, M is the molecular ion, "psi" is pounds per square inch, DMSO = dimethylsulfoxide, DMF = dimethylformamide, CDI = 1,1'-carbonyldiimidazole, DCM = dichloromethane, HCl = hydrochloric acid, TBTU = tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, PS-TBD = 1,5,7-diazabicyclo[4.4.0]Dec-5-ene-polystyrene, PS-BEMP = 2-tert-butylamino-2-diethylamino-1,3-dimethylpyridine-1,3,2-diazaphospholidine; "MP-carbonate" = macroporous carbonate trimethylamino is inetrpretatora, SPA = SPA assay (scintillation analysis using molecular imprinted polymers), ATTC = American type culture collection, FBS = fetal bovine serum, IPU = minimal supportive environment, "imp./minutes" = number of pulses per minute, EtOAc = ethyl acetate, THF = tetrahydrofuran, MeOH = methanol, EtOH = ethanol, PBS = phosphate buffer saline, TMW = transmembrane domain, IBMX = 3-isobutyl-1-methylxanthines, cAMP = cyclic monophosphate, "pddf" = complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in dichloromethane, bis-(pinacolato)dibor" = 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolane].

EXAMPLES

Example 1

3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile

Stage 1. A solution of 3-fluoro-4-methoxybenzaldehyde [of 5.05 g of the intermediate compound (1)], nitromethane (5,3 ml) and ammonium acetate (6.3 g) in glacial acetic acid (60 ml) is heated at 110°C for 16 hours, cooled and poured into water (300 ml). The aqueous solution is twice extracted with EtOAc (200 ml). The combined extracts washed with sodium bicarbonate solution (10%), water, dried over sodium sulfate and evaporated, obtaining 2-fluoro-1-methoxy-4-(2-nitrovinyl)benzene [4,2 g of the intermediate compound (2)]. MS: 198 (M+H);1H NMR (CDCl3): δ 7,9 (1H, d, J=10 Hz); and 7.5 (1H, d, 10 Hz); and 7.3 (2H, m); 6,5-to 7.15 (1H, m); 4 (3H, s).

Stage 2. A solution of 2-fluoro-1-methoxy-4-(2-nitrovinyl)benzene (1.5 g, the intermediate compound (2)] in THF (50 ml) is treated with added dropwise a solution of lithium aluminum hydride in ether (23 ml, 1M). The mixture is heated at 40°C for 3 hours, cooled to room temperature, diluted with ether and quenched with Na2SO4·10 H2O (104 g). Left overnight at room temperature, the reaction mixture was filtered, and the filtrate is evaporated. The remainder chromatographic on silica gel with elution EtOAc and get 2-(3-fluoro-4-methoxyphenyl)ethylamine [0,81 g of the intermediate compound (3)] in the form of oil. MS: 170 (M+H);1H NMR (CDCl3): 6,9-7 (3H, m); of 3.85 (3H, s); 2,95 (2H, t); 2,7 (2H, t).

Stage 3. A solution of 4,6-dichloro-2-methoxypyridine [0.7 g, the intermediate compound (4)], 2-(3-fluoro-4-methoxyphenyl)ethylamine [0.66 g, the intermediate compound (3)] and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated at 80°C for three hours and poured into water (400 ml). The obtained solid is filtered and dried in the air, getting (6-chloro-2-methoxypyridine-4-yl)-[2-(3-fluoro-4-methoxyphenyl)ethyl]amine [1,1 g of the intermediate compound (5)]. MS: 312 (M+H);1H NMR (CDCl3): δ 6,9-7 (3H, m); 6,05 (1H, s); of 3.95 (3H, s); of 3.85 (3H, s); 3,6-3,7 (2H, m); 2,95 (2H, t).

Stage 4. (6-Chloro-2-methoxypyridine-4-yl)-[2-(3-fluoro-4-methoxyphenyl)ethyl]amine [1,6 g of the intermediate compound (5)], 3-cyanoaniline acid [1.5 g, temporarily the second connection (6)], Cs2CO3(8,3 g) and tetrakis(triphenylphosphine)palladium (45 mg) in a solution of water (8 ml) and dimethyl ether of ethylene glycol (32 ml) is heated at 90°C for 16 hours. The solution was poured into water and twice extracted with EtOAc (200 ml). The mixture of the extracts dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution EtOAc and get 3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile [1.1 g, example 1]. MS: 379 (M+H);1H NMR (CDCl3): δ 8,3 (1H, s); 8,2 (1H, d, J=5,1 Hz)); 7,9 (1H, d, J=5,1 Hz)); and 7.6 (1H, t); 7-7,2 (4H, m); at 6.4 (1H, s); 5 (1H, m); of 3.95 (3H, s); and 3.8 (3H, s); 3,7 (2H, t); 3 (2H, t).

Example 2

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. Following the method similar to the method of example 1, step 3, but using 4,6-dichloro-2-methoxypyridine [3.1 g, the intermediate compound (4)], 2-(4-methoxyphenyl)ethylamine [0.66 g, the intermediate compound (7)] and sodium bicarbonate (0.88 g) receive (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxy)phenyl]amine [5 g of the intermediate compound (8)]. MS: 294 (M+H);1H NMR (CDCl3): δ 7,1 (2H, d, J=7 Hz); 6.8 cm (2H, d, J=7 Hz); 6 (1H, s); of 3.95 (3H, s); and 3.8 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t).

Stage 2. Following the method similar to the method described in example 1, step 4, but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [0.26 g, ex is offered by the compound (8)], 3-aminophenylarsonic acid [0.27 g, the intermediate compound (9)], Cs2CO3(1,43 g) and tetrakis(triphenylphosphine)palladium(0) (6 mg), conducting the reaction at 90°C for 16 hours, receive [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [0,22 g, example 2]. MS: 351 (M+H);1H NMR (CDCl3): δ 7,2 (1H, s); 7-7,1 (4H, m); 6.8 cm (2H, m, J=7,0 Hz); 6 (1H, s); of 3.95 (3H, s); of 3.75 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t).

Example 3

3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide

Stage 1. [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [1,46 g, example 2] in dimethylformamide (4 ml) is added to concentrated hydrochloric acid and crushed ice (8 ml), the mixture is cooled to 0°C and treated with added dropwise with sodium nitrite (0.32 g) in water (3 ml). After stirring at 0°C for 15 minutes, the mixture is treated with a solution of copper chloride (0.36 g) in a saturated solution of sulfur dioxide in acetic acid (15 ml), previously cooled to 0°C. the Reaction mixture was kept at room temperature for 30 minutes and poured into water. The formed precipitate is filtered and dried in the air, getting 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulphochloride [0.4 g of the intermediate compound (10)].1H NMR [(CD3)2SO]: δ 8 (1H, s); of 7.7 to 7.8 (1H, m); 7,5 (1H, m); 7,2 (1H, s); and 7.1 (2H, d, J=7.0 G is); to 6.8 (2H, d, J=7,0 Hz); and 6.6 (1H, s); 4 (3H, s); of 3.85 (3H, s); 3,7-3,8 (2H, m); 2,8 (2H, t).

Stage 2. A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [0.2 g of the intermediate compound (10)] and triethylamine (0.3 ml) in dimethylformamide (5 ml) cooled to 0°C and treated with a solution of ammonia in 1,4-dioxane (5 ml, 0,5M). The solution is kept overnight at room temperature and poured into water (100 ml). The mixture was twice extracted with EtOAc (100 ml). The combined extracts washed with water, dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution EtOAc and get 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [140 mg, example 3]. MS: 415 (M+H)1H NMR [(CD3)2SO]: δ and 8.4 (1H, s); 8,2 (1H, m); 7,9 (1H, d, J=3 Hz), and 7.7 (1H, m); of 7.4 (2H, m); and 7.1 (2H, d, J=7 Hz); 6.8 cm (2H, d, J=7 Hz); and 6.6 (1H, s); a 3.9 (3H, s); 3,7 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t). IC50=2,9 nm.

Example 4

(a)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide

A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [0.05 g of the intermediate compound (10)] and triethylamine (0,064 ml) in dimethylformamide (5 ml) cooled to 0°C and treated with a solution of methylamine in THF (5 ml, 2M). The mixture is left overnight at room temperature and poured into water (100 ml). The mixture twice extragear who have EtOAc (100 ml). The mixture of the extracts washed with water, dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution EtOAc and get 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide [21,5 mg, example 4(a)]. MS: 429 (M+H)1H NMR [(CD3)2SO]: δ and 8.4 (1H, s); 8,2 (1H, m); a 7.85(1H, d, J=3 Hz); 7,75 one-7.8 (1H, m); 7.5 to about 7.6 (2H, m); to 7.2 (2H, d, J=7 Hz); to 6.95 (2H, d, J=7 Hz); and 6.6 (1H, s); a 3.9 (3H, s); 3,7 (3H, s); 3,5-3,6 (2H, m,); 2,8 (2H, t); of 2.45 (3H, d, J=2 Hz).

(b)N-Ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide

A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [0,065 g of the intermediate compound (10)] and triethylamine (0.25 ml) in dimethylformamide (3 ml) cooled to 0°C and treated with a solution of ethylamine in MeOH (3 ml, 2M). The mixture is left overnight at room temperature and poured into water (100 ml). The mixture was twice extracted with EtOAc (100 ml). The combined extracts washed with water, dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution EtOAc and get N-ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [20 mg, example 4(b)]. MS: 443 (M+H)1H NMR [(CD3)2SO]: δ and 8.4 (1H, s); 8,2 (1H, m); a 7.85 (1H, d, J=3 Hz); 7,75 one-7.8 (1H, m); 7.5 to about 7.6 (2H, m); to 7.2 (2H, d, J=7 Hz); to 6.95 (2H, d, J=7 Hz); and 6.6 (1H, s); a 3.9 (3H, s); 3,7 (3H, s); 3,5-3,6 (2H, m,); 2,8 (2H, m) 1 (3H, t). IC50=6,6 nm.

(c)N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide

A solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [100 mg, example 3] in THF (10 ml) is treated with sodium hydride (20 mg). The mixture is stirred at 0°C for 60 minutes, treated with methylchloroform (1 ml) and stirred at 0°C for another 60 minutes. The reaction mixture was poured into water and twice extracted with EtOAc (50 ml). The combined extracts washed with water, dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of EtOAc and heptanol (1:1 vol./about.) and get N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide [41 mg, example 4(c)] in the form of solids. MS: 473 (M+H)1H NMR [(CD3)2SO]: δ 12,2 (1H, s); and 8.4 (1H, s); 8,15 (1H, m); 8 (1H, d, J=3 Hz); the 7.65 to 7.8 (1H, m); to 7.2 (2H, d, J=7 Hz); and 6.9 (2H, d, J=7 Hz); 6,7 (1H, s); a 3.9 (3H, s); 3,7 (3H, s); 3,5-3,6 (2H, m); to 3.6 (3H, s); 2,8 (2H, t).

Example 5

[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine

Stage 1

Method A. a Solution of (4-trifloromethyl)acetonitrile [of 5.05 g of the intermediate compound (11)] in MeOH (75 ml) saturated with gaseous ammonia and treated with Raney Nickel in water (2 ml, 50%). The suspension is placed is on a Parr shaker under a pressure of 50 pounds per square inch (344,7 kPa) at 50°C for 3 hours and filtered through cellit. The filtrate is evaporated and the residual oil is divided between water and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in MeOH and the solution is treated with concentrated hydrochloric acid (1 ml). The solution is evaporated under vacuum to a solid substance, which is ground to powder in ether and air-dried, obtaining the hydrochloride of 2-(4-trifloromethyl)ethylamine [5,15 g of the intermediate compound (12)]. MS: 206 (M+H);1H NMR (CDCl3): δ 8,2 (2H, m); of 7.4 (2H, d, J=5 Hz); and 7.3 (2H, d, J=5 Hz); 3-3,1 (2H, m); 2,9-3 (2H, m).

Method B. a Solution of 4-triphtalocyaninine (1 g, of 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10,6 ml) is treated with ammonium acetate (1.01 g, 13,2 mmol) and heated in a microwave oven at 150°C for 15 minutes. The reaction mixture was diluted with water and three times extracted with DCM (50 ml). The combined extracts washed sequentially 2 N. sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel and receive a 4-triptoreline-(2-nitrovinyl)benzene (1.23 g) as a solid. Part 4-triptoreline-(2-nitrovinyl)benzene (0,504 g of 2.16 mmol) hydrogenizing hydrogen from a cylinder, 10% Pd/C (115 mg, 5 mol.%) in MeOH (22 ml) containing concentrated hydrochloric acid (0.27 m is) at room temperature for 15 hours. The mixture is filtered and the filtrate concentrated to a solid, which was washed with diethyl ether, obtaining the hydrochloride of 2-(4-trifloromethyl)ethylamine [0.3 g, 57%, the intermediate compound (12)] in the form of solids. LC/MS: MS: 206 (M+H).

Stage 2. Following the method similar to the method described in example 1, step 3, but using 4,6-dichloro-2-methoxypyridine [0.39 g, the intermediate compound (4)], 2-(4-trifloromethyl)ethylamine [0,38 g of the intermediate compound (12)] and sodium bicarbonate (0.74 g) receive (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine [0,61 g of the intermediate compound (13)]. MS: 360 (M+H);1H NMR (CDCl3): δ of 7.4 (2H, d, J=7 Hz); and 7.3 (2H, d, J=7 Hz); 6,2 (1H, s); and 3.8 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t).

Stage 3. Following the method similar to the method described in example 1, step 4, but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine [3,26 g of the intermediate compound (13)], 3-aminophenylarsonic acid [2.9 g of intermediate compound (9)], Cs2CO3(12,43 g) and tetrakis(triphenylphosphine)palladium (21 mg) and a solution of water (20 ml) and dimethyl ether of ethylene glycol receive (80 ml) [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine [3.5 g, example 5]. MS: 405 (M+H)1H NMR [(CD3)2SO]: δ 9,6 (2H, m); for 8.2 (1H, s); 7,8 (1H, m); of 7.6 to 7.7 (3H, m); 7.3 to 7.4 (3H, m); to 7.2 (2H, d, J=3 Hz); 6,8 (1H, s); 4 (3H, s); 3,7-3,7(2H, m); 2,9 (2H, t). IC50=9,6 nm.

Example 6

(a)N-(3-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide

A solution of 6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine [850 mg, example 5] and triethylamine (0,32 ml) in DCM (10 ml) at 0°C is treated with acetylchloride (0.17 ml). After stirring at 0°C for 1 hour, the reaction mixture was poured into water and twice extracted with EtOAc (50 ml). The mixture of the extracts washed with water, dried over sodium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of EtOAc and heptane (1:1 vol./about.) and get N-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide [550 mg, example 6(a)] in the form of solids. MS: 447 (M+H)1H NMR [(CD3)2SO]: δ of 10.4 (1H, s); and 9.6 (1H, m); for 8.2 (1H, s); 7,8 (1H, m); of 7.7 to 7.8 (3H, m); between 7.4 to 7.5 (3H, m); to 7.2 (2H, d, J=3 Hz); and 6.6 (1H, s); of 4.05 (3H, s); 3,7-3,8 (2H, m); 3 (2H, t); is 2.05 (3H, s). IC50=4,8 nm.

(b)N-(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide

In the acetate solution of [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [156 mg, 0.38 mmol, example 2] in pyridine (1.3 ml) add acetylchloride (32 μl, 0.45 mmol). The reaction mixture is stirred for 3 hours at ambient temperature, quenched by addition of water (20 m is) and thrice extracted with EtOAc (20 ml). The combined extracts are washed four times with an aqueous solution of copper sulfate (10 ml), water (10 ml), brine (10 ml), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The resulting solid is purified flash chromatography on a column of silica gel (4.5 g) with elution with 3% MeOH in DCM and get N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide [51 mg, example 6(b)]. LC/MS: RT=2,3 minutes, MS: 393 (M+H).

(c)Ethyl ester of (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid

By a method similar to that described in example 6(b), but using [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [169 mg, example 2] and ethylchloride (47 μl) purification of the reaction product flash chromatography on a column of silica gel (10 g) with elution of 20-40% solution of EtOAc in heptane get ethyl ester (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid [40,1 mg, 23%), example 6(c)]. LC/MS: RT=2,84 minutes, MS: 423 (M+H).

Example 7

3-{6-[2-(2,4-Differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

Stage 1. Following the method similar to the method described in example 5, step 1, but using (2,4-differenl)acetonitrile [of 5.05 g, ex is offered by the compound (17)], receive hydrochloride 2-(2,4-differenl)ethylamine [4.8 g, the intermediate compound (18)]. MS: 158 (M+H)1H NMR [(CD3)2SO]: δ 8,8 (1H, m); and 7.3 (1H, s); and 7.3 (1H, t); 6,9 (1H, t); 3,5-3,6 (2H, m); 2,8 (2H, t).

Stage 2. Following the method similar to the method described in example 1, step 3, but using 4,6-dichloro-2-methoxypyridine [of 1.03 g of the intermediate compound (4)], hydrochloride 2-(2,4-differenl)ethylamine [1.4 g of the intermediate compound (18)] and sodium bicarbonate (2,44 g) receive (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-differenl)ethyl]amine [1.4 g of the intermediate compound (19)]. MS: 300 (M+H)1H NMR [(CD3)2SO]: δ 8,8 (1H, m); 7.3 to 7.4 (1H, m); and 7.3 (1H, t); 6,9 (1H, t); 6,2 (1H, s); and 3.8 (3H, s); 3,5-3,6 (2H, m); 2,8 (2H, t).

Stage 3. Following the method similar to the method described in example 1, step 3, but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine [220 mg, intermediate compound (19)], 3-carboxybenzeneboronic acid [240 mg, intermediate compound (20)], Cs2CO3(1.2 g) and tetrakis(triphenylphosphine)palladium(0) (0.4 mg) obtained 3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [93 mg, example 7]. MS: 386 (M+H)1H NMR [(CD3)2SO]: δ to 8.45 (2H, m); 8-8,1 (3H, m); and 7.6 (1H, d, J=3 Hz); 6,2 (1H, s); 4 (3H, s); 3,5-3,6 (2H, m); 2,9 (2H, t). IC50=0.8 nm.

Example 8

(a)Triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-arbonboy acid

A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [250 mg, 0.85 mmol, intermediate compound (8)obtained as described in example 2, stage 1], 5-(dihydroxyaryl)-2-thiophencarboxylic acid [200 mg of 1.16 mmol, intermediate compound (21)], Cs2CO3(760 mg, of 1.87 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (54 mg, of 0.066 mmol) in acetonitrile (4 ml) and water (4 ml) Tegaserod vacuum/nitrogen several times and stirred at 90°C for 4.5 hours. The reaction mixture was separated between EtOAc and water, the organic phase is separated and dried over magnesium sulfate. The mixture is filtered and concentrated, obtaining a solid substance, which was purified flash chromatography on a column of silica gel with elution with a mixture of EtOAc and heptane. The substance is recrystallized from MeOH and purified by HPLC (gradient of water/acetonitrile)to give triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid [34 mg, yield of 10.4%, example 8(a)]. LC/MS: RT=7,44 minutes, MS: 386 (M+H). IC50=0,33 nm.

(b)5-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde

By a method similar to that described above in example 8(a), but replacing 5-formyl-2-tiefenbronn acid 5-(dihydroxyaryl)-2-thiencarbazone the Yu acid, get 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [example 8(b)]. IC50or =0.6 nm.

(c)4-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde

By a method similar to that described above in example 8(a), but replacing 5-formyl-3-tiefenbronn acid 5-(dihydroxyaryl)-2-thiencarbazone acid, receive 4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [example 8(c)].

(d)[6-(3,5-Dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 8(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (250 mg), 3,5-dimethylisoxazol-4-Bronevoy acid (120 mg), Cs2CO3(985 mg) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (70 mg), receive [6-(3,5-dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [example 8(d)]. LC/MS: RT=of 6.49 minutes, MS: 355 (M+H). IC50=1,9 nm.

(e)[2-Methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 8(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (293,76 mg), 5-methylthiophene-2-Bronevoy acid (290 mg), Cs 2CO3(1,181 g) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (75 mg), heating the reaction mixture under reflux during the night and purifying the reaction product by the method of flash-chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receive [2-methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [252 mg, 70%, example 8(e)]. LC/MS: RT=7,87 minutes, MS: 356 (M+H). IC50=8,2 nm.

(f)[2-(4-Methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-yl)pyrimidine-4-yl]amine

By a method similar to that described above in example 8(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (250 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (329 mg), Cs2CO3(985 mg) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (70 mg), heating the reaction mixture at 90°C for 5 hours, and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receive [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-yl)pyrimidine-4-yl]Amin [50 mg, 18%, example 8(f)]. LC/MS: RT=5,04 minutes, MS: 326 (M+H). IC50=26 nm.

(g)(6-Isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 8(a), but use the isua (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (250 mg), 5-ethanolammonium acid (249 mg), Cs2CO3(985 mg) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (70 mg), heating the reaction mixture at 90°C for 5 hours, and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, get (6-isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [163 mg, 50%, example 8(g)]. LC/MS: RT=of 5.05 minutes, MS: 387 (M+H). IC50=64 nm.

Example 9

(a)(5-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol

A mixture of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [200 mg, 0.54 mmol, example 8(b)] in MeOH (5 ml) and THF (5 ml) at 0°C is treated with sodium borohydride (41 mg, of 1.08 mmol). The mixture is stirred at room temperature for 1 hour and concentrated on a rotary evaporator to remove the solvent. The residual solid is dissolved in water and the solution extracted with ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated and the obtained solid is purified flash chromatography on a column of silica gel with elution with a mixture of EtOAc with cyclohexane, receiving (5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol [75 mg, 37%), example 9(a)] in the form of a solid wisestar/MS: R T=6,09 minutes, MS: 372 (M+H). IC50=0,55 nm.

(b)(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol

By a method similar to that described above in example 9(a), but replacing 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [110 mg, 0,298 mmol, example 35(l)] 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid, and purifying the reaction product by chromatography on a SCX column with elution of ammonia (2M) in MeOH and ethyl acetate, get (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol [45 mg, 41%), example 9(b)] in the form of solids. LC/MS: RT=by 5.87 minutes, MS: 372 (M+H).1H NMR [400 MHz, (CD3)2SO] δ of 7.48 (1H, s), and 7.4 (1H, d, J=5.6 Hz), 7,35 (1H, s), 7,18 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), 6,4 (1H, s), 5,9 (1H, t, J=5.6 Hz), 3,85 (3H, s), and 3.72 (3H, s), of 3.45 (2H, m), 2,8 (2H, t, J=6,8 Hz). IC50=1,7 nm.

(c)(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanol

A solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [33 mg, 0.08 mmol, example 35(u)] in a mixture of DCM (3 ml) and MeOH (1 ml) is treated with sodium borohydride (100 mg). After 10 minutes at 20°C the mixture is concentrated and twice extracted with EtOAc (10 ml). The combined extracts are dried over magnesium sulfate and filtered through silica gel, receiving (3-{2-methoxy-6-[2-(4-meth is xifei)ethylamino]pyrimidine-4-yl}phenyl)methanol [32 mg, 100%, example 9(c)]. LC/MS: RT=2.18 minutes, MS: 366 (M+H).

(d)(3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol

A solution of 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde [150 mg, 0,39 mmol, example 35(v)] in DCM (4 ml) and MeOH (1 ml) is treated with sodium borohydride (74 mg, of 1.95 mmol) at 0°C. After 1 hour at 20°C the mixture is concentrated and twice extracted with EtOAc (10 ml). The combined extracts are dried over magnesium sulfate and filtered through silica gel, receiving (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol [110 mg, 73%, example 9(d)]. LC/MS: RT=2,79 minutes, MS: 388 (M+H). IC50=2,4 nm.

Example 10

(a)[2-(4-Methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)Amin

A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg, 0.51 mmol, intermediate compound (8)obtained as described in example 2, stage 1), quinoline-6-Bronevoy acid [176 mg, of 1.02 mmol, intermediate compound (22)], Cs2CO3(590 mg, is 1.81 mmol), tetrakis(triphenylphosphine)palladium(0) (59 mg, 0,051 mmol), dimethyl ether of ethylene glycol (4 ml) and water (1 ml) is placed in a container for a microwave oven, seal, pump out the air, rinsed three times with argon and treated in a microwave oven at 140°C for 10 minutes. P is a promotional divide mixture between EtOAc and water. The organic phase is separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residual solid is purified flash chromatography on silica gel with elution with a mixture of EtOAc and heptane. The substance is recrystallized from MeOH and receive [2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine [140 mg, 71%, example 10(a)]; LC/MS: RT=5,97 minutes, MS: 387 (M+H). IC50or =0.6 nm.

(b)[2-(4-Methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)Amin

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (200 mg), 3-hinolinovogo acid (235 mg), Cs2CO3(787 mg) and tetrakis(triphenylphosphine)palladium(0) (79 mg) and conducting the reaction in a microwave oven at 140°C for 6 minutes to obtain [2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine [156 mg, 59%, example 10(b)]. LC/MS: RT=7,44 minutes, MS: 387 (M+H). IC50=0.7 nm.

(c)[6-(1H-Indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 5-indeliberately acid (165 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg), receive [6-(1H-shall ndol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [example 10(c)]. LC/MS: RT=6.3 minutes, MS: 375 (M+H).1H NMR [(CD3)2SO]: δ by 8.22 (1H, s), 7,73 (1H, m), 7,45 (2H, d, J=9,2 Hz), 7,39 (2H, m), 7,19 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), and 6.6 (1H, s), 6,55 (1H, s)of 3.9 (3H, s), and 3.72 (3H, s), 3,55 (2H, m), 2,8 (2H, t, J=6,8 Hz). IC50=0.7 nm.

(d)N-(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 2-(methylsulfonylamino)phenylboronic acid (219 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (59 mg) and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receive N-(2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide [115 mg, 53%, example 10(d)]. LC/MS: RT=8,17 minutes, MS: 429 (M+H). IC50=2 nm.

(e)4-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 4-(aminocarbonylmethyl)baronova acid (168 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg) and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of from 20 to 100% EtOAc is cyclohexane, get 4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [30 mg, or 15.5%, example 10(e)]. LC/MS: RT=5,32 minutes, MS: 379 (M+H). IC50=2,3 nm.

(f)[2-Methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), N-methylindol-5-Bronevoy acid (178,5 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg) and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of from 20 to 100% EtOAc and cyclohexane, receive [2-methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [70 mg, 35%, example 10(f)]. LC/MS: RT=6,75 minutes, MS: 389 (M+H).1H NMR [(CD3)2SO]: δ of 8.25 (1H, s), 7,78 (1H, s), and 7.5 (1H, d, J=9,2 Hz), 7,38 (1H, d, J=2.3 Hz), 7,18 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), 6,62 (1H, s), 6,55 (1H, d, J=2.3 Hz), a 3.9 (3H, s), 3,82 (3H, s), 3.72 points (3H, s), of 3.45 (2H, m), 2,8 (2H, t, J=6,8 Hz).

(g)(6-Benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), benzo[b]thiophene-2-Bronevoy acid (182 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg) and purifying the reaction product is a lash-by chromatography on a column of silica gel with elution with a mixture of from 20 to 100% EtOAc and cyclohexane, get (6-benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [85 mg, yield 42%, example 10(g)]. LC/MS: RT=accounted for 10.39 minutes, MS: 392 (M+H). IC50=5,1 nm.

(h)1-(4-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)alanon

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (200 mg), 4-acetylphenylalanine acid (223 mg), Cs2CO3(787 mg) and tetrakis(triphenylphosphine)palladium(0) (79 mg), conducting the reaction in a microwave oven at 140°C for 6 minutes and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, get 1-(4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon [160 mg, 62%, example 10(h)]. LC/MS: RT=6.2 minutes, MS: 378 (M+H).1H NMR [(CD3)2SO]: δ 8,1 (4H, m), 7,78 (1H, s), a 7.62 (1H, s), 7,18 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), 6,7 (1H, s)of 3.9 (3H, s), and 3.7 (3H, s), 3,55 (2H, m), 2,8 (2H, t, J=6.8 Hz), 2,6 (3H, s). IC50=6,3 nm.

(i)[6-(3-Methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 3-(methylsulphonyl)phenylboronic acid (204 mg), Cs2CO3(590 mg) and tetrakis(triphenyl spin)palladium(0) (59 mg) and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, get [6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [142 mg, 67%, example 10(i)]. LC/MS: RT=6,74 minutes, MS: 414 (M+H).1H NMR [(CD3)2SO]: δ to 8.45 (1H, s), 8,35 (1H, s), 8 (1H, d, J=9,2 Hz), 7,78 (1H, t, J=7.9 Hz), the 7.65 (1H, s), 7,18 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), a 3.9 (3H, s), and 3.7 (3H, s), 3,55 (2H, m)of 3.25 (3H, s)that 2.8 (2H, t, J=6,8 Hz). IC50=7,3 nm.

(j)[6-(2,3-Dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (200 mg), 2,3-dihydro-1-benzofuran-5-Voronovo acid (223 mg), Cs2CO3(787 mg) and tetrakis(triphenylphosphine)palladium(0) (79 mg), conducting the reaction in a microwave oven at 140°C for 35 minutes and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receive [6-(2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [165 mg, 64%, example 10(j)]. LC/MS: RT=5,56 minutes, MS: 378 (M+H).1H NMR [(CD3)2SO]: δ 8,9 (1H, s), 8,79 (1H, s), and 7.4 (1H, s), 7,2 (1H, d, J=9,2 Hz), 6,85 (1H, t, J=9,2 Hz), 6,83 (2H, d, J=9,2 Hz), and 6.5 (1H, s), 4,6 (2H, t, J=8 Hz), 3,85 (3H, s), and 3.7 (3H, s), 3,55 (2H, m), up 3.22 (2H, t, J=8 Hz), 2,8 (2H, t, J=6,8 Hz). IC50=13 nm.

(k)[2-Methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

/p>

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 4-(morpholino)phenylboronic acid (211 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (59 mg), conducting the reaction in a microwave oven at 140°C for 10 minutes at 165°C for 10 minutes and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receive [2-methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [130 mg, 61%, example 10(k)]. LC/MS: RT=6,28 minutes, MS: 421 (M+H). IC50=13 nm.

(l)[6-(4-Dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (200 mg), 4-(N,N-dimethylamino)phenylboronic acid (224,4 mg), Cs2CO3(787 mg) and tetrakis(triphenylphosphine)palladium(0) (79 mg) and purifying the reaction product flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane and then crushed into powder with methanol, receive [6-(4-dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [50 mg, 19%, example 10(l)]. LC/MS: RT=5,77 minutes, MS: 379 (M+H). IC50=42 nm.

(m)2,2'-Dimethoxy-N*6*,N*6'*-bis-[2-(4-IU is oxiranyl)ethyl]-[4,4']bipyridinyl-6,6'-diamine

By a method similar to that described above in example 10(a)but using (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (150 mg), 4-(aminocarbonylmethyl)baronova acid (168 mg), Cs2CO3(590 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg) and purifying the reaction product flash chromatography on a column of silica gel with gradient elution with a mixture of from 20 to 100% EtOAc and cyclohexane, followed by re-crystallization from methanol receive 2,2'-dimethoxy-N*6*,N*6'*-bis-[2-(4-methoxyphenyl)ethyl]-[4,4']bipyridinyl-6,6'-diamine [20 mg, 15%, example 10(m)] as a by-product. LC/MS: RT=8,13 minutes, MS: 517 (M+H).

Example 11

(a)[2-Methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stir a mixture of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [300 mg, 0.81 mmol, example 8(b)], toiletrieschoice (174 mg, 0.89 mmol), K2CO3(246 mg, 1.78 mmol) and MeOH (30 ml) is heated under reflux for 4 hours. The mixture is cooled to room temperature, concentrated on a rotary evaporator to remove the solvent. The remainder is divided between EtOAc and water. The organic phase is dried over magnesium sulfate, filtered and concentrated. The solid residue purified flash chromatography on silica the Le with elution EtOAc and cyclohexane and receive [2-methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [240 mg, 73%, example 11(a)]. LC/MS: RT=8,99 minutes, MS: 409 (M+H). IC50=2,3 nm.

(b)[2-Methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

In a vessel mix 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde (200 mg, 0.55 mmol), dosimetrician (119 mg, 0.61 mmol), polymer Ambersep 900 OH (1 g), methyl ether of ethylene glycol (3.5 ml) and water (3.5 ml). The vessel is sealed and the mixture is heated to 85°C and stirred for 18 hours. The mixture is cooled to ambient temperature, then filtered to remove the polymer, and washing the polymer in 10 ml of methanol. The combined filtrates and washings are concentrated on a rotary evaporator and the residue purified flash chromatography on a column of silica gel with gradient elution with a mixture of from 10 to 40% EtOAc in heptane, receiving [2-methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [65 mg, 29.4%, example 11(b)]. LC/MS: RT=2,59 minutes, MS: 403 (M+H). IC50=2,6 nm.

Example 12

6-(5-Deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stir a mixture of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [300 mg, 0.81 mmol, example 8(b)] and the TRIFLUORIDE diethylaminoethyl (213 μl, of 1.62 mmol) in DCM is heated under reflux for 4 hours. To ablaut some more of the TRIFLUORIDE diethylaminoethyl (106 μl, 0.81 mmol), and stirring at reflux is continued throughout the night. The reaction mixture was poured into water and twice extracted with DCM. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated. The solid residue purified flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane and receive [6-(5-deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [65 mg, 17%, example 12]. LC/MS: RT=10.03 minutes, MS: 406 (M+H). IC50=11 nm.

Example 13

(a)[2-(4-Methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmatieteen-2-yl)pyrimidine-4-yl]amine

A mixture of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [250 mg, of 0.68 mmol, example 8(b)], pyrrolidine (170 μl, 2.03 mmol) and triacetoxyborohydride sodium (502 mg, is 2.37 mmol) in MeOH (10 ml) and 1,2-dichloroethane (10 ml) is treated with acetic acid (116 ml, 2.03 mmol)to bring the pH to 6.0, stirred at ambient temperature in for 6 hours and treated with pyrrolidine (170 μl, 2.03 mmol) and triacetoxyborohydride sodium (502 mg, is 2.37 mmol). The reaction mixture was stirred at ambient temperature overnight and concentrated on a rotary evaporator. The residual resin is divided between EtOAc and a saturated solution of sodium bicarbonate. The PR is onicescu phase is separated, dried over magnesium sulfate, filtered and concentrated and the obtained solid is purified flash chromatography on a column of silica gel with elution with a mixture of EtOAc with cyclohexane, receiving [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmatieteen-2-yl)pyrimidine-4-yl]Amin [202 mg, 70%, example 13(a)]. LC/MS: RT=lower than the 5.37 minutes, MS: 425 (M+H). IC50=44 nm.

(b)The hydrochloride of 6-{4-fluoro-3-[(2-methoxyethylamine)methyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine

A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [300 mg, 0,787 mmol, example 35(j)], 2-methoxyethylamine (170 μl, 1.97 mmol), triacetoxyborohydride sodium (500 mg, 2.36 mmol) and SITA 3Ǻ (500 mg) in DCM (7 ml) was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake washed with dichloromethane (50 ml). The combined filtrates and washings are extracted with water (50 ml). The aqueous extract is extracted with dichloromethane (50 ml). New organic extract washed with water (30 ml), brine (30 ml), dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The obtained solid is purified flash chromatography on a column of silica gel (4.5 g) with gradient elution with a mixture of from 0 to 8% MeOH in DCM, getting solid. Substance handling is up with hcl in EtOAc and concentrate, getting hydrochloride 6-{4-fluoro-3-[(2-methoxyethylamine)methyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [260 mg, 75%, example 13(b)] in the form of solids. LC/MS: RT=1.98 min, MS: 441 (M+H).1H NMR (300 MHz, CDCl3): δ 9,65 (1H, s), of 8.27 (1H, s), to $ 7.91 (1H, s), 7,47 (1H, t, J=0.03 Hz), 7,21 (2H, d, J=0,027 Hz), 6,85 (2H, d, J=0,027 Hz), 4.26 deaths (2H, s), a 4.03 (2H, s), and 3.72 (6H, s), and 3.31 (3H, s), 3,17 (2H, m), 2 (2H, t, J=0,024 Hz), 2,5 (2H, s).

(c)Hydrochloride 4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol

A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [80 mg, 0.22 mmol, example 35(u)], 2-(4-hydroxyphenyl)ethylamine (45 mg, 0.33 mmol), cyanoborohydride sodium (16.6 mg, 0,264 mmol) and acetic acid (15 μl, 0,264 mmol) in EtOH (2 ml) was stirred at room temperature under nitrogen atmosphere for 17 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (10 ml) and extracted with EtOAc (15 ml). The extract was concentrated and the residue purified by chromatography on silica gel with elution by 5% solution of ammonia in methanol. The substance is treated with hydrogen chloride in EtOAc, concentrated and receive hydrochloride 4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol [55 mg, 51.5%, example 13(c)] in the form of solids. LC/MS: RT=2,63 minutes, MS: 485 (M+H). IC50=10 nm.

(d)The hydrochloride of N-(2-photo the-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N',N'-dimethylated-1,2-diamine

A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [275 mg, to 0.72 mmol, example 35(j)], unbalanced dimethylethylenediamine (217 μl, 1.97 mmol), triacetoxyborohydride sodium (500 mg, 2.36 mmol) and SITA 3Ǻ (500 mg) in DCM (7 ml) was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture is filtered and the filter cake washed with dichloromethane (50 ml). The combined filtrates and washings are extracted with water (50 ml) and the aqueous phase extracted with dichloromethane (50 ml). New organic extract washed with water (30 ml), brine (30 ml), dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The obtained solid is purified flash chromatography on a column of silica gel (4.5 g) with gradient elution with a mixture of from 0 to 7% MeOH in DCM, getting dissolved in methanol solid. The solution is treated with hydrogen chloride in EtOAc, concentrated and receive hydrochloride N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N',N'-dimethylated-1,2-diamine [300 mg, 92%, example 13(d)]. LC/MS: RT=2,04 minutes, MS: 454 (M+H). IC50=56 nm.

Example 14

(a)[6-(1H-Benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. A mixture of 5-bromo-1-trityl-1H-benzoimidazole [439 mg, mmol, the intermediate compound (26)obtained as described in Tetrahedron 56, 3245-3253, 2000], bis(pinacolato)Debora (280 mg, 1.1 mmol), potassium acetate (393 mg, 4 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (82 mg, 0.1 mmol) and dimethyl sulfoxide (8 ml) Tegaserod under vacuum/ nitrogen several times and stirred at 85°C for 2 hours. The reaction mixture was separated between EtOAc and water. The organic phase is separated and the aqueous phase is additionally extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining a solid substance, which was purified flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, receiving 1 trityl-1H-benzoimidazol-5-Voronovo acid [(500 mg), intermediate compound (27)].

Stage 2. By a method similar to that described above in example 1, but replacing 1-trityl-1H-benzoimidazol-5-Voronovo acid [intermediate compound (27)] 5-(dihydroxyaryl)-2-thiencarbazone acid, receive [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1-trityl-1H-benzoimidazol-5-yl)pyrimidine-4-yl]amine [intermediate compound (28)].

Stage 3. A mixture of [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1-trityl-1H-benzoimidazol-5-yl)pyrimidine-4-yl]amine [300 mg, 0,485 mmol, intermediate compound (28)], DCM (5 ml), triperoxonane acid (2 ml) and water (5%) mix p is at room temperature. The reaction mixture was concentrated on a rotary evaporator to remove the solvent. The residue is placed in a saturated solution of sodium bicarbonate and the solution extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and concentrated and the obtained solid is purified flash chromatography on a column of silica gel with elution with a mixture of 5% MeOH in DCM, getting[6-(1H-benzoimidazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [90 mg, 49%, example 14(a)]. LC/MS: RT=4,73 minutes, MS: 376 (M+H). IC50=2,7 nm.

(b)[6-(1H-Benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 14(a), but (i) substituting 5-bromo-1-trityl-1H-benzotriazol 5-bromo-1-trityl-1H-benzoimidazol in stage 1 and getting 1 trityl-1H-benzotriazol-5-Voronovo acid; (ii) replacing 1-trityl-1H-benzotriazol-5-Voronovo acid 1-trityl-1H-benzoimidazol-5-Voronovo acid in stage 2 and receiving [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1-trityl-1H-benzotriazol-5-yl)pyrimidine-4-yl]amine (130 mg, 0.21 mmol); (iii) replacing [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1-trityl-1H-benzotriazol-5-yl)pyrimidine-4-yl]amine [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1 trityl-1H-benzoimidazol-5-yl)pyrimidine-4-yl]amine in stage 3 receive [6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyp the Nile)ethyl]amine [25 mg, 32%, example 14(b)]. LC/MS: RT=5,65 minutes, MS: 377 (M+H).1H NMR [(CD3)2SO]: δ 8,55 (1H, s), 7 (2H, m), 7,58 (1H, s), 7,22 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), to 6.75 (1H, s), of 3.95 (3H, s), and 3.72 (3H, s), 3,55 (2H, m), 2,8 (2H, t, J=6,8 Hz).

(c)6-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3H-benzoxazol-2-he

By a method similar to that described above in example 14(a), but (i) substituting 5-bromo-1-trityl-1,3-dehydrobenzperidol-2-it 5-bromo-1-trityl-1H-benzoimidazol in stage 1 and getting 2-oxo-2,3-dihydroisoxazole-6-Bronevoy acid; (ii) substituting 2-oxo-2,3-dihydroisoxazole-6-Bronevoy acid 1-trityl-1H-benzoimidazol-5-Voronovo acid in stage 2 and getting 6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3-trityl-3H-benzoxazol-2-he; (iii) replacing 6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3-trityl-3H-benzoxazol-2-he (52 mg) per [2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1-trityl-1H-benzoimidazol-5-yl)pyrimidine-4-yl]amine in stage 3 and purifying the product to flash chromatography on a column of silica gel with elution with a mixture of EtOAc and cyclohexane, get 6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3H-benzoxazol-2-he [19 mg, 59%, example 14(c)]. LC/MS: RT=of 5.84 minutes. MS: 393 (M+H).1H NMR [(CD3)2SO]: δ 11.8 in (1H, s), and 7.8 (1H, s), and 7.5 (1H, s), 7,18 (1H, s), 7,18 (2H, d, J=9,2 Hz), 6,85 (2H, d, J=9,2 Hz), and 6.6 (1H, s)of 3.9 (3H, s), and 3.7 (3H, s), 3,55 (2H, m), 2,8 (2H, t, J=6,8 Hz). IC50=7 nm.

p> Example 15

(a)Hydrochloride 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol

To a solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol [0.3 g, example 35(p)] in EtOAc add a saturated solution of hydrogen chloride in EtOAc (3 ml), the precipitate is filtered and dried, yielding the hydrochloride of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol [0.31 g, example 15(a)] in the form of solids. LC/MS: RT=2,55 minutes, MS: 352 (M+H).1H NMR [(CD3)2SO]: δ 10,1 (1H, USS), and 9.6 (1H, OSS), to 7.64-rate of 7.54 (1H, m), 7,34 (1H, t, J=8.1 Hz), 7,21 for 7.12 (4H, m), 7,02 (1H, d, J=7.5 Hz), 6,85 (2H, d, J=8,4 Hz), to 6.67 (1H, s)4,06 (3H, s), 3,71 (3H, s), 3,7-3,6 (2H, m,), 2,85 (2H, t, J=7.2 Hz). IC50=0.1 nm.

(b)Hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

A suspension of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [0.2 g, example 35(w)] in DCM and MeOH is treated with a saturated solution of hydrogen chloride in EtOAc (0.5 ml) and chromatographic on silica gel with elution with 10% MeOH in DCM, and the resulting product dissolved in a mixture of acetonitrile/water/hydrochloric acid, lyophilizers and receive hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [172 mg, example 15(b)] in the form of solids. LC/MS: RT=2,72 minutes, MS: 417 (M+H).

(c)Hydrochloride 3-{6-[2-(-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

A solution of 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [0.1 g, example 20(b)] in DCM and MeOH is treated with a saturated solution of hydrogen chloride in EtOAc (2 ml), the mixture is concentrated, dissolved in acetonitrile and water, lyophilizers and receive hydrochloride 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [83 mg, example 15(c)] in the form of solids. LC/MS: RT=2,85 minutes, MS: 402 (M+H).

(d)Hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid

A solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [4.3 g, 9,35 mmol, example 49(b)] in MeOH is treated with hcl 1M in ether (18 ml). The mixture is evaporated and the resulting residue is dissolved in acetone (10 ml). After 2 minutes precipitation. The precipitate is filtered, obtaining the hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [4,043 g, 87%, example 15(d)] in the form of solids. LC/MS: RT=2,42 minutes, MS: 460 (M+H).1H NMR [(CD3)2SO]: δ 12,4 (1H, OSS), was 7.36-7,8 (7H, m), and 6.6 (1H, s), 4 (3H, s), 3,7 (2H, m), to 3.02 (2H, m), and 1.54 (6H, s). IC50=0.3 nm.

Example 16

(a)[2-(3,4-Acid)ethyl]-[6-(3,4-acid)-2-methylsulfonylamino-4-yl]amine

Stage 1. A mixture of 4,6-dichloro-2-methylsulfonylamino [1 g, 5.1 mmol, intermediate compound (29)], 3,4-dimethoxyphenylethylamine [0,98 g, 5.4 mmol, intermediate compound (30)] and sodium bicarbonate (0,86 g, 10 mmol) in EtOH (5 ml) heated under reflux. After stirring at 85°C for 4 hours the mixture is diluted with water and filtered. The solid is washed with water, dried and receive (6-chloro-2-methylsulfonylamino-4-yl)-[2-(3,4-acid)ethyl]amine [1,8 g of the intermediate compound (31)]. LC/MS: RT=3.25 minutes, MS: 340 (M+H).

Stage 2. By a method similar to that described in example 35(o) above, but substituting commercially available 3,4-dimethoxyphenylacetone acid [intermediate compound (32)] 2-methoxy-5-pyridylamino acid and (6-chloro-2-methylsulfonylamino-4-yl)-[2-(3,4-acid)ethyl]amine [0,57 g of the intermediate compound (31)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and cleaning the reaction product flash chromatography on a column of silica gel by elution with 50% EtOAc in heptane, to obtain [2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methylsulfonylamino-4-yl]Amin [0.73 g, example 16(a)]. LC/MS: RT=2,72 minutes, MS: 442 (M+H).

(b)3-{6-[2-(3,4-Acid), ethylamino]-2-methylsulfonylamino-4-yl}benzoic acid

By a method similar to that described in Primera(a) above, but using commercially available 3-carboxybenzeneboronic acid and (6-chloro-2-methylsulfonylamino-4-yl)-[2-(3,4-acid)ethyl]amine (0,57 g) in stage 2, extragere the reaction mixture (pH which increased to 2) EtOAc followed by evaporation of the organic extract, receive 3-{6-[2-(3,4-acid), ethylamino]-2-methylsulfonylamino-4-yl}benzoic acid [0,48 g, example 16(b)]. LC/MS: RT=2,75 minutes, MS: 426 (M+H). IC50=243 nm.

(c)[2-(4-Methoxyphenyl)ethyl]-[6-(3-methoxyphenyl)-2-methylsulfonylamino-4-yl]amine

By a method similar to that described in example 16(a) above but (i) by replacing 4-methoxyphenylethylamine 3.4-dimethoxyphenylethylamine in stage 1, get (6-chloro-2-methylsulfonylamino-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [3 g, MS: 310 (M+H)], and (ii) replacing (6-chloro-2-methylsulfonylamino-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (1 g) to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and substituting 3-methoxyphenylalanine acid 2-methoxy-5-pyridylamino acid in stage 2 and purifying the product by chromatography on a short column of silica gel with elution by ethyl acetate, receive [2-(4-methoxyphenyl)ethyl]-[6-(3-methoxyphenyl)-2-methylsulfonylamino-4-yl]Amin [1.5 g, example 16(c)]. MS: 382 (M+H).

Example 17

(a)[2-(3,4-Acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-and the]Amin

Stage 1. A solution of [2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methylsulfonylamino-4-yl]amine [0.73 g, 1,68 mmol, example 16(a)] in DCM (12 ml) was treated with 3-chloroperoxybenzoic acid (70%, 0.9 g, 3.6 mmol). After 3 hours at 20°C the mixture was quenched with a 1M solution of sodium bicarbonate (10 ml) and twice extracted with DCM (50 ml). The combined extracts are dried over magnesium sulfate, filtered, concentrated and the residue purified by chromatography on silica gel with elution with a mixture of 70% EtOAc in heptane and receive [2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methanesulfonamido-4-yl]Amin [0.51 g, 64%, the intermediate compound (33)]. LC/MS: RT=2.97 minutes, MS: 474 (M+H).

Stage 2. A solution of [2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-methanesulfonamido-4-yl]amine [200 mg, 0.42 mmol, intermediate compound (33)] and isopropyl alcohol (1 ml) in N,N'-dimethylformamide (2 ml) at 0°C is treated with sodium hydride (60%, 102 mg, 12.7 mmol). After 1 hour at 20°C the mixture is concentrated and twice extracted with EtOAc (50 ml). The combined extracts washed twice with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel with elution with a mixture of 60% EtOAc in heptane and receive [2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-yl]Amin [0.15 g, 79%, intermediate compound 17(a); LC/MS RT=2.57 m minutes, MS: 454 (M+H).1H NMR (300 MHz, CDCl3): δ of 7.64 (1H, d, J=2.1 Hz), 7,55 (1H, DD, J=8,4, 2.4 Hz), 6,91 (1H, d, J=8,4 Hz), 6,86-6,76 (3H, m), and 6.3 (1H, s), 5,43-of 5.34 (1H, m), a 4.83 (1H, OSS), to 3.99 (3H, s), of 3.95 (3H, s)to 3.89 (3H, s), 3.75 to the 3.65 (2H, m), only 2.91 (2H, t, J=6.9 Hz), a 1.45 (6H, d, J=6 Hz). IC50=6728 nm.

(b)[6-(3,4-Acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine

By a method similar to that described in example 17(a) above, but substituting EtOH in isopropyl alcohol and 1,2-dimethoxyethane N,N'-dimethylformamide in stage 2 and purifying the product by filtration through a short column with silica gel, get [6-(3,4-acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine [54 mg, example 17(b)]. LC/MS: RT=2,62 minutes, MS: 440 (M+H). IC50=655 nm.

Example 18

[2-Ethyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. A solution of [2-(4-methoxyphenyl)ethyl]-[6-(3-methoxyphenyl)-2-methylsulfonylamino-4-yl]amine [1.5 g, 3.9 mmol, example 16(c)] in DCM (30 ml) was treated with 3-chloroperoxybenzoic acid (70%, 2.1 g, 8.6 mmol). After 3 hours at 20°C the mixture is filtered through alkaline alumina with elution by ethyl acetate and the solution concentrated. The residue is purified by chromatography on silica gel with elution with a mixture of 50% EtOAc in heptane and receive [2-methanesulfonyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyp the Nile)ethyl]Amin [1 g, 62%, the intermediate compound (34)]; MS: 414 (M+H).

Stage 2. A solution of [2-methanesulfonyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [0.14 g, 0.34 mmol, intermediate compound (34)] in THF (5 ml) is treated with 1M solution of ethylmagnesium (5 ml, 5 mmol) at -50°C. the Reaction mixture was warmed to room temperature for 2 hours, then treated with MeOH (0.5 ml), concentrated and divided between EtOAc and water. Then the aqueous phase is extracted with ethyl acetate. The residue is purified by chromatography on silica gel with elution with a mixture of 40% EtOAc in heptane and receive [2-ethyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [89 mg, 72%, example 18]. LC/MS: RT=2,38 minutes, MS: 364 (M+H). IC50=219 nm.

Example 19

The hydrochloride of 6-(3-methoxyphenyl)-N*4*-[2-(4-methoxyphenyl)ethyl]-N*2*,N*2*-dimethylpyrimidin-2,4-diamine

A solution of [2-methanesulfonyl-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [200 mg, 0.42 mmol, intermediate compound (34), obtained as described in example 18, step 1] in 2M solution of dimethylamine in MeOH (2 ml, 4 mmol) was heated to 150°C for 20 minutes in a microwave oven. The mixture is concentrated and the residue purified by chromatography on silica gel with elution with a mixture of 70% EtOAc in heptane, getting 6-(3-methoxyphenyl)-N*4*-[2-(4-methoxyphenyl)ethyl]-N*2*,N*2*-dimethylpyrimidin-2,4-diamine, which amrabat who live a saturated solution of hydrogen chloride in EtOAc (1 ml). The resulting precipitate is filtered and dried, obtaining the hydrochloride of 6-(3-methoxyphenyl)-N*4*-[2-(4-methoxyphenyl)ethyl]-N*2*,N*2*-dimethylpyrimidin-2,4-diamine [0.11 g, 70%example 19] in the form of solids. LC/MS: RT=2,85 minutes, MS: 379 (M+H).1H NMR (300 MHz, CD3OD): δ 7,46 (1H, t, J=8.1 Hz), 7,26, and 7.1 (5H, m), 6,83 (2H, d, J=8.1 Hz), 6,27 (1H, s), is 4.85 (1H, USS), a 3.87 (3H, s), 3,74 (3H, s), 3,71 (2H, t, J=7.2 Hz), or 3.28 (6H, s), 2,89 (2H, t, J=7.2 Hz). IC50=4652 nm.

Example 20

(a)2-Fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid

Solution2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde[120 mg, 0.31 mmol, example 35(j)] and 2-methyl-2-butene (2,93 ml, 28 mmol) in tert-butanol (4 ml) and THF (2 ml) is treated with a solution of the monohydrate of sodium dihydrophosphate (303 mg, 2.2 mmol) and sodium chlorite (0.28 g, 3.2 mmol) in water (2 ml) at room temperature. After 15 hours at 20°C the mixture was concentrated and diluted with water. The acidity of the mixture was adjusted to pH 3 and the resulting solid is filtered and dried, obtaining 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid. [118 mg, 96%, example 20(a)]. LC/MS: RT=2,38 minutes, MS: 398 (M+H). IC50=0.4 nm.

(b)3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

By a method similar to that described in example 20(a) to enter the, but replacing 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde [example 35(v)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, obtained 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid acid [1 g, example 20(b)]. LC/MS: RT=2,92 minutes, MS: 402 (M+H).

(c)2-Methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid

By a method similar to that described in example 20(a) above, but replacing 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [120 mg, example 35(y)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde, get 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [150 mg, example 20(c)]. LC/MS: RT=2,22 minutes, MS: 410 (M+H).

Example 21

(a)[2-Methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

A solution of [2-methoxy-(6-pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [0.24 g, 0.71 mmol, example 35(x)] in DCM (10 ml) was treated with 3-chloroperoxybenzoic acid (70%, 0.21 g, 0.85 mmol). After 15 hours at 20°C the mixture was quenched with 2M solution of sodium bicarbonate (10 ml) and twice extracted with DCM (50 ml). The combined extracts are dried over magnesium sulfate, filtered, concentrated and purified chromate what graphy on silica gel with elution with 5% MeOH in DCM, receiving [2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [0.14 g, 56%, example 21(a)]; LC/MS: RT=2,69 minutes, MS: 353 (M+H). IC50=149 nm.

(b)[2-(2,2-Debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]amine

By a method similar to that described in example 21(a)but substituting [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine [21 mg, 0,0544 mmol, see example 46(b)] [2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine with chloroform as solvent and chromatographia product on silica gel with elution 0-10% MeOH in DCM, receive [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]Amin [20 mg, example 21(b)] in the form of solids. LC/MS: RT=2,85 minutes, MS: 403 (M+H).1H NMR (300 MHz, CDCl3): δ 8,8 (1H, s), and 8.2 (1H, m), to 7.84 (1H, m), 7,34 (1H, m), 6,86-7 (3H, m), 6,36 (1H, s), are 5.36 (1H, USM), to 3.99 (3H, s), of 3.69 (2H, m), 2,96 (2H, m). IC50=2155 nm.

Example 22

(a)Ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid

A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol [400 mg, to 1.14 mmol, example 35(p)], Cs2CO3(1.1 g, to 3.41 mmol) and ethyl-2-bromo-2-methylpropionate (0.5 ml, to 3.41 mmol) in N,N'-dimethylformamide (4 ml) heated to 60°C in ECENA 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on silica gel with elution with 50% EtOAc in heptane and receive the ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid [0.33 mg, 62%, example 22(a)]. LC/MS: RT=2,95 minutes, MS: 466 (M+H). IC50=60 nm.

(b)Methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid

By a method similar to that described in example 22(a), but replacing methylbromide on ethyl-2-bromo-2-methylpropionate and conducting the reaction at room temperature, to obtain methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid [430 mg, example 22(b)]. LC/MS: RT=2,52 minutes, MS: 424 (M+H).

(c)Methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid

By a method similar to that described in example 22(a), but replacing methylbromide on ethyl-2-bromo-2-methylpropionate and 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol [example 35(i)] 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol and conducting the reaction at room temperature, to obtain methyl ether (3-{6-[2-(2,4-dichlorophenyl)e is ylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid [430 mg, example 22(c)]. LC/MS: RT=2.88 minutes, MS: 462 (M+H). IC50or =0.6 nm.

(d)Methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid

By a method similar to that described in example 22(a), but replacing methylbromide on ethyl-2-bromo-2-methylpropionate and 5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-he [example 32] 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol and conducting the reaction at room temperature, get methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid [400 mg, example 22(d)]. LC/MS: RT=2,89 minutes, MS: 447 (M+H). IC50=14 nm.

(e)(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile

By a method similar to that described in example 22(a), but using bromoacetonitrile (of 0.11 ml, 1.5 mmol) and 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol (400 mg, of 1.02 mmol, example 35(i)], Cs2CO3(0,98 g, 3 mmol) and N,N'-dimethylformamide (2 ml) and conducting the reaction at room temperature, receive (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile [example 22(e)]. MS: 429 (M+H). IC50=0.4 nm.

(f)(3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile

By a method similar to that described in example 22(a), but using bromoacetonitrile (of 0.11 ml, 1.5 mmol) and 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol (300 mg, example 46(e)], Cs2CO3(0,785 g) and N,N'-dimethylformamide (2.7 ml) and conducting the reaction at room temperature, receive (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile [300 mg, example 22(f)] in the form of solids. LC/MS: 413 (M+H).

Example 23

(a)2-(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionate acid

A solution of ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid [330 mg, 0.7 mmol, example 22(a)] 2M sodium hydroxide solution (5 ml, 10 mmol) in MeOH (4 ml), THF (2 ml) and water (4 ml) is heated at 60°C for 30 minutes. After another 5 hours at room temperature the mixture is concentrated and diluted with water and ethyl acetate. The solution is acidified with diluted hydrochloric acid to pH 2.0 and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, concentrated and receive 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid [0.21 g, 72%, example 23(a)]. LC/MS: RT=2,47 minutes, MS: 438 (M+H).

(b)(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]the feast is midin-4-yl}phenoxy)acetic acid

By a method similar to that described in example 23(a), but replacing methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid [example 22(b)] ethyl ester 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid and carrying out the reaction at room temperature, get (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid [297 mg, example 23(b)]. LC/MS: RT=2,22 minutes, MS: 410 (M+H).

(c)(5-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid

By a method similar to that described in example 23(a), but replacing methyl ester (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid [example 22(d)] ethyl ester 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid and carrying out the reaction at room temperature, to obtain (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid [79 mg, example 23(c)]. LC/MS: RT=2,28 minutes, MS: 433 (M+H). IC50=0.3 nm.

(d)2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionate acid

By a method similar to opisannogo example 23(a), but replacing the ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid [410 mg, 0.81 mmol, example 42] ethyl ester 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid [386 mg, 100%, example 23(d)] in the form of solids. LC/MS: RT=2,63 minutes, MS: 476 (M+H).

(e)Hydrochloride of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid

A solution of ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [120 mg, 0.27 mmol, example 35(z)] and sodium hydroxide (2 ml, 4 mmol, 2M in MeOH (8 ml) and water (2 ml) is stirred for 15 hours at 60°C. the Mixture is concentrated, diluted with water and ethyl acetate. The mixture is acidified with diluted hydrochloric acid to pH 3 and extracted with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and concentrated. The residue is treated with saturated hydrogen chloride in EtOAc, concentrated and receive hydrochloride 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [101 mg, 82%, example 23(e)]. LC/MS: RT=2,47 minutes, MS: 414 (M+H).

Example 24

(a)[2-(4-Methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylphenyl]pyrimidine-4-yl]amine

A solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile [0.12 g, 0.33 mmol, example 35(t)], trimethylsilane (0,22 ml of 1.65 mmol) and oxide dibutyrate (41 mg, 0.16 mmol) in toluene (5 ml) is heated to 95°C for 6 hours. The reaction mixture was concentrated and extracted with water and ethyl acetate. The aqueous phase is acidified with diluted hydrochloric acid to pH 3.0 and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel with elution with a mixture of 5% MeOH in DCM and receive [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine [60 mg, 45%, example 24(a)]. LC/MS: RT=2,65 minutes, MS: 404 (M+H).

(b)Hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine

By a method similar to that described in example 24(a) above, but replacing (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile [example 35(s)] 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile receive [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl}amine. The substance is treated with a solution of hydrochloric acid in EtOAc, followed by lyophilization and receive hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ILM is Teal)phenyl]pyrimidine-4-yl]amine [134 mg, example 24(b)]. LC/MS: RT=2,62 minutes, MS: 418 (M+H).1H NMR (300 MHz, (CD3)2SO): δ 9,65 (1H, USS), and 7.7 and 7.5 (4H, m), 7,2 (2H, d, J=8,4 Hz), 6.87 in (2H, d, J=8,4 Hz), of 6.68 (1H, s), 4,4 (2H, s)4,08 (3H, s), 3,71 (3H, s), 3,6 (2H, m), 2,85 (2H, t, J=7.2 Hz). IC50=0.1 nm.

(c){2-Methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described in example 24(a) above, but replacing 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile [example 55] 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile, receive {2-methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine [310 mg, example 24(c)]. LC/MS: RT=2,43 minutes, MS: 434 (M+H). IC50=0.5 nm.

Example 25

(a)N-(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide

A solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [100 mg, 0.26 mmol, example 35(a)], methanesulfonamide (38 mg, 0.4 mmol) and dimethylpyridin-4-ylamine (64 mg, of 0.53 mmol) in DCM (5 ml) is treated with the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (101 mg, of 0.53 mmol). After 8 hours at 20°C the mixture is diluted with water, acidified (citric acid to pH 2) and extracted with DCM. The extracts are dried over magnesium sulfate, filtered and concentrated. OST is OK purified flash chromatography on silica gel with elution with 10% MeOH in DCM and get N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide [53 mg, 45%, example 25(a)]. LC/MS: RT=2,35 minutes, MS: 457 (M+H).1H NMR (300 MHz, CDCl3): δ 8,3 (1H, s), 8,08 (1H, USS), and 7.9 (1H, d, J=4,8 Hz), 7,34 (1H, USS), 7,12 (2H, d, J=8,4 Hz), PC 6.82 (2H, d, J=8,4 Hz), 6,46 (1H, USS), 6 (1H, USS), 3,91 (3H, s), 3,76 (3H, s), 3,61 (2H, USS), and 3.31 (3H, ), of 2.86 (2H, t, J=6.9 Hz).

(b)3-{6-[2-(3,4-Acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamid

A solution of 3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid [0.15 mmol, example 35(k)], hydroxybenzotriazole (41 mg, 0.3 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (58 mg, 0.3 mmol), N-(2-amino-ethyl)pyrrolidine (38 μl, 0.3 mmol) and N,N-diisopropylethylamine (105 μl, 0.6 mmol) in DCM (3 ml) was stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was poured into water (20 ml) and twice extracted with EtOAc (25 ml). The organic extracts are mixed, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The resulting solid is purified flash chromatography on a column of silica gel with elution with a mixture of from 10 to 60% EtOAc in heptane and get 3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamide [18 mg, 24%), example 25(b)]. LC/MS: RT=2.1 minutes, MS: 506 (M+H). IC50=30 nm.

Example 26

(a)The reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrim the DIN-4-yl}benzaldehyde

A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [700 mg of 1.84 mmol, example 35(j)], sodium acetate (2.5 g, 18.4 mmol) and hydroxylamine hydrochloride (1.3 g, 18.4 mmol) in EtOH (95%, 20 ml) is stirred for 20 hours at 20°C. the Reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered through silica gel and concentrated, obtaining the reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [0,86 g, 100%, example 26]. LC/MS: RT=2,53 minutes, MS: 397 (M+H). IC50=4,5 nm.

(b)The oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde

By a method similar to that described in example 26(a) above but: (i) replacing 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [25 mg, example 35(u)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde and conducting the reaction for 6 hours at 20°C, receive the oxime 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [15,2 mg, 58%, example 26(b)]. LC/MS: RT=2,27 minutes, MS: 379 (M+H).

(c)The reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde

By a method similar to that described in example 26(a) above, but replacing the 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [510 mg, example 35(y)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde and conducting the reaction at 20°C for 15 hours to obtain the reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [0,54 g, 100%, example 26(c)]. LC/MS: RT=3,37 minutes, MS: 409 (M+H).

(d)The oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde

By a method similar to that described above in example 26(a), but replacing 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [105 mg, example 35(l)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde by reaction under reflux and purifying the reaction product by chromatography on a column of treated EtOAc, and the elution of ammonia (2M in methanol, get the oxime 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [45 mg, 41%, example 26(d)]. LC/MS: RT=6,28 minutes. MS: 385 (M+H). IC50=0.4 nm.

(e)The oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone

By a method similar to that described in example 26(a) above, but substituting 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)Etalon [example 35(m)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde and spending is eakly under reflux for 4 hours, get the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone [88 mg, 85%, example 26(e)]. LC/MS: RT=to 7.77 minutes. MS: 399 (M+H). IC50=0.8 nm.

(f)The reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde

By a method similar to that described above in example 26(a), but replacing 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [200 mg, example 8(b)] 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde by reaction under reflux for 2 hours, and purifying the reaction product by chromatography on silica gel with elution with a mixture of EtOAc and cyclohexane, get the oxime 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [121 mg, 58%, example 26(f)]. LC/MS: RT=7.2 minutes. MS: 385 (M+H).

Example 27

Hydrochloride [6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

A mixture of oxime 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [860 mg, example 26(a)] in acetic acid (10 ml) is treated with zinc dust (0.6 g, 9.2 mmol). After 1 hour at 20°C, the reaction mixture was filtered through cellit, concentrated, diluted with 1M solution of sodium hydroxide and extracted with ethyl acetate. Extracts sushi is t over magnesium sulfate, filtered and purified by chromatography on silica gel with elution with 10% MeOH in DCM, getting free base which was treated with saturated HCl in EtOAc and receive hydrochloride [6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [720 mg, example 27]. LC/MS: RT=1,88 minutes, MS: 383 (M+H). IC50=41 nm.

Example 28

The hydrochloride of N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate

A solution of [6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [200 mg, 0.52 mmol, see example 27) and triethylamine (264 mg, 2,61 mmol) in DCM (5 ml) is treated with methoxyacetanilide (114 mg, 1.1 mmol) at 0°C. After 15 hours at 4°C in the refrigerator the mixture was quenched with water (10 ml) and filtered through a Chem-Elut. The filtrate is concentrated and purified by chromatography on silica gel with elution with 10% MeOH in DCM, receiving N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate, which is treated with a saturated solution of hydrochloric acid in EtOAc, followed by lyophilization, getting hydrochloride N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate [190 mg, 74%, example 28]. LC/MS: RT=2,35 minutes, MS: 455 (M+H). IC50=9 nm.

Example 29

[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-m is ylpropyl]Amin

Stage 1. To a solution of (4-methoxyphenyl)acetonitrile [5 g, 34 mmol] in THF (40 ml) was added 1,5M solution diisopropylamide lithium in cyclohexane (36 ml, 54 mmol) at -78°C. After 2 hours at -78°C add methyliodide (3.4 g, 54 mmol) and heat the mixture to room temperature within 3 hours. After another 12 hours at 20°C the mixture is diluted with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on silica gel with elution with a mixture of 40% EtOAc in heptane and get a mixture of 2-(4-ethoxyphenyl)propionitrile and 2-(4-methoxyphenyl)-2-methylpropionitrile. In the mixture (5 g) in THF (20 ml) is added 2M solution of lithium aluminum hydride (35 ml, 70 mmol) at 0°C. After 12 hours at 20°C the mixture was carefully quenched with a solution of 10% sodium hydroxide and the resulting white slurry was diluted with ether. The mixture is dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on silica gel, obtaining 2-(4-methoxyphenyl)-2-methylpropylamine [2 g, 33%intermediate, compound (35)]. MS: 180 (M+H).

Stage 2. A mixture of 2-(4-methoxyphenyl)-2-methylpropylamine [172 mg, 0.96 mmol, intermediate compound (35)], sodium bicarbonate (0.12 g) and 4-chloro-2-methoxy-6-(3-methoxyphenyl)pyrimidine [120 mg, 0.48 mmol, intermediate compound (53)] N-methylpyrrolidone (3 ml) is heated to 175°C in accordance with the s 3 hours. The mixture is diluted with water and extracted with ethyl acetate. The extracts washed with water, dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on silica gel with elution with a mixture of 30% EtOAc in heptane and receive [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-methylpropyl]Amin [131 mg, 69%, example 29]. LC/MS: RT=2,73 minutes, MS: 394 (M+H).1H NMR (300 MHz, CDCl3): δ to 7.59 (1H, s), 7,51 (1H, d, J=7.8 Hz), 7,35-7,27 (3H, m), of 6.96 (1H, DD, J=8,1, 2.4 Hz), to 6.88 (2H, d, J=9 Hz), of 6.31 (1H, s), was 4.02 (3H, s), 3,86 (3H, s), with 3.79 (3H, s), 3,62 (2H, USS), 1,4 (6H, s). IC50=792 nm.

Example 30

[2-(2-Chloro-6-forfinal)ethyl]-[6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino-4-yl]amine

Stage 1. A mixture of 2-methoxy-5-pyridylamino acid (600 mg, 2.04 mmol, intermediate compound (37), obtained as described in J. Org. Chem., 67, 7541, 2002), 4,6-dichloro-2-methylsulfonylamino [700 mg and 3.59 mmol, intermediate compound (29)] and Cs2CO3(2.9 g, 8,97 mmol) in dimethyl ether of ethylene glycol (8 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) at room temperature. After 3 hours at 85°C the mixture was diluted with water (50 ml) and twice extracted with EtOAc (50 ml). The extracts are dried over magnesium sulfate, filtered and concentrated, obtaining 4-chloro-6-(6-methoxypyridine-3-yl)-2-m is tranferability [1.1 g, the intermediate compound (38)] in the form of oil. LC/MS: RT=3,72 minutes, MS: 268 (M+H).

Stage 2. A mixture of 2-(2-chloro-6-forfinal)ethylamine [1,02 g, 5,88 mmol, intermediate compound (23)], Na2CO3(1,65 g and 19.6 mmol) and 4-chloro-6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino [1,05 g, to 3.92 mmol, intermediate compound (38)] N-methylpyrrolidone (10 ml) is heated to 175°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracts washed with water, dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on a short column of silica gel with elution EtOAc and receive [2-(2-chloro-6-forfinal)ethyl]-[6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino-4-yl]Amin [1.5 g, example 30]. LC/MS: RT=3,37 minutes, MS: 405 (M+H).

Example 31

5-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methylsulfonylamino-4-yl}-1H-pyridine-2-he

A solution of [2-(2-chloro-6-forfinal)ethyl]-[6-(6-methoxypyridine-3-yl)-2-methylsulfonylamino-4-yl]amine [1.5 g, 3.7 mmol, example 30] and conc. hydrochloric acid (5 ml) in EtOH (95%, 30 ml) heated to 90°C for 15 hours and concentrated. The residue is diluted with water and adjusted the pH to 7. The resulting solid is filtered and dried, obtaining5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methylsulfonylamino-4-yl}-1H-pyridin-2-[1.1 g, 76%, example 31]. The x/MS: R T=3,12 minutes, MS: 391 (M+H).

Example 32

5-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-he

To the mixture obtained above 5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methylsulfonylamino-4-yl}-1H-pyridine-2-it [1 g, 2.56 mmol, example 31] in a mixture of MeOH (30 ml) and DCM (20 ml) is added 3-chloroperoxybenzoic acid (70%, of 1.32 g of 7.68 mmol) at room temperature. After 3 hours at 20°C add 25% solution of sodium methoxide in MeOH (12 ml) at 0°C. after 1 hour the mixture was concentrated, diluted with water and neutralized 3M hydrochloric acid (pH 7). The formed solid is filtered and re-dissolved in the basic solution (pH 12). After acidification to pH 3 precipitate is filtered and dried, obtaining 5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridin-2-[0,92 g, 96%, example 32] in the form of solids. LC/MS: RT=2,23 minutes, MS: 375 (M+H).

Example 33

5-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-he

Stage 1. A solution of methyl ester (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid [220 mg, 0.49 mmol, example 22(d)] in a mixture of MeOH (5 ml) and DCM (2 ml) is treated with hydrazinehydrate (of 0.18 ml, 5.8 mmol). After 15 hours at 20°C the mixture of concentrate and p is to obtain the hydrazide (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid.

MS: 447 (M+H). The substance is used without additional purification.

Stage 2. In a mixture of hydrazide (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl) acetic acid and triethylamine [0.33 ml, 2.35 a mmol] in N-methylpyrrolidine (2 ml) is added 1,1-carbonyldiimidazole (0.29 grams, of 1.76 mmol) at room temperature. After 24 hours at 20°C the mixture is diluted with water and acidified with 1M hydrochloric acid (pH 5.5). The formed solid is filtered, washed with water and ether and dried, yielding 5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-he [108 mg, 47%, example 33] in the form of solids. LC/MS: RT=was 2.76 minutes, MS: 473 (M+H). IC50=1.2 nm.

Example 34

(a)Hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it

Stage 1. A mixture of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile [example 22(e)] and hydroxylamine hydrochloride (1.4 g, 20 mmol) in MeOH (35 ml) and DCM (15 ml) is treated with 25% solution of sodium methoxide in MeOH (3.4 ml, 15 mmol) at room temperature. After 24 hours at 20°C the mixture is concentrated, diluted with water and filtered, obtaining 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl-phenoxy)-N-hydroxyacetamido [intermediate compounds is their (39)]. [MS: 462 (M+H)].

Stage 2. A solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-elfenix)-N-hydroxyacetamido [intermediate compound (39)] and 1,8-diazabicyclo[5,4,0]undec-7-ene (0,61 ml, 4.1 mmol) in N-methylpyrrolidine (2 ml) is treated with 1,1-carbonyl diimidazol (0.5 g, 3.1 mmol) at room temperature. After 20 hours at 20°C the mixture is diluted with water, acidified with 1M hydrochloric acid (pH 3.0) and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, concentrated and receive 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-intenacional)-4H-[1,2,4]oxadiazol-5-he that is treated with saturated hydrogen chloride in ethyl acetate, lyophilizers and receive hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-intenacional)-4H-[1,2,4]oxadiazol-5 - [200 mg, example 34(a)] in the form of solids. LC/MS: RT=2,73 minutes, MS: 488 (M+H).

(b)Hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-it

By a method similar to that described in example 34(a) above but: (i) replacing (3-{2-methoxy-6-[2-(2-chloro-6-forfinal)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile in stage 1, and conducting the reaction at room temperature for 2 days (conversion of 40%), receive 2-(3-{6-[-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-hydroxyacetamido [intermediate compound (40), MS: 430 (M+H)]; and (ii) substituting 2-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-hydroxyacetamido [intermediate compound (40)] 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-elfenix)-N-hydroxyacetamido in stage 2, receive hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-he [example 34(b)]. LCMS: RT=2,32 minutes, MS: 456 (M+H). IC50=1 nm.

(c)Hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it

By a method similar to that described in example 34(a) above but: (i) replacing (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile [164 mg, example 22(f)] (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile, get 2-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-N-hydroxyacetamido (166 mg, 94%), (ii) substituting 2-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-N-hydroxyacetamido 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-elfenix)-N-hydroxyacetamido and (iii) chromatographia product on silica gel with elution with a mixture of from 0 to 7% MeOH in DCM receive hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-she [example 34(c)] as Tverdov the matter. LC/MS: RT=2.4 minutes, MS: 472 (M+H).1H NMR (300 MHz, (CD3)2SO): δ 12,82 (1H, USS), 7,18-of 7.55 (7H, m), and 6.6 (1H, s), is 5.18 (2H, s), 4 (3H, s), 3,68 (2H, m), is 3.08 (2H, m). IC50=0.3 nm.

Example 35

(a)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid

A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [300 mg, of 1.02 mmol, intermediate compound (8)], 3-carboxybenzeneboronic acid [339 mg, 2.04 mmol, intermediate compound(20)] and Cs2CO3(1.66 g, 5.1 mmol) in dimethyl ether of ethylene glycol (8 ml) and water (2 ml), rinsed with argon for 5 minutes. The mixture was added tetrakis(triphenylphosphine)palladium(0) (59 mg, 0,051 mmol), a reaction chamber is sealed and heated to 90°C. After stirring for 17 hours the mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The aqueous layer was acidified to pH 6 with 10% hydrochloric acid and twice extracted with EtOAc (50 ml). Organic extracts of the acid solution are mixed, dried over magnesium sulfate, filtered, concentrated and receive 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [350 mg, 90.4 percent, example 35(a)] in the form of solids. JHMS: RT=2,69 minutes, MS: 380 (M+H).1H NMR [(CD3)2SO]: δ charged 8.52 (1H, s)8,28 (3H, m), 8 (2H, m), to 7.61 (2H, t, J=0,027 Hz), 7,47 (1H, m), 7,17 (2H, d, J=0,027 Hz), 6,85 (2H, d, J=0,027 Hz), 6,69 (1H, s)to 3.89 (3H, s), 3,71 (3H, s), 2,8 (2H, t, J=0,024 Hz).

(b)3-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid

By a method similar to that described in example 35(a), but replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine [503 mg, 1,45 mmol, intermediate compound (13)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and precrystallization from EtOH, get 3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid [95 mg, 15%, example 35(b)]. LC/MS: RT=2,93 minutes, MS: 434 (M+H).

(c)[2-(3,4-Acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl)Amin

Stage 1. By a method similar to that described in example 1, step 3, but replacing 2-(3,4-acid)ethylamine [intermediate compound (41)] 2-(3-fluoro-4-methoxyphenyl)ethylamine, get (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine [intermediate compound (42)].

Stage 2. By a method similar to that described in example 35(a) above but (i) replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine [132 mg, 0.41 mmol, intermediate compound (42)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, (ii) substituting 2-tiefenbronn acid (63 mg, 0.49 mmol) 3-carboxybenzeneboronic acid and (iii) purifying the reaction product flash chromatography on a column of C is imaginem with gradient elution with a mixture of from 0 to 30% EtOAc in heptane, get [2-(3,4-acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl)amine [9.1 mg, 6%, example 35(c)]. LC/MS: RT=2,56 minutes, MS: 372 (M+H).

(d)[2-(3,4-Acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl]amine

By a method similar to that described in example 35(a) above but (i) replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine [100 mg, intermediate compound (42)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, (ii) substituting 2-Farnborough acid (69 mg) for 3-carboxybenzeneboronic acid and (iii) purifying the reaction product flash chromatography on a column of silica gel with gradient elution with a mixture of from 0 to 30% EtOAc in heptane, to obtain [2-(3,4-acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl)amine [32.4 mg, 30%, example 35(d)]. LC/MS: RT=2.18 minutes, MS: 356 (M+H). IC50=256 nm.

(e)(6-Biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine

By a method similar to that described in example 35(a) above but (i) replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine [100 mg, intermediate compound (42)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, (ii) replacing 4-biphenylmethanol acid (122 mg) for 3-carboxybenzeneboronic acid and (iii) purifying the reaction product flash chromatography on a column of silica gel (10 g) is a gradient elution with a mixture of from 20 to 60% EtOAc in heptane, get (6-biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine [79,7 mg, 58.6%of example 35(e)]. LC/MS: RT=3,05 minutes, MS: 442 (M+H).1H NMR (300 MHz, CDCl3): δ at 8.36 (1H, d, J=0,027 Hz), of 8.09 (2H, d, J=0,027 Hz), to 7.84 (1H, d, J=0,027 Hz), 7,78 (1H, d, J=0,027 Hz), 7,68 (9H, m), 7,45 (4H, m), at 6.84 (1H, t, J=0,027 Hz), 6,79 (2H, m), 6,44 (1H, s), is 4.93 (1H, s), 4,77 (1H, s)4,07 (3H, s)of 3.9 (6H, s), and 3.72 (2H, m)to 2.94 (2H, t, J=0,022 Hz). IC50=369 nm.

(f)Hydrochloride 3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

Stage 1. By a method similar to that described in example 1, step 3, but replacing 2-(4-forfinal)ethylamine for 2-(3-fluoro-4-methoxyphenyl)ethylamine, get (6-chloro-2-methoxypyridine-4-yl)-[2-(4-forfinal)ethyl]amine [intermediate compound (43)]. LC/MS: RT=3,22 minutes, MS: 282 (M+H).

Stage 2. By a method similar to that described in example 35(a), but (i) replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(4-forfinal)ethyl]amine [132 mg, 0.41 mmol, intermediate compound (43)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and (ii) treating the reaction product with hydrogen chloride in ethyl acetate to obtain hydrochloride of 3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [54 mg, 16.5 percent, example 35(f)]. LC/MS: RT=2,47 minutes, MS: 368 (M+H).

(g)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide

By a method similar to OPI is anomo above in example 35(a), but replacing (3-aminocarbonylmethyl)baronova acid 3-carboxybenzeneboronic acid, receive 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [example 35(g)].

(h)1-(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)alanon

By a method similar to that described above in example 35(a), but replacing 3-acetylphenylalanine acid 3-carboxybenzeneboronic acid, receive 1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon [example 35(h)]. LC/MS: RT=2.57 m minutes, MS: 378 (M+H). IC50=5 nm.

(i)3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol

Stage 1. By a method similar to that described in example 1, step 3, but replacing 2-(2,4-dichlorophenyl)ethylamine for 2-(3-fluoro-4-methoxyphenyl)ethylamine, get (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [intermediate compound (44)].

Stage 2. By a method similar to that described in example 35(a), but (i) replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [intermediate compound (44)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and (ii) 3-hydroxyphenylarsonic acid 3-carboxybenzeneboronic acid, receive 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol [example 35(i)]. LC/MS: RT=2.57 m minutes, MS: 390 (M+H).

(j)u> 2-Fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde

By a method similar to that described above in example 35(a), but replacing 4-fluoro-3-formylbenzeneboronic acid 3-carboxybenzeneboronic acid will receive 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [example 35(j)]. LC/MS: RT=2,77 minutes, MS: 382 (M+H).

(k)3-{6-[2-(3,4-Acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid

By a method similar to that described in example 35(a), but replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, get 3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid [example 35(k)]. LC/MS: RT=2,39 minutes, MS: 410 (M+H).

(l)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde

By a method similar to that described above in example 35(a), but replacing 2-formyl-3-tiefenbronn acid (797 mg) for 3-carboxybenzeneboronic acid, receive 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [450 mg (36%, example 35(l)]. LC/MS: RT=7,42 minutes. MS: 370 (M+H).

(m)1-(5-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)alanon

By a method similar to that described above in example 35(a), but replacing 5-acetyl-2-tiefenbronn acid 3-carboxybenzeneboronic acid, receive 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)Etalon [200 mg, 51%, example 35(m)]. IC50=3,8 nm.

(n)Hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

Stage 1. A solution of 4,6-dichloro-2-methoxypyridine [0.7 g, the intermediate compound (4)], 2-(4-chlorophenyl)ethylamine (0.66 g) and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated to 80°C for three hours, poured into water (400 ml), the solid is filtered, air-dried and receive (6-chloro-2-methoxypyridine-4-yl)-[2-(4-chlorophenyl)ethyl]amine [1.1 g, the intermediate compound (14)]. MS: 299 (M+H).1H NMR [(CD3)2SO]: δ 8 (d, 2H, J=3 Hz); of 7.4 (2H, d, J=3 Hz); 6,05 (1H, s); 4 (3H, s); 3,6-3,7 (2H, m); 2,95 (2H, t).

Stage 2. By a method similar to that described in example 35(a), but replacing (6-chloro-2-methoxypyridine-4-yl)-[2-(4-chlorophenyl)ethyl]amine [intermediate compound (14)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and treating the reaction product with 1.2 equivalent of hydrogen chloride in ether (1M) followed by evaporation and the friction in the air, get hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid, [1,1 mg, example 35(n)] in the form of solids. MS: 84 (M+H). 1H NMR (CDCl3): δ 8,5 (1H, s); 8 (2H, d, J=5,1 Hz); 7,9 (1H, m); and 7.6 (1H, t); 7,2-7,4 (4H, m); and 6.6 (1H, s); of 3.95 (3H, s); 3,7 (2H, t); 3 (2H, t). IC50or =0.6 nm.

(o)[2-Methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine (600 mg, 2.04 mmol), 2-methoxy-5-pyridylamino acid (469 mg, a 3.06 mmol, obtained according to the procedure described in J. Org. Chem., 2002, 67, 7541) and Cs2CO3(1.66 g, 5,11 mmol) in dimethyl ether of ethylene glycol (8 ml) and water (2 ml) at room temperature Tegaserod with argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.1 mmol). The mixture is heated at 85°C for 5 hours, diluted with water (50 ml) and twice extracted with EtOAc (50 ml). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of EtOAc and heptane (1:1, vol/vol.), receiving [2-methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [0.75 g, 100%, example 35(o)] in the form of oil. LC/MS: RT=2,74 minutes, MS: 367 (M+H).1H NMR (300 MHz, CDCl3): δ 8,78 (1H, d, J=2.1 Hz), 8,21 (1H, DD, J=8,7, 2.4 Hz), 7,16 (2H, d, J=8,4 Hz), to 6.88 (1H, DD, J=8,7, 2.4 Hz), PC 6.82 (2H, d, J=8,4 Hz), and 6.3 (1H, s), of 4.95 (1H, USS), a 4.03 (3H, s), was 4.02 (3H, s), 3,82 (3H, ), and 3.72-3,63 (2H, s), of 2.92 (2H, t, J=6.9 Hz). IC50=1,7 nm.

(p)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-and the}phenol

By a method similar to that described above in example 35(o), but substituting commercially available 3-hydroxyphenylarsonic acid 2-methoxy-5-pyridylamino acid and filtering the reaction product on a short column of silica gel, get 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol [1.1 g, example 35(p)].

(q)[2-(4-Methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-4-Yeremey-4-yl)Amin

By a method similar to that described above in example 35(o), but substituting commercially available 4-pyridylamino acid 2-methoxy-5-pyridylamino acid and purifying the reaction product by chromatography on silica gel with elution MeOH in DCM (5:95.vol.), get [2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-4-Yeremey-4-yl)amine [129 mg, example 35(q)]. LC/MS: RT=2,35 minutes, MS: 337 (M+H). IC50=8 nm.

(r)2-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol

By a method similar to that described above in example 35(o), but substituting commercially available 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 2-methoxy-5-pyridylamino acid and rubbing in the air of the raw reaction product, get 2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol [143 mg, example 35(r)] in the form of solids. LC/MS: RT=is 3.08 is displaced, MS: 352 (M+H). IC50=17 nm.

(s)(3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile

By a method similar to that described above in example 35(o), but substituting commercially available pinacoline ether (3-cyanomethylene)Bronevoy acid 2-methoxy-5-pyridylamino acid and purifying the reaction product by chromatography on silica gel with elution with 60% EtOAc in heptane, to obtain (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile [350 mg, example 35(s)]. LC/MS: RT=2,48 minutes, MS: 375 (M+H). IC50=6 nm.

(t)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile

By a method similar to that described above in example 35(o), but substituting commercially available 3-cyanoaniline acid 2-methoxy-5-pyridylamino acid and purifying the reaction product by chromatography on silica gel with elution with 40% EtOAc in heptane, to obtain 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)benzonitrile [220 mg, example 35(t)]. LC/MS: RT=3,15 minutes, MS: 361 (M+H). IC50=0,9 nm.

(u)3-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde

By a method similar to that described above in example 35(o), but substituting commercially available 3-formylphenylboronic acid is the 2-methoxy-5-pyridylamino acid and purifying the reaction product by chromatography on silica gel with elution with a mixture of 40-60% EtOAc in heptane, get 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [12,4 mg, example 35(u)]. LC/MS: RT=3,05 minutes, MS: 364 (M+H).

(v)3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde

Stage 1. Following a method similar to that described in example 1, step 3, but using 4,6-dichloro-2-methoxypyridine [3.1 g, the intermediate compound (4)], 2-(2-chloro-6-forfinal)ethylamine [1.84 g, the intermediate compound (23)] and sodium bicarbonate (2,02 g) receive (6-chloro-2-methoxypyridine-4-yl)-[2-(2-chloro-6-forfinal)ethyl]amine [3,2 g of the intermediate compound (24)] in the form of a white solid. LC/MS: RT=3,63 minutes, MS: 317 (M+H).

Stage 2. By a method similar to that described above in example 35(o), but substituting commercially available 3-formylphenylboronic acid [intermediate compound (25)] 2-methoxy-5-pyridylamino acid and (6-chloro-2-methoxypyridine-4-yl)-[2-(2-chloro-6-forfinal)ethyl]amine [2 g of the intermediate compound (24)obtained in stage 1] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, get 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde [2.76 g, example 35(v)]. LC/MS: RT=3.2 minutes, MS: 386 (M+H). IC50=3,6 nm.

(w)3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

M is Todd, similar to that described above in example 35(o), but substituting commercially available 3-carboxybenzeneboronic acid 2-methoxy-5-pyridylamino acid and (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [2 g of the intermediate compound (44)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine and extragere crude reaction mixture was brought to pH 2 with by using EtOAc receive 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [2.5 g, example 35(w)]. IC50=0.3 nm.

(x)[2-Methoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described above in example 35(o), but substituting commercially available 3-pyridylamino acid 2-methoxy-5-pyridylamino acid and purifying the reaction product by chromatography on silica gel with elution with 5% MeOH in DCM, receive [2-methoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [45 mg, example 35(x)]. LC/MS: RT=2,33 minutes, MS: 337 (M+H). IC50=10 nm.

(y)2-Methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde

By a method similar to that described above in example 35(o), but substituting commercially available 3-formyl-4-methoxybutanol acid 2-methoxy-5-pyridylamino acid and rubbing the reaction product in the air, the floor is given 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [780 mg, example 35(y)]. LC/MS: RT=2,55 minutes, MS: 394 (M+H).

(z)Ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid

Stage 1. In nitrogen atmosphere in the flask with a round bottom volume of 50 ml was placed bis(pinacolato)DIBORANE (1,16 g, 4,55 mmol), potassium acetate (1,11 g of 11.4 mmol) and ethyl ester of 5-bromo-2-chlorbenzoyl acid (1 g, with 3.79 mmol). After blowing the mixture with nitrogen for 5 minutes add adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium in DCM [PdCl2(dppf), 93 mg, 0.11 mmol]. The resulting mixture was heated to 60°C for 2 hours, cooled to room temperature and poured into EtOAc (50 ml). The mixture is washed with water and brine, dried over sodium sulfate, filtered and concentrated, obtaining the ethyl ester of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid [LC/MS: RT=5.1 minutes, MS: 311 (M+H)] and dimenisonal by-product dimethyl ether, 4,3'-dichloro-biphenyl-3,4'-bicarbonate acid in a ratio of 2:1 (0.65 g). The crude mixture was used in the next stage without additional purification.

Stage 2. By a method similar to that described in example 35(o) above, but substituting the crude ethyl ester of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzoic acid obtained in stage 1 above, 2-methoxy-5-pyridylamino acid and purifying the crude about the SPS chromatography on a short column of silica gel, get the ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [0.21 g, example 35(z)]. LC/MS: RT=3,28 minutes, MS: 442 (M+H). IC50=32 nm.

Example 36

{2-Methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. To a solution of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid [200 mg of 0.53 mmol, example 35(a)] in dimethylformamide (1.75 ml) add diisopropylethylamine (0,23 ml of 1.33 mmol), and then TBTU (205 mg, 0.64 mmol). The solution is stirred for 15 minutes and then add the oxime ndimethylacetamide (59 mg, 0.8 mmol). After 4 hours stirring at ambient temperature the mixture is diluted with water (20 ml) and twice extracted with EtOAc (20 ml). The combined organic extracts washed three times with water (20 ml) and brine (20 ml), dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and receive N-(1-iminoethyl)-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [60 mg, 69%, intermediate compound (45)].

Stage 2. A solution of N-(1-iminoethyl)-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [160 mg, 0,367 mmol, intermediate compound (45)] in THF (2 ml) double-treated in a microwave oven at 140°C for 4 minutes. The reaction mixture was applied to silica gel and the sight of the try flash chromatography on silica gel (9 g) with gradient elution with a mixture of from 0 to 50% EtOAc in heptane, receiving {2-methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine [41 mg, 27%, example 36]. LC/MS: RT=2.9 minutes, MS: 418 (M+H).1H NMR (300 MHz, CDCl3): δ 8,64 (1H, s), compared to 8.26 (1H, dt, J=0,027, 0,0044 Hz), 8,15 (1H, dt, J=0,027, 0,0044 Hz), to 7.59 (1H, t, J=0,026 Hz), 7,14 (2H, d, J=0,029 Hz)6,86 (2H, d, J=0,029 Hz), to 6.43 (1H, s), 4,94 (1H, s), Android 4.04 (3H, s), of 3.78 (3H, ), of 3.69 (2H, m), 2,9 (2H, t, J=0,022 Hz), 2.49 USD (3H, s). IC50=2,6 nm.

Example 37

{2-Methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. A mixture of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [50 mg, 0,132 mmol, example 35(g)] and dimethylacetal dimethylacetamide (2 ml) hermeticum in a vessel and heated at 110°C for 45 minutes. The mixture is concentrated on a rotary evaporator and receive N-(1-dimethylaminoethyl)-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [intermediate compound (46)] with a quantitative yield.

Stage 2. A solution of N-(1-dimethylaminoethyl)-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide [0,132 mmol, intermediate compound (46)] and hydrazine hydrate is added (15 μl, 0.48 mmol) in acetic acid (1 ml) heated to 90°C. After 30 minutes stirring the mixture no longer be heated, quenched with a saturated solution of sodium bicarbonate (20 ml) and twice extracted with EtOAc (20 ml). The organic extracts are dried n the l magnesium sulfate, filtered and concentrated on a rotary evaporator. The resulting oil purified flash chromatography on silica gel with gradient elution with a mixture of 40% EtOAc in heptane, getting {2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine [38 mg, 69%, example 37]. LC/MS: RT=2,59 minutes, MS: 417 (M+H). IC50=3,7 nm.

Example 38

{2-Methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. A mixture of 1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)ethanone [125 mg, 0.33 mmol, example 35(h)] and dimethylacetal dimethylacetamide (2 ml) in a round bottom flask heated at 90°C for 4 hours. The reaction mixture is treated with water (20 ml) and thrice extracted with EtOAc (20 ml). The mixture of organic substances are dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and receive 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)-but-2-EN-1-[intermediate compound (47)] with a quantitative yield.

Stage 2. In a sealed vessel mix 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)-but-2-EN-1-[60 mg, 0,134 mmol, intermediate compound (47)], hydroxylamine (40 mg) and EtOH (3 ml). The mixture is heated at 95°C with stirring for 6 hours and concentrate the Resulting oil purified flash chromatography on silica gel with gradient elution with a mixture of 40% EtOAc in heptane, receiving {2-methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine [56 mg, 100%, example 38] in the form of solids. LC/MS: RT=2,82 minutes, MS: 417 (M+H). IC50=6 nm.

Example 39

{2-Methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine

In a sealed vessel mix 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)but-2-EN-1-[147 mg, 0.33 mmol, intermediate compound (47), obtained as described in example 38, step 1], hydrazinehydrate (200 μl) and EtOH (3 ml). The mixture is heated to 85°C and stirred for 1.5 hours. The reaction mixture was concentrated and get the oil, which is purified flash chromatography on silica gel with gradient elution with a mixture of from 20 to 60% EtOAc in heptane, getting {2-methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine [136 mg, 99%, example 39]. LC/MS: RT=2,79 minutes, MS: 416 (M+H).1H NMR (300 MHz, CDCl3): δ 8,29 (1H, s), and 7.9 (1H, d, J=0,027 Hz), 7,72 (1H, d, J=0,025 Hz), and 7.4 (1H, t, J=0,026 Hz), to 7.09 (2H, d, J=0,028 Hz), PC 6.82 (2H, d, J=0,028 Hz), 6.35mm (2H, d, J=0,024 Hz), 5,18 (1H, s), 3,98 (3H, in), 3.75 (3H, C)and 3.59 (2H, m), and 2.83 (2H, t, J=0,023 Hz), 2,3 (3H, s).

Example 40

[2-(3-Fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}Amin

A solution of 3-{6-[2-(3-fluoro-4-methoxyphenyl)is thylamino]-2-methoxypyridine-4-yl}benzonitrile [1.5 g, example 1] and azide presence of TBT (1,66 ml) in toluene (80 ml) is heated at 115°C for 20 hours. The solution is cooled and treated with glacial acetic acid (20 ml)to give a white precipitate. The mixture was twice extracted with EtOAc (200 ml). The combined extracts dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on silica gel with elution EtOAc and receive [2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine [0,31 mg, example 40]. MS: 422 (M+H);1H NMR (CDCl3): δ 8,6 (1H, s); 8,1 (1H, d, J=5,1 Hz)); 7,9 (2H, m); and 7.6 (1H, t); 7-7,2 (4H, m); 6,7 (1H, s); of 3.95 (3H, s); and 3.8 (3H, s); 3,6 (2H, t); 2,8 (2H, t); 1,6 (1H, m); 1,3 (1H, m). IC50=0.4 nm.

Example 41

1-Ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea

To a solution of [6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [184 mg, 0.45 mmol, example 2] in pyridine (1.5 ml) is added utilizationa (43 μl, 0.54 mmol). The reaction mixture is stirred for 18 hours at ambient temperature, quenched by addition of water (25 ml) and extracted four times EtOAc (25 ml). The combined extracts are washed four times with an aqueous solution of copper sulfate (25 ml), water (25 ml), brine (25 ml), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The resulting solid is purified flash chrome is ografia on a column of silica gel (4.5 g) with elution with a mixture of from 20 to 40% EtOAc in heptane and get 1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea [98.3 mg, 52%, example 41]. LC/MS: RT= 2.68 minutes, MS: 422 (M+H).1H NMR (300 MHz, CDCl3) δ: 8,11 (1H, d, J=0,17 Hz), 7,88 (2H, s), a 7.62 (1H, d, J=0,026 Hz), 7,49 (1H, d, J=0,026 Hz), 7,18 (4H, m), for 6.81 (2H, m), from 6.22 (1H, d, J=0,08 Hz), of 5.83 (1H, s), to 5.35 (1H, s), 3,93 (3H, d, J=0,04 Hz), to 3.73 (3H, d, J=0,012 Hz), 3,55 (2H, m), 3,19 (2H, q, J=0,022 Hz), of 2.81 (2H, m), 2,13 (1H, s)1,04 (2H, t, J=0,022 Hz). IC50=7,6 nm.

Example 42

Ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid

A mixture of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol [945 mg, 2,42 mmol, example 35(i)], PS-TBD (to 3.38 g, 5 mmol), ethyl-2-bromoisobutyrate (888 ml, 605 mmol) and acetonitrile (20 ml) is heated under reflux and stirred for 2 hours. The heating is stopped and the mixture is stirred over night at room temperature. The reaction mixture is filtered to remove the polymer, and the polymer was washed with MeOH (20 ml) and acetonitrile (20 ml). The combined filtrates and washings are concentrated on a rotary evaporator. The residue is purified flash chromatography on silica gel (40 g) with gradient elution with a mixture of from 20 to 50% EtOAc in heptane and receive the ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid [450 mg, 37%, example 42]. LC/MS: RT=2.9 minutes, MS: 504 (M+H).

Example 43

(a)[2-(4-Chlorophenyl)-1-methylethyl]-[6-(3,4-acid)methoxypyridine-4-yl]amine

Stage 1. A mixture of 4,6-dichloro-2-(methylthio)pyrimidine [to 4.98 g, 25,55 mmol, intermediate compound (29)], 3,4-dimethoxyphenylacetic acid [3,874 g, 21,29 mmol, intermediate compound (32)] and Cs2CO3(17,34 g, 53,23 mmol) in dimethyl ether of ethylene glycol (56 ml) and water (14 ml), rinsed with argon for 15 minutes. The mixture was added tetrakis(triphenylphosphine)palladium(0) (1.22 g, 1.06 mmol) and the reaction container is heated to 100°C. After stirring overnight the mixture was diluted with water (250 ml) and thrice extracted with EtOAc (100 ml). The organic extracts are combined washed with brine (100 ml) and dried over magnesium sulfate. The mixture is filtered and concentrated, obtaining a solid substance, which is dissolved in boiling isopropyl alcohol (40 ml) and cooled to ambient temperature. After 24 hours, the solid is collected by filtration, washed with cold isopropyl alcohol and dried under high vacuum, receiving 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylsulfonylamino [5,28 g, 83.5%of intermediate compound (48)].

Stage 2. A solution of 4-chloro-6-(3,4-acid)-2-methylsulfonylamino [5,28 g, 0,0178 mol, intermediate compound (48)] in DCM (120 ml) cooled to 0°C. To the cooled solution add 3-chloroperoxybenzoic acid (9,66 g, 0,0392 mol). After 30 minutes the cooling bath is removed and the mixture paramesh what happens at room temperature over night. The resulting precipitate is collected by filtration and washed with DCM (50 ml). The organic filtrate is washed with an aqueous solution of sodium hydroxide (150 ml, 2 BC) and dried over magnesium sulfate. The mixture is filtered and concentrated, obtaining 4-chloro-6-(3,4-acid)-2-methanesulfonamide [of 5.05 g, 86%, intermediate compound (49)] as a solid substance.

Stage 3. A mixture of 4-chloro-6-(3,4-acid)-2-methanesulfonamide [of 5.05 g, 0,0154 mol, intermediate compound (49)] in dimethyl ether of ethylene glycol (100 ml) cooled to 0°C and add 25 wt.%/wt. of sodium methoxide in MeOH (1,32 ml, 0,0231 mol). After 15 minutes the reaction mixture is heated to ambient temperature and stirred overnight. The mixture of concentrate and get 4-chloro-6-(3,4-acid)-2-methoxypyridine [4.3 g, 100%, intermediate compound (50)].

Stage 4. To a solution of 4-chloro-6-(3,4-acid)-2-methoxypyridine [140 mg, 0.5 mmol, intermediate compound (50)] and N,N-diisopropylethylamine (392 μl, 2.25 mmol) in THF (1.7 ml) is added hydrochloride DL-para-chloroamphetamine [154, 6mm mg, 0.75 mmol, intermediate compound (51)]. The mixture is heated under reflux for 2 hours, quenched with water (20 ml) and twice extracted with EtOAc (20 ml). The combined extracts are concentrated and the residue purified flash chromatography on a column of silica gel with gradient elution with a mixture of from 0 to 50% EtOAc in heptane is, receiving [2-(4-chlorophenyl)-1-methylethyl]-[6-(3,4-acid)-2-methoxypyridine-4-yl]Amin [52,7 mg, 25.5%, example 43(a)]. LC/MS: RT=2,66 minutes, MS: 414 (M+H).1H NMR (300 MHz, CDCl3): δ the 7.65 (1H, d, J=of 0.066 Hz), 7,53 (1H, DD, J=of 0.066, 0,028 Hz), 7,28 (2H, d, J=0,028 Hz), 7,14 (2H, d, J=0,028 Hz), 6,93 (1H, d, J=0,028 Hz), of 6.31 (1H, s), 4.72 in (1H, s), 4,34 (1H, s), Android 4.04 (3H, s)to 3.99 (3H, s), of 3.95 (3H, s), 2,89 (2H, CVD, J=0,045, to 0.022 Hz)to 1.79 (1H, s)of 1.24 (3H, d, J=0,22 Hz). IC50=1726 nm.

(b)[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine

Stage 1. To a mixture of 4,6-dichloro-2-methylsulfonylamino [4.9 g, 25,12 mmol, intermediate compound (29)] and 3-methoxyphenylacetic acid [3,47 g, 22.84 to mmol] in dimethyl ether of ethylene glycol (40 ml) and water (10 ml) add Cs2CO3(18.6 g, to 57.1 mmol). Through a mixture of nitrogen purge for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (1,32 g to 1.14 mmol). A reaction chamber is sealed and heated at 90°C for 22 hours. The reaction mixture was quenched with 30 ml of water. The black precipitate is filtered, the filtrate is concentrated under vacuum and thrice extracted with EtOAc (100 ml). The organic layers are combined, washed with saline (20 ml) and dried over sodium sulfate. The mixture is concentrated and receiving the oil, which is purified column flash chromatography (silica gel: 0-7% ethyl acetate/heptane) and receive 4-chloro-6-(3-methoxyphenyl)-2-methylsulfinylphenyl is in [to 3.92 g, 64%, the intermediate compound (52)] in the form of solids. LC/MS: RT=4,14 minutes, MS: 267 (M+H).

Stage 2. To a solution of 4-chloro-6-(3-methoxyphenyl)-2-methylsulfonylamino [3,63 g, 13,61 mmol, intermediate compound (52)] in DCM (70 ml) is added 3-chloroperoxybenzoic acid (10,06 g, 40,83 mmol) and stirred at room temperature for 4 hours. The reaction mixture was quenched with 2 N. a sodium hydroxide solution to pH 9, extracted with DCM (3×100 ml). The organic layers are combined, washed with saline (10 ml) and dried over sodium sulfate. The mixture of concentrate and get 4-chloro-2-methanesulfonyl-6-(3-methoxyphenyl)pyrimidine [4.35 g, LC/MS: RT=3.3 minutes, MS: 299 (M+H)] in the form of solids. of 4.25 g of the substance dissolved in a mixture of MeOH (70 ml) and DCM (40 ml) and the solution process is added dropwise with sodium methoxide (25 wt.% in methanol, to 3.58 ml, 15,64 mmol). The mixture is stirred at room temperature for 2 hours, quenched with water (20 ml), concentrated to remove MeOH and DCM, and thrice extracted with EtOAc (100 ml). The combined extracts washed with brine (10 ml) and dried over sodium sulfate. The mixture is concentrated and receiving solid, which is purified flash chromatography (silica gel: 2-20% ethyl acetate/heptane) and receive 4-chloro-2-methoxy-6-(3-methoxyphenyl)pyrimidine [2,73 g, the output of the two stages of 80%, the intermediate compound (53)] in the form of solid substances is A. LC/MS: RT=3,84 minutes, MS: 251 (M+H).

Stage 3. To a solution of 4-chloro-2-methoxy-6-(3-methoxyphenyl)pyrimidine [80 mg, 0.32 mmol, intermediate compound (53)] and the hydrochloride of 2-(4-nitrophenyl)ethylamine (77,6 mg, 0.38 mmol) in EtOH (1.1 ml) add diisopropylethylamine (0,139 ml, 0.80 mmol). The reaction mixture is heated in a microwave oven at 170°C for 45 minutes. The solvent is removed and the residue purified flash chromatography (silica gel: 10-50% ethyl acetate/heptane)to give [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine [62 mg, 51%, example 43(b)] in the form of solids. LC/MS: RT=2.57 m minutes, MS: 381 (M+H).1H NMR (300 MHz, (CD3)2SO): δ to 8.14 (2H, d, J=9.8 Hz), 7,53 (2H, d, J=9.8 Hz), 7,52 (3H, m), 7,38 (1H, t, J=8.6 Hz), 7,01 (1H, m), to 6.58 (1H, s), of 3.84 (3H, s), with 3.79 (3H, s), 3,6 (2H, m), 2,99 (2H, m). IC50=0,9 nm.

(c)[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine

By a method similar to that described in example 43(b) above, but substituting 2-(4-trifloromethyl)ethylamine [intermediate connection 12] 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 and carrying out the reaction in a microwave oven at 170°C for 45 minutes, get [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine [88 mg, 44 %, example 43(c)] in the form of solids. LC/MS: RT=2,92 minutes, MS: 420 (M+H).1N I Is R (300 MHz, CDCl3): δ of 7.6 (1H, m), 7,55 (1H, d, J=9 Hz), 7,52 (1H, t, J=7.4 Hz), 7,24 (2H, d, J=9.8 Hz), 7,16 (2H, d, J=9.8 Hz), 6,99 (1H, m), 6,36 (1H, s), a 4.86 (1H, OSS), to 4.01 (3H, s), 3,86 (3H, s), 3,7 (2H, m), 2,96 (2H, m).

(d)Hydrochloride [2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described in example 43(b), but (i) replacing 2-(2-chloro-6-forfinal)ethylamine for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine which is dissolved in ether and treated with hcl 1M in ether, receiving hydrochloride [2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine [51 mg, 60%, example 43(d)] in the form of solids. LC/MS: RT=2,82 minutes, MS: 388 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7,12-of 7.48 (7H, m), and 6.6 (1H, s)to 3.99 (3H, s), 3,82 (3H, s)to 3.67 (2H, m), of 3.07 (2H, m).

(e)Hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-ileti]amine

By a method similar to that described in example 43(b), but (i) substituting 2-thiophene-2-ylethylamine 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-retil)amine which is dissolved in ether and treated with hcl 1M, getting hydrochloride [2-methoxy-6-(3-label iphenyl)pyrimidine-4-yl]-(2-thiophene-2-retil)amine [33,7 mg, 45%, example 43(e)] in the form of solids. LC/MS: RT=2,52 minutes, MS: 342 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7,32 and 7.5 (4H, m), 7,13 (1H, m), of 6.96 (2H, m), only 6.64 (1H, s), 4 (3H, s), and 3.8 (3H, s), 3,7 (2H, m), of 3.12 (2H, m). IC50=9,7 nm.

(f)3-{2-[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol

By a method similar to that described in example 1(a), but replacing the hydrochloride of 3-(2-amino-ethyl)-1H-indol-5-ol for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3, get 3-{2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol [19.5 mg, 25%), example 43(f)] in the form of solids. LC/MS: RT=2.13 minutes, MS: 391 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 10,46 (1H, s), 8,56 (1H, s)of 7.48 (2H, m), 7,38 (1H, m), 6,99 for 7.12 (3H, m), for 6.81 (1H, s), to 6.58 (2H, m), of 3.84 (3H, s), with 3.79 (3H, s), of 3.57 (2H, m), 2,84 (2H, m).

(g)Hydrochloride [2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described in example 43(b), but (i) replacing 2-(6-methoxy-1H-indol-3-yl)ethylamine for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine which is dissolved in ether and treated with 1M solution of hydrogen chloride in ether, receiving hydrochloride [2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-meth is xifei)pyrimidine-4-yl]amine [58,6 mg, 66%, example 43(g)] in the form of solids. LC/MS: RT=2,48 minutes, MS: 405 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ is 10.6 (1H, s), 7,3-7,5 (4H, m), 7,12 (1H, m), 7,02 (1H, m), 6,8 (1H, s), is 6.61 (2H, m)to 3.99 (3H, s), and 3.8 (3H, s), and 3.72 (3H, s)to 3.58 (2H, m)to 2.94 (2H, m). IC50=104 nm.

(h)Hydrochloride [2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described in example 43(b), but substituting 2-(5-methoxy-1H-indol-3-yl)ethylamine for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine which is dissolved in ether and treated with 1M solution of hydrogen chloride in ether getting hydrochloride [2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine [52,1 mg, 59%, example 43(h)] in the form of solids. LC/MS: RT=2,45 minutes, MS: 405 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 10,65 (1H, s), 7,41 (1H, m), of 7.36 (2H, m), 7,2 (1H, m), 7,13 (2H, m), 7,01 (1H, m), 6,7 (1H, DD, J=a 9.6, 1.2 Hz), and 6.6 (1H, s), 3,98 (3H, s), and 3.8 (3H, s), and 3.72 (3H, s), of 3.56 (2H, m), of 2.97 (2H, m,).

(i)Hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)Amin

By a method similar to that described in example 43(b), but replacing 2-pyridine-3-ylethylamine 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3, the floor is given [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)amine, which is dissolved in ether and treated with 1M solution of hydrochloric acid in ether, receiving hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)amine [33,2 mg, 45%, example 43(i)] in the form of solids. LC/MS: RT=1,53 minutes, MS: 337 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 8,82 (1H, s), 8,76 (1H, m), 8,43 (1H, m), 7,95 (1H, m), 7,32 was 7.45 (3H, m), 7,11 (1H, m), only 6.64 (1H, s), 3,98 (3H, s), with 3.79 (3H, s), 3,76 (2H, m)to 3.09 (2H, m). IC50=248 nm.

(j)Hydrochloride [2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described in example 43(b), but substituting 2-(4-AMINOPHENYL)ethylamine for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine which is dissolved in ether and treated with 1M solution of hydrogen chloride in ether, receiving hydrochloride [2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine [52,4 mg, 68%, example 43(j)] in the form of solids. LC/MS: RT=1,72 minutes, MS: 351 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7.24 to a 7.5 (7H, m), was 7.08 (1H, m), of 6.65 (1H, s), 4 (3H, s), and 3.8 (3H, s)to 3.64 (2H, m), of 2.92 (2H, m).

(k)Hydrochloride (4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described in example 43(b), but replacing 4-methoxybenzylamine 2-(4-shall trienyl)ethylamine and acetonitrile in EtOH as solvent at stage 3, receive (4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine which is dissolved in ether and treated with 1M solution of hydrogen chloride in ether, obtaining hydrochloride (4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine [56,3 mg, 73%, example 43(k)] in the form of solids. LC/MS: RT=2.5 minutes, MS: 352 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ was 7.36 and 7.5 (3H, m), 7,28 (2H, d, J=9,2 Hz), and 7.1 (1H, m), 6,9 (2H, d, J=9,2 Hz), of 6.65 (1H, s), of 4.57 (2H, d, J=5 Hz), 4 (3H, s), and 3.8 (3H, s), and 3.72 (3H, s). IC50=1073 nm.

(l)Hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)Amin

By a method similar to that described in example 43(b), but replacing 3-phenylpropylamine 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)amine which is dissolved in ether and treated with 1M solution of hydrogen chloride in ether, receiving hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl Amin [to 60.6 mg, 79%, example 43(l)] in the form of solids. LC/MS: RT=2,65 minutes, MS: 350 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ a 7.1 to 7.5 (9H, m), 6,62 (1H, s), of 3.95 (3H, s), and 3.8 (3H, s), 3,42 (2H, m)of 2.64 (2H, m), a 1.88 (2H, m). IC50=1686 nm.

(m)[2-(1H-Imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine

By a method similar to that described what WMD in example 43(b), but replacing 2-(1H-imidazol-4-yl)ethylamine for 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-(1H-imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]Amin [39,2 mg, 54%, example 43(m)] in the form of solids. LC/MS: RT=1,45 minutes, MS: 326 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 7,8 (1H, s), 7,52 (2H, m), 7,37 (1H, m), 7,01 (1H, m)6,94 (1H, s), and 6.6 (1H, s), of 3.84 (3H, s), with 3.79 (3H, s), of 3.56 (2H, m), and 2.79 (2H, m).

(n)(2S)-2-[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid

By a method similar to that described in example 43(b), but replacing L-O-methyltyrosine 2-(4-nitrophenyl)ethylamine in stage 3, get (2S)-2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid [40,2 mg, 45%, example 43(n)] in the form of solids. LC/MS: RT=2,38 minutes, MS: 410 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 12 (1H, USS), a 7.62 (1H, m), 7,49 (1H, m), 7,38 (1H, m), 7,18 (2H, m), 7 (1H, m), 6,8 (2H, m), of 6.73 (1H, s), 4,59 (1H, m), and 3.8 (3H, s), of 3.78 (3H, s), 3,68 (3H, s), 3,1 (1H, m)to 2.94 (1H, m,). IC50=548 nm.

(o)[2-Methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

By a method similar to that described in example 43(b), but replacing 4-methoxyphenylethylamine 2-(4-nitrophenyl)ethylamine and acetonitrile in EtOH as solvent in stage 3 receive [2-methoxy-6-(3-methoxyphenyl)pyrimi the Jn-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [58 mg, example 43(o)].

Example 44

[2-Methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. To a mixture of methyl ester of 2,6-dichloropyrimidine-4-carboxylic acid [1 g of 4.83 mmol, intermediate compound (54)] and N,N-diisopropylethylamine (1,27 ml of 7.25 mmol) in THF (16 ml) is added 2-(4-methoxyphenyl)ethylamine (707 μl of 4.83 mmol). The resulting mixture was stirred at ambient temperature for 20 hours, poured into 50 ml of water and extracted three times with 40 ml of ethyl acetate. The organic extracts are combined and washed with 20 ml of brine, dried over magnesium sulfate, filtered and concentrated, obtaining a solid, which is purified by chromatography on a column of silica gel (35 g) with gradient elution with a mixture of from 5 to 50% EtOAc in heptane, receiving the methyl ester of 2-chloro-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid [1 g, 64.5%of intermediate compound (55)]. LC/MS: RT=2.9 minutes, MS: 322 (M+H).

Stage 2. A mixture of methyl ester of 2-chloro-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid [650 mg, 2.02 mmol, intermediate compound (55)], 5M sodium methoxide in MeOH (20 ml, 10.1 mmol) in MeOH (10 ml) is heated under reflux and stirred for 5 hours. The heating is stopped and the mixture is stirred for 15 hours at room temperature, and is eat concentrate on a rotary evaporator, to remove the solvent. The solid is dissolved in water and the solution acidified to pH 2 by addition of 1 N. hydrochloric acid. The mixture is extracted three times with 75 ml of EtOAc and concentrate the combined organic extracts, receiving 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid [390 mg, 64%, the intermediate compound (56)] in the form of solids. LC/MS: RT=1.99 min, MS: 304 (M+H).

Stage 3. To a solution of 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid (100 mg, 0.33 mmol, example 56] in dimethylformamide (1 ml) is added N,N-diisopropylethylamine (145 μl, 0.83 mmol), and then TBTU (128 mg, 0.4 mmol). The reaction mixture is stirred for 5 minutes, then add acetic hydrazide (37 mg, 0.5 mmol) and continue stirring the reaction mixture overnight at ambient temperature. The reaction mixture was poured into water (25 ml) and three times successively extracted with 25 ml ethyl acetate. The combined organic extracts washed with water (25 ml), brine (25 ml), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The resulting material purified flash chromatography on a column of silica gel (10 g) with gradient elution with a mixture of from 0 to 5% MeOH in DCM, receiving N'-acetylhydrazide 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid (42 mg). A mixture of N'-acetylides the Yes 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid (42 mg, 0.12 mmol), para-toluensulfonate (34 mg, 0.18 mmol) and PS-BEMP (218 mg, 0.48 mmol) in THF (1.5 ml) is treated in a microwave oven at 140°C for 6 minutes. The substance is filtered and applied to silica gel and purified flash chromatography on silica gel with gradient elution with a mixture of from 10 to 50% EtOAc in heptane, receiving [2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [25,1 mg, 63%, example 44]. LC/MS: RT=2,64 minutes, MS: 342 (M+H). IC50=55 nm.

Example 45

(2-Methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. A mixture of methyl ester of 2-chloro-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carboxylic acid [7,43 g, 23,09 mmol, intermediate compound (55)] dimethoxyethane (100 ml) cooled in an ice bath to 3°C and treated with added dropwise via syringe a solution of 2M lithium borohydride in THF (17.3 ml, 34.6 mmol), without increasing the temperature of the reaction mixture above 7°C. Upon completion of the addition stirring is continued at 5°C for 1 hour. The reaction mixture was poured into ice water (250 ml) and extracted four times EtOAc (100 ml). The blend of organic extracts washed with water (100 ml), then brine (100 ml), dried over magnesium sulfate, filtered, concentrated by rotary evaporator to obtain {2-chloro-6-[2-(4-methoxyphenyl)ethylamino]p is rimidine-4-yl}methanol [6,51 g, 96%, intermediate compound (57)].

Stage 2. A mixture of {2-chloro-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}methanol [6.5 g, 22,1 mmol, intermediate compound (57)] and 25 wt.% of sodium methoxide in MeOH (15.2 ml, to 66.3 mmol) in MeOH (20 ml) is heated to 90°C, stirred for 3 hours and concentrated on a rotary evaporator to remove the solvent. The solid is dissolved in water and the solution acidified to pH 8 by addition of saturated solution of ammonium chloride. The mixture is twice extracted with 150 ml of ethyl acetate, the extracts combined, dried over magnesium sulfate, filtered, concentrated and receive {2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}methanol [5,6 g, 88%, example 58] in the form of solids. LC/MS: RT=2,35 minutes, MS: 290 (M+H).

Stage 3. The solution oxalicacid (305 μl, 3,55 mmol) in DCM (10 ml) cooled to -78°C. To the cooled solution are added dropwise dimethyl sulfoxide (492 μl, 6,92 mmol). After 10 minutes stirring via syringe a solution of {2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}methanol [500 mg, of 1.73 mmol, intermediate compound (58)] in DCM (7 ml). The mixture was stirred at -78°C for 30 minutes, and then add triethylamine (1,95 ml, 13.84 mmol) via syringe. After stirring for a further 40 minutes at -78°C the reaction mixture was poured into water (30 ml) and this mixture is extracted twice with 30 ml DCM. The combined extracts are dried on the magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue is transferred into the toluene and again concentrated and dried under high vacuum, obtaining 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carbaldehyde [450 mg, 90.5 per cent, intermediate compound (59)].

Stage 4. In vitro mixed 2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-carbaldehyde [120 mg, 0.42 mmol, intermediate compound (59)], dosimetrician (90 mg, 0.46 mmol), polymer Ambersep 900 OH (800 mg), methyl ether of ethylene glycol (3.5 ml) and water (3.5 ml). The vessel is sealed and the mixture heated to 90°C and stirred for 18 hours. Mixture was allowed to cool to ambient temperature, then filtered to remove the polymer, and washing the polymer in 10 ml of methanol. The combined filtrates and washings are concentrated on a rotary evaporator and the residue purified flash chromatography on a column of silica gel with gradient elution with a mixture of from 0 to 40% EtOAc in heptane, receiving (2-methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [11.6 mg, 8.5%), example 45]. LC/MS: RT=2.57 m minutes, MS: 327 (M+H). IC50=7,8 nm.

Example 46

(a)3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

Stage 1. To a solution of 2,2-debtorrent[1,3]dioxol-5-carbaldehyde [5,48 g, 29,44 mmol, intermediate compound (60)] and nitromethane (4,78 is l, 88,32 mmol) in acetic acid (90 ml) is added ammonium acetate (5,67 g, 73,6 mmol). The reaction mixture is heated under reflux for 5.5 hours. Acetic acid is removed under vacuum, the residue is added water (20 ml) and extracted with DCM (3×50 ml), the organic layers are combined and washed with 2 N. sodium hydroxide, water and brine, dried over sodium sulfate and concentrated. The obtained solid is crystallized in a mixture of methanol/DCM (1:1) and obtain the intermediate compound 2,2-debtor-5-(2-nitrovinyl)benzo[1,3]dioxol [3,83 g of the intermediate compound (61)] in the form of solids.

Stage 2. 2.2-Debtor-5-(2-nitrovinyl)benzo[1,3]dioxol (2 g, 8,73 mmol) dissolved in THF (50 ml) and treated with lithium aluminum hydride (44 ml, 26,2 mmol, 1M solution in THF)added dropwise over 20 minutes at 0°C. the Mixture is heated under reflux for 2 hours, quenched with water (2 ml) and 2 N. sodium hydroxide (4 ml). The mixture is stirred for 5 minutes and filtered through cellit. The filtrate is concentrated, treated with water and three times extracted with EtOAc (50 ml). The mixture of the extracts washed with brine, dried over sodium sulfate and evaporated. The residue is dissolved in ether, treated with hcl 1M in ether and receive hydrochloride 2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamine [1.04 g, 50%, intermediate compound (62)] in the form of solids. LC/PROV.: MS: 202 (M+H).

Stage 3. To a solution of 4,6-dichloro-2-methoxypyridine (0,606 g, to 3.38 mmol, intermediate compound (4)] hydrochloride and 2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamine [0,884 g, 3.72 mmol, intermediate compound (62)]) in EtOH (11 ml) is added sodium bicarbonate (0.85 grams, 10,14 mmol) and the solution heated under reflux for 4 hours. The reaction mixture is filtered, the filtrate is concentrated and the residual solid washed with a small amount of EtOH and receive (6-chloro-2-methoxypyridine-4-yl)-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]amine [0,918 g, 79%, intermediate compound (63)] in the form of solids. LC/MS: MS: 344 (M+H).

Stage 4. A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]amine [150 mg, 0,437 mmol, intermediate compound (63)] and 3-carboxybenzeneboronic acid [87 mg, 0,524 mmol, intermediate compound (20)] in acetonitrile (2 ml) and an aqueous solution of Na2CO3(0,4M, 2 ml) Tegaserod nitrogen for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (25,2 mg, 5 mol.%). A reaction chamber is sealed and heated in a microwave oven at 130°C for 20 minutes. The reaction mixture was added 2 ml of water and pH adjusted to about 6 by 6 N. aqueous hydrochloric acid. The mixture is extracted three times with ethyl acetate (50 ml). The mixture of the extracts washed with brine, dried over sodium sulfate, concentrate the t and get a solid substance, which re-dissolved in MeOH and added DCM, and then in the form of a solid precipitate 3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [166 mg, 88%, example 46(a)]. LC/MS: RT=2,67 minutes, MS: 430 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 13,2 (1H, USS), and 8.4 (1H, s), of 8.06 (2H, m), to 7.61 (1H, t, J=4.9 Hz), was 7.36 (1H, s), 7,31 (1H, m), 7,06 (1H, m), of 6.68 (1H, s)to 3.99 (3H, s)to 3.64 (2H, m), 2,9 (2H, m).

(b)Hydrochloride [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine

By a method similar to that described in example 46(a), but replacing 3-pyridylamino acid 3-carboxybenzeneboronic acid in stage 4 and processing the crude reaction product with hcl 1M in ether, receive hydrochloride [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine [132 mg, example 46(b)] in the form of solids. LC/MS: RT=2,72 minutes, MS: 387 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 9,2 (1H, s), 8,84 (1H, m), and 8.6 (1H, m), a 7.85 (1H, m), and 7.4 (1H, s), of 7.36 (1H, d, J=9.6 Hz), 7,11 (1H, d, J=9.6 Hz), 6,78 (1H, s), 3,98 (3H, s), 3,62 (2H, m), 2,96 (2H, m). IC50=212 nm.

(c)The hydrochloride of N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)ndimethylacetamide

By a method similar to that described above in stages 3 and 4 of example 46(a), but (i) replacing the hydrochloride of 2-(4-deformational)e is Ilumina [LC/MS: MS: 188, obtained as described in example 5, step 1, method B, but replacing 4-deformationally 4-triphtalocyaninine] the hydrochloride of 2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamine in stage 3; (ii) replacing 3-acetaminophenydrocodone acid 3-carboxybenzeneboronic acid in stage 4 and carrying out the reaction in a microwave oven at 130°C for 23 minutes; (iv) treating the reaction product with hcl 1M in ether, receive hydrochloride N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)ndimethylacetamide [195 mg, example 46(c)] in the form of solids. LC/MS: RT=2,45 minutes, MS: 429 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 10,22 (1H, USS), 8,18 (1H, s), to 7.64 (1H, USS), 7,44 (1H, m), of 7.36 (2H, d, J=9,2 Hz), 7,19 (1H, t, J=67,3 Hz), 7,12 (2H, d, J=9,2 Hz), 6,59 (1H, s)to 4.01 (3H, s)to 3.64 (2H, m), 2,9 (2H, m), of 2.08 (3H, C). IC50=4 nm.

(d)Hydrochloride [2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine

Stage 1. By a method similar to that described in example 43(b), stage 1, but (i) replacing 3-methanesulfonylaminoethyl acid 3-acetaminophenydrocodone acid and (ii) substituting 4,6-dichloro-2-methoxypyridine 4.6-dichloro-2-methylsulfonylamino receive 4-chloro-6-(3-methanesulfonyl)-2-methoxypyridine [intermediate compound (64)].

Stage 2. By a method similar to that described in example 46(a), stage 3, but (i) for INAA 4-chloro-6-(3-methanesulfonyl)-2-methoxypyridine 4.6-dichloro-2-methoxypyridine, (ii) replacing the hydrochloride of 2-(4-deformational)ethylamine on the hydrochloride of 2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamine and (iii) treating the product with hcl 1M in ether, receive hydrochloride [2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine [188 mg, example 46(d)]) in the form of solids. LC/MS: RT=2,73 minutes, MS: 450 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 8,39 (1H, USS), 8,21 (1H, OSD, J=9 Hz), 8,08 (1H, d, J=9.4 Hz), 7,81 (1H, t, J=9.4 Hz), 7,35 (2H, d, J=9.6 Hz), 7,18 (1H, t, J=74,5 Hz), 7,12 (2H, d, J=9.6 Hz), 6,76 (1H, s)to 4.01 (3H, s)to 3.64 (2H,, m), or 3.28 (3H, s), 2,9 (2H, m). IC50=17 nm.

(e)3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol

By a method similar to that described in example 46(a), stage 4, but (i) replacing [2-(2-chloro-6-forfinal)ethyl]-(6-chloro-2-methoxypyridine-4-yl)amine [500 mg, was 1.58 mmol, intermediate compound (24)] 4,6-dichloro-2-methoxypyridine and (ii) replacing 3-hydroxyphenylarsonic acid (240 mg, of 1.74 mmol) of 3-carboxybenzeneboronic acid, receive 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol [390 mg, 66%, example 46(e)] in the form of solids.

Example 47

Hydrochloride [2-(2,4-dichlorophenyl)ethyl]-(2-methoxy-6-{3-[1-methyl-1-(1H-tetrazol-5-yl)ethyl]phenyl}pyrimidine-4-yl)amine

Stage 1. To a solution of (3-bromophenyl)acetonitrile (2.3 g, 11,77 mmol) in anhydrous is THF (30 ml) is added tert-piperonyl potassium (2,92 g, 25,89 mmol) at -40°C. Portions add modesty methyl (1,95 ml, 29,43 mmol). The reaction mixture is heated to room temperature, stirred for 15 hours, quenched with 2 N. hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by chromatography on silica gel with elution with a mixture of from 0 to 50% EtOAc in heptane and get 2-(3-bromophenyl)-2-methylpropionitrile (1.7 g) [intermediate compound (65)] in the form of oil. MS: 225 (M+H).

Stage 2. To a solution of 2-(3-bromophenyl)-2-methylpropionitrile [0.5 g, 2.2 mmol, intermediate compound (65)] in toluene (8 ml) and THF (2 ml) add triisopropylsilyl (and 0.61 ml, 2.68 mmol) at -78°C. dropwise within 15 minutes add tert-utility (1,7M in pentane, of 1.55 ml, 2.68 mmol). The reaction mixture was stirred at -78°C for another 1 hour, heated to -20°C and quenched with 2 N. hydrochloric acid (10 ml). The reaction mixture is extracted with ether, the combined ether layers washed with brine, dried and concentrated, obtaining 3-(centimetres)phenylboronic acid (0.5 g), [intermediate compound (66)] in the form of oil.

Stage 3. By a method similar to that described in example 49(a), step 3, but replacing 3-(centimetres)phenylboronic acid [intermediate compound (66)] 3-(1-carboxyethyl)phenylboronic acid will receive 2-(3-{6-[2-(2,4-dichlorophe the Il)ethylamino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionitrile [100 mg, the intermediate compound (67)] in the form of solids. LC/MS: RT=2,74 minutes, MS: 441 (M+H).

Stage 4. To a solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionitrile [50 mg, 0.11 mmol, intermediate compound (67)] α,α,α-triptoreline (2 ml) add usedatabaseyou (0,251 ml, 0.88 mmol) and heated in a microwave oven at 180°C for 1.5 hours. The reaction mixture was concentrated and purified by chromatography on silica gel with elution with a mixture of from 20 to 100% EtOAc in heptane, getting[2-(2,4-dichlorophenyl)ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)ethyl]phenyl}pyrimidine-4-yl)amine in the form of a solid substance, which is treated with hcl 1M in ether and receive hydrochloride [2-(2,4-dichlorophenyl)ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)ethyl]phenyl}pyrimidine-4-yl)amine [47 mg, 80%, example 47] in the form of solids. LC/MS: RT=2,47 minutes, MS: 484 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 8,64 (1H, USS), 7,3 one-7.8 (7H, m), 6,56 (1H, s), 3,98 (3H, s)to 3.64 (2H, m), 3 (2H, m), 1.8 m (6H, s). IC50=0.4 nm.

Example 48

Hydrochloride [2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

To a suspension of (2-methoxyphenyl)methanol (860 mg, from 6.22 mmol) and sodium hydride (60%, 0.3 g) in DMF (10 ml) is added (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [0.54 g, 1.8 mmol, intermediate compound (8)] n and 10°C. After 1 hour at 60°C the mixture was diluted with H2O and extracted with ethyl acetate. The extracts are dried (MgSO4), filtered, concentrated and chromatographic (SiO2, 40% EtOAc in heptane)to give undivided a mixture of products [2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine and disubstituted by-product, [2,6-bis-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine. In the above mixture in CH2Cl2add a solution of HCl in EtOAc, the mixture is concentrated and triturated (ether), filtered and obtain 141 mg (19%) of the hydrochloride of 4-(2-methoxybenzyloxy)-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-2-ol in the form of solids. LC/MS: RT=2,07 minutes, MS: 382 (M+H). The filtrate is concentrated and chromatographic (silica gel, 40% EtOAc in heptane)to give the hydrochloride [2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [39 mg, 5%, example (48)] in the form of oil. LC/MS: RT=3.3 minutes, MS: 396 (M+H). IC50=12 nm.

Example 49

(a)Hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid

Stage 1. The LDA solution in a mixture of THF/n-heptane/ethylbenzene (1,8M, 23.25 ml, 41,85 mmol) cooled to -78°C and added dropwise a solution of 3-bromoferrocene acid [3 g, to 13.95 mmol, intermediate compound (68)] in THF (7 ml) dropwise within 15 minutes. A mixture of AC who're asked for 1 hour at -78°C and treated with added dropwise idestam the stands (6,34 g, 44,64 mmol) for 15 minutes. The reaction mixture is heated to room temperature and after stirring over night extinguish 2 N. hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice 2 N. hydrochloric acid (20 ml) and twice extracted with 10% sodium hydroxide (20 ml). Mixed extracts of acidified sodium hydroxide 6 N. hydrochloric acid to pH 1 and extracted three times with ether (50 ml). The blend of organic extracts washed with brine, dried over sodium sulfate and concentrated, obtaining 2-(3-bromophenyl)propionic acid [3 g, 100%, intermediate compound (69)] in the form of solid, which is further used without additional purification. LC/MS: 229 (M+H).

Stage 2. To a solution of 2-(3-bromophenyl)propionic acid [500 mg, of 2.18 mmol, intermediate compound (69)] in anhydrous ether (20 ml) is added tert-utility (1,7M in pentane, to 5.4 ml, 9,16 mmol) dropwise at -78°C and the mixture stirred for 30 minutes with tributyrate (2,34 ml 8,72 mmol). The reaction mixture is heated to room temperature, stirred for 15 hours, diluted with ether and quenched with 1M H3PO4. After stirring for 30 minutes, the ether layer is separated and extracted three times 2 N. sodium hydroxide (20 ml). The combined extracts with sodium hydroxide acidified with 6 N. hydrochloric acid to pH 1 and three times extragear the Ute ether (50 ml). The combined organic extracts washed with brine, dried over sodium sulfate and concentrated, obtaining 3-(1-carboxyethyl)phenylboronic acid [intermediate compound (70)] in the form of solid, which is further used without additional purification.

Stage 3. A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [170 mg, 0.51 mmol, intermediate compound (44)] and 3-(1-carboxyethyl)phenylboronic acid [119 mg, 0.61 mmol, intermediate compound (70)] in acetonitrile (2.5 ml) and aqueous solution of Na2CO3(0,4M, 2.5 ml) Tegaserod nitrogen for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 5 mol.%). A reaction chamber is sealed and heated in a microwave oven at 130°C for 30 minutes. The reaction mixture was added 2 ml of water, pH adjusted to about 7 using 2 N. aqueous hydrochloric acid and the mixture was thrice extracted with EtOAc (30 ml). The combined extracts washed with brine, dried over sodium sulfate and concentrated. The resulting oil chromatographic on silica gel with elution with a mixture of from 0 to 7% MeOH in DCM, receiving 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid in the form of a solid substance, which is then treated with hcl 1M in ether, obtaining the hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypurine the Jn-4-yl}phenyl)propionic acid [122 mg, 50%, example 49(a)] in the form of solids. LC/MS: RT=2,47 minutes, MS: 446 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 12,4 (1H, OSS), was 7.36 - 7,8 (7H, m), and 6.6 (1H, s), 4 (3H, s), of 3.78 (1H, HF), 3,68 (2H, m), to 3.02 (2H, m)of 1.42 (3H, d). IC50=1 nm.

(b)2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. In the LDA solution in a mixture of THF/n-heptane/ethylbenzene (1,8M, 17 ml) at 0°C, add a solution of 2-(3-bromophenyl)propionic acid [3 g, a 13.9 mmol, intermediate compound (69)] in THF (5 ml) dropwise within 15 minutes. Is stirred for one hour, and then add modesty methyl (4,93 g, 34.8 mmol) in THF (5 ml) dropwise over 10 minutes. The reaction mixture is stirred for 15 hours, quenched with 2 N. hydrochloric acid, concentrated under vacuum and diluted with ether (150 ml). The ether layer was washed with 2 N. hydrochloric acid, extracted three times 2 N. sodium hydroxide (50 ml). The combined layers of sodium hydroxide acidified with 6 N. hydrochloric acid to pH 1 and extracted three times with ether (75 ml). The combined organic layers washed with brine, dried over sodium sulfate and concentrated, obtaining 2-(3-bromophenyl)-2-methylpropionic acid (is 3.08 g, yield 91%), which is further used without additional purification. LC/MS: 243 (M+H).

Stage 2. By a method similar to that described in example 49(a), step 2, but substituting 2-(3-bramp the Nile)-2-methylpropionic acid 2-(3-bromophenyl)propionic acid, get 3-(1-carboxy-1-methylethyl)phenylboronic acid in the form of semi-solid substances, which are further used without additional purification. LC/MS: 209 (M+H).

Stage 3. By a method similar to that described in example 49(a), step 3, but replacing 3-(1-carboxy-1-methylethyl)phenylboronic acid 3-(1-carboxyethyl)phenylboronic acid will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [205 mg, 75%, example 49(b)] in the form of solids. LC/MS: RT=2,39 minutes, MS: 460,2 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 12,38 (1H, s), of 7.36-8 (7H, m), to 6.58 (1H, s), of 3.84 (3H, s)to 3.58 (2H, m), 2,98 (2H, m), and 1.54 (6H, s).

Example 50

Hydrochloride of 1-ethoxycarbonylmethylene ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid

To a solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [100 mg, 0,218 mmol, example 49(b)] in dimethylformamide (2 ml) add ethylcarbonate 1-chloroethyl (0,053 ml, 0,392 mmol) and Cs2CO3(142 mg, 0,436 mmol). The mixture is heated in a microwave oven at 110°C for 10 minutes, quenched with water and extracted with ethyl acetate. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel with eleirovania the m mixture from 0 to 40% EtOAc in heptane, getting 1-ethoxycarbonylmethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid in the form of oil, which is then treated with hcl 1M in ether, receiving hydrochloride 1-ethoxycarbonylmethylene ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [80 mg, 64%, example 50] in the form of solids. LC/MS: RT=2,94 minutes, MS: 576 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ was 7.36-7,8 (7H, m), only 6.64 (1H, HF), and 6.6 (1H, s), of 4.05 (2H, q), of 3.96 (3H, s), 3,68 (2H, m), 3 (2H, m), of 1.57 (6H, s)to 1.38 (3H, d)and 1.15 (3H, t). IC50=4 nm.

Example 51

The dihydrochloride of 2-dimethylaminoethanol ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid

A solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [100 g, 0,218 mmol, example 49(b)] in DCM (2 ml) was treated with HBTU (515,2 mg, 1.35 mmol). The mixture is stirred at room temperature for 2 hours and treated with 2-dimethylaminoethanol (0,154 ml, 1.53 mmol). After stirring over night the mixture was quenched with water and extracted with ethyl acetate. The combined organic phases are washed with saline, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel with elution with a mixture of from 0 to 7.5% MeOH in CM, getting 2-dimethylaminoethyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid in the form of oil, which is then treated with hcl 1M in ether, receiving the dihydrochloride of 2-dimethylaminoethanol ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid [88 mg, 67%, example 51] in the form of solids. LC/MS: RT=2.1 minutes, MS: 531 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 10,16 (1H, USS), 7,3 - of 7.82 (7H, m), 6,62 (1H, s), 4,37 (2H, m), of 3.96 (3H, s), 3,68 (2H, m), 3,32 (2H, m), 3 (2H, m), 2.63 in (6H, s), and 1.6 (6H, s).

Example 52

(5-{6-[2-(2-Fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid

Stage 1

(6-Chloro-2-methoxypyridine-4-yl)-[2-(2-fluoro-4-triptoreline)ethyl]amine

2-Fluoro-4-triftormetilfullerenov (2 g, 9,85 mmol) hydrogenizing hydrogen from a cylinder, 10% Pd/C (522 mg, 5 mol.%) in 95% EtOH (50 ml) containing concentrated hydrochloric acid (1,64 ml) at room temperature for 15 hours. The mixture is filtered and the filtrate concentrated to a solid, which was washed with diethyl ether, obtaining the hydrochloride of 2-(2-fluoro-4-triptoreline)ethylamine (1.88 g, 78%) as a solid. LC/MS: 208 (M+H). This compound (1.8 g, 8,7 mmol) dissolved in EtOH (25 ml) and treated with 4,6-dig the PR-2-methoxypyridine [1,3 g, of 7.25 mmol, intermediate compound (4)] and sodium bicarbonate (1.52 g, 18,13 mmol). The reaction mixture is heated under reflux for 5 hours. The solid is filtered and remove EtOH under vacuum. The residue was washed with a small amount of DCM and receive (6-chloro-2-methoxypyridine-4-yl)-[2-(2-fluoro-4-triptoreline)ethyl]amine (2,59 g, 76%) as a solid. LC/MS: 350 (M+H).

Stage 2

3-Carboxymethyl-1H-indol-5-Voronova acid

To a solution of (5-bromo-1H-indol-3-yl)acetic acid (1 g, of 3.94 mmol) in THF (66 ml) at -78°C add tert-utility (1,7M in pentane, and 11.6 ml of 19.7 mmol) dropwise and stirred at -78°C for 30 minutes and at -30°C for 1 hour. Again cooled to -78°C and treated with added dropwise triisopropylsilane (4,53 ml of 19.7 mmol). The reaction mixture is heated to room temperature over 1 hour and quenched with 2 N. hydrochloric acid. The mixture is extracted with ether. The extract is dried over sodium sulfate and concentrated, obtaining oil, which chromatographic on silica gel, receiving 3-carboxymethyl-1H-indol-5-Voronovo acid (185 mg, 20%) as a solid.

Stage 3

(5-{6-[2-(2-Fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid

To a solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(-fluoro-4-triptoreline)ethyl]amine (493 mg, 1,408 mmol) and 3-carboxymethyl-1H-indol-5-yl-Bronevoy acid (370 mg, 1,689 mmol) in toluene (9 ml), EtOH (4.5 ml) and water (1 ml) add Cs2CO3(1,146 g to 3.52 mmol) and Tegaserod nitrogen for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (81,3 mg, 5 mol.%). A reaction chamber is sealed and heated in a microwave oven at 130°C for 15 minutes. In the reaction mixture was added 1 N. hydrochloric acid to bring the pH to approximately 2. This mixture thrice extracted with EtOAc (40 ml). The mixture of the extracts washed with brine, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel and receive (5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid [116 mg, 17%, example 52] in the form of solids. LC/MS: RT=2.57 m minutes, MS: 489 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 12,18 (1H, s)11,05 (1H, s), 8,18 (1H, s), 7.24 to 7,76 (7H, m), and 6.6 (1H, s), a 3.87 (3H, s), 3,7 (2H, s), 3,6 (2H, m), 3 (2H, m). IC50=0.4 nm.

Example 53

(a)Triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium

Stage 1. A solution of 6-bromoindole (200 mg, of 1.02 mmol) in anhydrous ether (4 ml), at -78°C, treated with added dropwise tert-butyllithium (1,7M solution in pentane, 2 ml, 3.4 mmol). After stirring for 30 minutes, the mixture is treated added by ka is the NML tributyrate (0,822 ml, a 3.06 mmol) and heat it to room temperature. After stirring over night the reaction mixture was diluted with ether, and this mixture is added in several portions in phosphoric acid (15 ml, 1M), stirred for 30 minutes and extracted three times with ether (20 ml). The mixture of extracts shaken out three times with a solution of sodium hydroxide (20 ml, 1 BC). Mixed extracts of sodium hydroxide acidified with phosphoric acid (1M) to pH 2 and extracted with ether. A mixture of ether extracts are washed with brine, dried over sodium sulfate and concentrated, obtaining 1H-indol-6-yl-Bronevoy acid [intermediate compound (77)] in the form of a solid substance, which is used in the next stage without additional purification.

Stage 2. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine [205,3 mg, 0,698 mmol, intermediate compound (8)] and 1H-indol-6-yl-Bronevoy acid [135 mg, 0.84 mmol, intermediate compound (77)] in acetonitrile (3.5 ml) and a solution of Na2CO3(3,7 ml, 0,4M) Tegaserod nitrogen for 5 minutes and then add tetrakis(triphenylphosphine)palladium(0) (40.5 mg, 0.035 mmol). The mixture is heated in a microwave oven at 130°C for 20 minutes and thrice extracted with EtOAc (30 ml). The combined extracts are washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated, gaining balance, the cat is who chromatographic on preparative Gilson HPLC (C18 column, 5-100% acetonitrile/water, 0.1% of triperoxonane acid), receiving triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium [87 mg, 33%, example 53(a)] in the form of oil. LC/MS: RT=2,47 minutes, MS: 375 (M+H).1H NMR (300 MHz, CDCl3): δ 10 (1H, USS), 8,14-6,2 (10H, m), of 3.78 (3H, s), of 3.73 (3H, s), 3,5 (2H, m), 2,8 (2H, m).

(b)[6-(1H-Indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine

Stage 1. By a method similar to that described in example 53(a), but replacing 6-bromo-1H-indazol 6-bromoindole in stage 1, get 1H-indazol-6-Voronovo acid [150 mg, intermediate compound (79)] in the form of solids. This substance is used in the next stage without additional purification.

Stage 2. By a method similar to that described in example 53(a), but substituting 1H-indazol-6-yl-Bronevoy acid [intermediate compound (79)] 1H-indole-6-Voronovo acid in stage 2 and carrying out the reaction in a mixture of toluene:EtOH:water (2.5 ml:1.3 ml:0.2 ml), receive [6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine [60 mg example 53(b)] in the form of solids. LC/MS: RT=2,33 minutes, MS: 376 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 13,2 (1H, s), and 8.2 (1H, m)and 8.1 (1H, s), 7,82 (1H, m), 7,68 (1H, m), 7,56 (1H, m), 7,2 (2H, d, J=8.6 Hz), at 6.84 (2H, d, J=8.6 Hz), 6,7 (1H, s)to 3.92 (3H, s), and 3.7 (3H, s), 3,5 (2H, m), 2,8 (2H, m). IC50=0,95 nm.

(c)3-{6-[2-(2,6-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-Albertina acid

By a method similar to that described in example 53(a), step 2, but substituting 3-carboxypropanoyl acid for 1H-indole-6-Voronovo acid and (6-chloro-2-methoxypyridine-4-yl)-[2-(2,6-dichlorophenyl)ethyl]amine [intermediate compound (44)] to (6-chloro-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine, get 3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [110 mg, example 53(c)] in the form of solids. LC/MS: RT=2,64 minutes, MS: 418 (M+H).1H NMR [300 MHz, (CD3)2SO]: δ 13,2 (1H, USS), 8,54 (1H, s), and 8.1 (1H, m), 8 (1H, m), 7,76 (1H, m), and 7.6 (1H, m), 7,44 (2H, m), 7,26 (1H, m), 6,62 (1H, s), 3,86 (3H, s), 3,6 (2H, m), up 3.22 (2H, m).

Example 54

Sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine

In a solution of 0.5 m of sodium methoxide (10 ml, 5 mmol) in MeOH add [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]Amin [1,2 g of 2.97 mmol, example 24(a)]. After 1 hour at room temperature the mixture is concentrated and filtered through a short column of silica gel with elution with a mixture of MeOH and DCM (1:4, vol/about.) and triturated in a mixture of heptane and ether, obtaining the sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine [1.13 g, 89%, example 54] in the form of solids. LC/MS: RT=2,37 minutes, MS: 404 (M+H). IC50=0.4 nm.

Por the measures 55

2-Methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile

In the solution of the oxime of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde [0,49 g, 1.2 mmol, example 26(c)] and triphenylphosphine (to 0.63 g, 2.4 mmol) in DCM (20 ml) is added N-chlorosuccinimide (0.32 g, 2.4 mmol) at 10°C. After 2 hours at 20°C the mixture of concentrate and chromatographic on silica gel with elution with a mixture of from 5% to 10% MeOH in DCM, receiving 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile [0.4 g, 85%, example 55]. LC/MS: RT=2,75 minutes, MS: 391 (M+H).

Example 56

(3-{6-[2-(2-Chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid

A solution of (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol (640 mg, of 1.65 mmol) and bromoxynil acid (0.25 g, 1.82 mmol) in N,N'-dimethylformamide (5 ml) is treated with sodium hydride (60%, 0.28 g, 6,94 mmol) at -30°C. the Mixture is heated to room temperature over 1 hour, stirred for another 1 hour and quenched with water. The mixture is diluted with water and washed with ether. The aqueous phase is acidified to pH of 3.8, the resulting solid is filtered and dried, obtaining (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid [3,9 g, 53%, example 56]. The filtrate extra the shape with ethyl acetate, the combined extracts washed with water, dried over magnesium sulfate, concentrated and receive an additional amount of (3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid (0,43 g, example 56). LC/MS: RT=2,43 minutes, MS: 446 (M+H). IC50or =0.6 nm.

Example 57

2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate sodium

A solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [540 g at 1.17 mmol, example 49(b)] in MeOH (60 ml) is treated with Na2CO3(187 mg, 1.78 mmol) and the mixture is stirred for 15 hours. The reaction mixture is filtered and the filtrate is concentrated until dry. To the residue add a mixture of methanol, EtOAc and acetone. The insoluble substance was filtered and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, insoluble matter is filtered and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, insoluble matter is filtered and the filtrate is evaporated. In the remainder added MeOH (1 ml) and EtOAc (5 ml), and then heptane until the turbidity of the solution and slow the formation of solids. Heptane add up until the solution is clear. The mixture is filtered and receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxide midin-4-yl}phenyl)-2-methylpropionate sodium in the form of a crystalline substance. LC/MS: RT=2,34 minutes, MS: 460 (M-Na+2H)+.1H NMR [300 MHz, (CD3)2SO]: δ of 7.97 (1H, USS), 7,24-in 7.7 (7H, m), to 6.57 (1H, s), 3,86 (3H, s)to 3.58 (2H, m), 2,98 (2H, m), 1,4 (6H, s).

Example 58

Ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid

A mixture of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid [127 mg, 0.3 mmol, example 35(w)], tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N, N'-tetramethylurea (116 mg, 0.36 mmol), diisopropylethylamine (131 μl, 0.75 mmol) and the hydrochloride of the ethyl ester of glycine (63 mg, 0.45 mmol) in dimethylformamide (3 ml) was stirred at ambient temperature within 18 hours. The mixture was poured into water and thrice extracted with EtOAc (20 ml). The organic extracts are combined and washed twice with water (20 ml), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator, obtaining a solid substance. Solid adsorb on silica gel and purified flash chromatography on silica gel (40 g) with gradient elution with a mixture of from 0 to 50% ethyl acetate in heptane and get ethyl ester (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid [120 mg, 79%, example 58]. MS: 503 (M+H).

Example 59

(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid

A mixture of ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid [120 mg, 0.24 mmol, example 58], lithium hydroxide (20 mg, 0.48 mmol) in THF (1 ml), MeOH (1 ml) and water (1 ml) is stirred for 20 hours at room temperature. The mixture is acidified to pH 1 with 10% hydrochloric acid and three times extracted with EtOAc (25 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and receive (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid [49 mg, 43%, example 59]. LC/MS: RT=2,77 minutes, MS: 475 (M+H). IC50=0.8 nm.

Example 60

(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid

Stage 1. A mixture of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol [220 mg, 0.51 mmol, example 35(i)], diisopropylethylamine (178 μl, 0.75 mmol) and 4-nitrophenylphosphate (123 mg, 0.61 mmol) in DCM (3 ml) was stirred at ambient temperature for 2 hours. The mixture was poured into water (25 ml) and twice extracted with EtOAc (25 ml). The organic extracts are combined washed twice with water (25 ml) and once with saline (25 ml), dried over magnesium sulfate, filtered, concentrated by rotary evaporator and poluchaut-nitrophenyloctyl ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether carboxylic acid [291 mg, 102%, the intermediate compound (80)]. MS: 555 (M+H).

Stage 2. A mixture of 4-nitrophenylthio ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether carboxylic acid [291 mg, 0.52 mmol, example 80] and 2M ethylamine in MeOH (of 0.65 ml, 1.3 mmol) in DCM was stirred at ambient temperature for 20 hours. The resulting precipitate is collected by filtration, washed with DCM, dried under vacuum and get 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid [80 mg, 33.3%of the sample 60]. LC/MS: RT=1,31 minutes, MS: 461 (M+H). IC50=0.5 nm.

Example 61

5-{2-Methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid

To a solution of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde [700 mg, 1,895 mmol, example 8(b)] in acetone (20 ml) add a solution of potassium permanganate (898 mg, 5,684 mmol) and NaH2PO4.H2O (79 mg, 0,568 mmol) in water (20 ml)and then silica gel (4 g). The mixture was stirred at ambient temperature for 6 hours, incubated overnight, evaporated to remove acetone and extracted several times with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated. The crude residue is dissolved in boiling acetonitrile and solids that arr is used for cooling, collected by filtration, receiving 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid [362 mg, yield 50%, example 61].

Example 62

Triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid

To a solution of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid [168 mg, 0.45 mmol, example 61] in dimethylformamide (15 ml) and DCM (15 ml) add 2,0M of methylamine in THF (275 ml, 0.55 mmol), and then hexaphosphate 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (224 mg, 0.59 mmol) and diisopropylethylamine (254 ml, a 1.46 mmol). The mixture was stirred at ambient temperature for 5 hours, diluted with DCM and washed several times with water. The organic layer is dried over magnesium sulfate, filtered and concentrated, obtaining the crude product. Substance twice purified by HPLC, getting triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid [29 mg, 13%, example 62]. LC/MS: RT=of 6.96 minutes. MS: 399 (M+H). IC50=0.3 nm.

Example 63

Methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid

Stage 1. A mixture of (6-chloro-2-methylsulfonylamino-4-yl)-[2-(3,4-acid)ethylamine [250 mg, to 0.74 mmol, intermediate compound (31)], ethyl ester 3-hydroxybenzoic acid (0.18 g, 1.1 mmol) and Cs2CO3(0,48 g, 1.48 mmol) in DMF (4 ml) heated to 90°C for 15 hours. The mixture is diluted with water and extracted with EtOAc. The extracts are washed (water), dried (MgSO4), filtered, concentrated and chromatographic (silica gel, 30% EtOAc in heptane)to give ethyl ester of 3-{6-[2-(3,4-acid), ethylamino]-2-methylsulfonylamino-4-yloxy}benzoic acid [0,29 g, 83%, intermediate compound (71)]. LC/MS: RT=3.7 minutes, MS: 470 (M+H).

Stage 2. To the mixture obtained above methyl ester 3-{6-[2-(3,4-acid), ethylamino]-2-methylsulfonylamino-4-yloxy}benzoic acid [0.25 g of 0.53 mmol, intermediate compound (71)] in CH2Cl2(5 ml) is added 3-chloroperoxybenzoic acid (70%, 0.26 g, 1.06 mmol). After 2 hours at 20°C the mixture is treated polimersvarka carbonate (MP-carbonate, 3 mmol/g, 1 g, 3 mmol) and stirred for 2 hours at 20°C. After chromatography was carried out on a short column of silica gel (EtOAc) to obtain ethyl ester 3-{6-[2-(3,4-acid), ethylamino]-2-methanesulfonamido-4-yloxy}benzoic acid [0.2 g, 75%, intermediate compound (72)]. LC/MS: RT=3.2 minutes, MS: 502 (M+H).

Stage 3. In the above solution of the ethyl ester of 3-{6-[2-(3,4-acid), ethylamino]-2-methanesulfonamido-4-yloxy}Ben is oinoi acid [180 mg, 0.36 mmol, intermediate compound (72)] 1,2-dimethoxyethane (5 ml) is added a 25% solution of sodium methoxide (3 ml). After 1 hour at 20°C the mixture is filtered through SiO2(EtOAc). The filtrate is concentrated and receive methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid [70 mg, 44%, example (63)]. LC/MS: RT=3,34 minutes, MS: 440 (M+H). IC50=6254 nm.

Example 64

N-[2-(3-{6-[2-(2-Fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate

Stage 1. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2-fluoro-4-triptoreline)ethyl]amine [800 mg, to 2.29 mmol, see example 52, step 1], (3-cyanomethylene)Bronevoy acid, pinacolato ether (563 mg, of 3.43 mmol) and Cs2CO3(1.86 g, 5,72 mmol) in dimethyl ether of ethylene glycol (15 ml) and water (4 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.11 mmol) at room temperature. After 1 hour at 85°C the mixture was diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The extracts are dried (MgSO4), filtered through a SiO2and concentrate, getting (3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile (1.2 g). LC/MS: RT=2,47 minutes, purity 92%. MS: 431 (M+H).

Stage 2. A solution of (3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxyp rimidine-4-yl}phenyl)acetonitrile (660 mg, 1.53 mmol) in MeOH (20 ml) and concentrated HCl (2 ml) Tegaserod by blowing argon for 5 minutes and treated with palladium hydroxide on carbon (0.4 g) at room temperature. The mixture hydrogenizing for 15 hours at room temperature with hydrogen from a balloon with hydrogen, filtered through cellit and concentrate on a rotary evaporator. The residue is diluted with water, alkalinized with NaOH solution and extracted with EtOAc. The extracts are dried (MgSO4), filtered and concentrated, obtaining {6-[3-(2-amino-ethyl)phenyl]-2-methoxypyridine-4-yl}-[2-(2-fluoro-4-triptoreline)ethyl]amine (0.55 g). LC/MS: RT=1,85 minutes, MS: 435 (M+H).

Stage 3. A solution of {6-[3-(2-amino-ethyl)phenyl]-2-methoxypyridine-4-yl}-[2-(2-fluoro-4-triptoreline)ethyl]amine (150 mg, 0.35 mmol) and triethylamine (0,24 ml of 1.73 mmol) in DCM (5 ml) is treated with methoxyacetanilide (75 mg, 0.69 mmol) at 10°C. After 10 minutes at 10°C the mixture was quenched with aqueous solution of NaHCO3(8 ml) and filtered through a Chem-Elut with irrigation of CH2Cl2(10 ml). The filtrate is concentrated and chromatographic on silica gel with elution with a mixture of 80% EtOAc in heptane and 5% MeOH in CH2Cl2receiving N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate, which is treated with a saturated solution of hydrogen chloride in EtOAc, followed by lyophilization, getting hydrochloride N-[2-(3-{6-[2-(2-fluoro-4-Tr is formationl)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate [76 mg, example 64]. LC/MS: RT=2,24 minutes, MS: 507 (M+H).1H NMR (300 MHz, CDCl3): δ a 9.35 (1H, s), and 7.9 (1H, USS), and 7.6 to 7.4 (7H, m), of 6.65 (1H, s), 4 (3H, s), 3,76 (3H, s), 3,8-3,7 (2H, m), 3,4 (2H, q, J=6.9 Hz)at 3.25 (2H, s), 3,06 (2H, t, J=6.6 Hz), 2,82 (2H, t, J=7.5 Hz). IC50=56 nm.

Example 65

The hydrochloride of N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]ndimethylacetamide

A solution of {6-[3-(2-amino-ethyl)phenyl]-2-methoxypyridine-4-yl}-[2-(2-fluoro-4-triptoreline)ethyl]amine [150 mg, 0.35 mmol, see example 64, step 2] and triethylamine (0,24 ml of 1.73 mmol) in DCM (5 ml) is treated with acetylchloride (54 mg, 0.69 mmol) at 10°C. After 10 minutes at 10°C the mixture was quenched with aqueous solution of NaHCO3(8 ml) and filtered through a Chem-Elut with irrigation of CH2Cl2(10 ml). The filtrate is concentrated and chromatographic through silica gel with elution with a mixture of 80% EtOAc in heptane and 5% MeOH in CH2Cl2receiving N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]ndimethylacetamide, which is treated with a saturated solution of hydrogen chloride in EtOAc, followed by lyophilization, getting hydrochloride N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]ndimethylacetamide [70 mg, example 65]. LC/MS: RT=2.2 minutes, MS: 477 (M+H);1H NMR (300 MHz, CDCl3): δ 9,1 (1H, s), 7,95 (1H, USS), and 7.7 to 7.4 (7H, m), of 6.65 (1H, s), 4 (3H, s), 3,8-of 3.75 (2H, m), 3,3 (2H, q, J=6.9 Hz), totaling 3.04 (2H, t, J=6.6 Hz),2,78 (2H, t, J=7.5 Hz), 2.49 USD (3H, s). IC50=37 nm.

Example 66

[2-(2-Fluoro-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]amine

Stage 1. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2-fluoro-4-triptoreline)ethyl]amine [1.47 g, 4.2 mmol, see example 52, step 1], (3-hydroxyphenyl)Bronevoy acid (637 mg, to 4.62 mmol) and Cs2CO3(3.4 g, 10.5 mmol) in dimethyl ether of ethylene glycol (20 ml) and water (4 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.21 mmol) at room temperature. After 15 hours at 85°C the mixture was diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The extracts are dried (MgSO4), filtered through a SiO2and concentrate, getting 3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenol (2 g). LC/MS: RT=2,32 minutes, MS: 408 (M+H).

Stage 2. To a suspension of 3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenol (280 mg, of 0.68 mmol) and Cs2CO3(0,44 g of 1.36 mmol) in DMF (2 ml) was added epichlorohydrin (80 μl, of 1.02 mmol) at room temperature. After 4 hours at 20°C the mixture was diluted with water (10 ml) and extracted with EtOAc (2×10 ml). The extracts washed with water (2×20 ml), dried (MgSO4), filtered and concentrated. The remainder chromatographic on SiO2by elution with 50% EtOAc in heptane and receive [2-(ftor-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]Amin [0.16 g, example 66]. LC/MS: RT=2,62 minutes, MS: 464 (M+H).

Example 67

2-{3-[6-(2,2-Debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionate acid

Stage 1. In the solution ethylbenzonitrile (0.36 g, 2 mmol) in CH2Cl2(10 ml) was added Deoxo-Fluor (1.1 ml, 6 mmol) at 10°C. After 20 hours at 20°C the mixture was quenched with water (10 ml) and poured into Chem-Elut CH2Cl2washing (10 ml). The filtrate is concentrated, obtaining the ethyl ester dipertanyakan acid, which is used in the next stage without additional purification.

Stage 2. The solution obtained above ethyl ester dipertanyakan acid and NH3in MeOH (7M, 10 ml) heated to 60°C for 2 hours in the ampoule high pressure. The mixture is cooled to room temperature and concentrated, gaining 2.2-debtor-2-phenylacetamide (0.33 g). LC/MS: RT=1.7 minutes, MS: 172 (M+H).

Stage 3. To a solution of 2,2-debtor-2-phenylacetamide (0,76 g, 4.4 mmol) in THF (5 ml) was added borane in THF (1M, 20 ml, 20 mmol) at 10°C. After 20 hours at 70°C the mixture was quenched with water (10 ml), concentrated and chromatographic on SiO2by elution with 90% EtOAc in heptane, getting 2,2-debtor-2-phenylethylmin(0,58 g). LC/MS: RT=0,92 minutes, MS: 158 (M+H);1H NMR (300 MHz, CDCl3) δ EUR 7.57 was 7.45 (5H, m); 3,2 (2H, t).

Stage 4. A mixture of 4,6-dichloro-2-methoxypyridine (0.66 g, of 3.69 mmol), 2,2-debtor-2-penile is ylamine (0,58 g, of 3.69 mmol)and NaHCO3(0,93 g, 11.1 mmol) in 95% EtOH (10 ml) heated under reflux. After stirring at 85°C for 5 hours the mixture is diluted with water, filtered, washed (water) and dried, obtaining (6-chloro-2-methoxypyridine-4-yl)-(2,2-debtor-2-phenylethyl)amine in the form of solids (0,58 g). LC/MS: RT=3,17 minutes, MS: 300 (M+H).1H NMR (300 MHz, CDCl3) δ EUR 7.57 was 7.45 (5H, m), 6,1 (1H, s), and 5.2 (1H, s), 4,2-4 (2H, m)to 3.92 (3H, s).

Stage 5. A mixture of (6-chloro-2-methoxypyridine-4-yl)-(2,2-debtor-2-phenylethyl)amine (0,19 g of 0.62 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [190 mg of 0.94 mmol, see example 49(b), stage 2] and Cs2CO3(0.51 g, 1.6 mmol) in dimethyl ether of ethylene glycol (10 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) at room temperature. After 6 hours at 85°C the mixture was diluted with water (15 ml) and extracted with EtOAc (C ml). The extracts are dried (MgSO4), filtered and concentrated. The remainder chromatographic on SiO2by elution with 70% EtOAc in heptane, receiving 2-{3-[6-(2,2-debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid [0.28 g, example 67]. LC/MS: RT=2,82 minutes, MS: 428 (M+H);1H NMR (300 MHz, CDCl3) δ and 9.6 (1H, s), 8 (1H, s), 7,81 (1H, d, J=7.5 Hz), 7,5 to 7.4 (7H, m), 6,4 (1H, s), 4,2-4 (2H, m), of 3.96 (3H, s), of 1.65 (6H, s). IC50=38 nm.

Example 68

2-[3-(2-Methoxy-6-{2-[4-(5-what ethyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionate acid

Stage 1. To a solution of 4-[2-(6-chloro-2-methoxypyridine-4-ylamino)ethyl]benzoic acid (0,41 g of 1.33 mmol), acetic acid hydrazide (0.14 g, 2 mmol) and triethylamine (0.7 ml, 3,99 mmol) in DMF (3 ml) add tetrafluoroborate [(benzotriazol-1 yloxy)dimethylaminomethylene]dimethylammonio (0.51 g, 1.6 mmol) at room temperature. After 15 hours at 20°C, the solid is separated by filtration and washed with water, receiving N'-acetylhydrazide 4-[2-(6-chloro-2-methoxypyridine-4-ylamino)ethyl]benzoic acid (267 mg). The filtrate is extracted with EtOAc and concentrated, gaining additional amount of N'-acetylhydrazide 4-[2-(6-chloro-2-methoxypyridine-4-ylamino)ethyl]benzoic acid (100 mg). LC/MS: RT=2 minutes, MS: 364 (M+H).

Stage 2. A mixture of N'-acetylhydrazide 4-[2-(6-chloro-2-methoxypyridine-4-ylamino)ethyl]benzoic acid (0.2 g, 0.55 mmol) and Burgess reagent (0.39 g, of 1.65 mmol) in THF (6 ml) was placed in a microwave reactor. After 5 minutes at 130°C the mixture was concentrated on a rotary evaporator and chromatographic with elution with 10% MeOH in CH2Cl2receiving (6-chloro-2-methoxypyridine-4-yl)-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethyl}amine (160 mg). LC/MS: RT=2,29 minutes, MS: 346 (M+H).

Stage 3. A mixture of (6-chloro-2-methoxypyridine-4-yl)-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethyl}amine (0.16 g, 0.46 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [25 mg, 0.6 mmol, see example 49(b), stage 2] and Cs2CO3(0,37 g, 1.15 mmol) in dimethyl ether of ethylene glycol (8 ml), acetonitrile (10 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with chloride 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) (20 mg) at room temperature. After 3 hours at 85°C the mixture was diluted with water (15 ml) and extracted with EtOAc (2×15 ml). The extracts are dried (MgSO4), filtered and concentrated. The remainder chromatographic on SiO2by elution with 80% EtOAc in heptane, receiving 2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionic acid [55 mg, example 68]. LC/MS: RT=1,82 minutes, MS: 474 (M+H);1H NMR (300 MHz, CDCl3): δ 7,98-7,81 (4H, m), 7.5 to 7,27 (4H, m), 6,33 (1H, s), of 3.97 (3H, s), 3.72 points-3,6 (2H, m), of 2.92 (2H, t, J=6.5 Hz), 2,6 (3H, s), and 1.6 (6H, s).

Example 69

5-(3-{6-[2-(3,4-Differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]triazole-3-one

Stage 1. A solution of 3,4-diferentialglea (of 5.05 g), nitromethane (5,3 ml) and ammonium acetate (6.3 g) in glacial acetic acid (60 ml) is heated at 110°C for 16 hours, cooled and poured into water (300 ml). The solution is extracted with EtOAc (2×200 ml). The mixture of the extracts washed with 10% NaHCO3, water, dried over sodium sulfate, filtered and evaporated under vacuum, obtaining 1,2-debtor-4-(2-nitrovinyl)benzene (4.2-d). WHO WITH: 198 (M+H); 1H NMR (300 MHz, CDCl3): δ 7,9 (1H, d, J=10 Hz); and 7.5 (1H, d, 10 Hz); and 7.3 (2H, m); 6,95-to 7.15 (1H, m).

Stage 2. To a solution of 1,2-debtor-4-(2-nitrovinyl)benzene (1.5 g) in THF (50 ml) is added dropwise to alumoweld lithium (23 ml, 1M in ether) and the solution heated at 40°C for 3 hours. The solution is cooled, diluted with ether and quenched with Na2SO4·10 H2O (104 g) during the night. The solid is filtered, the solution is removed under vacuum and chromatographic on silica gel with elution EtOAc, receiving 2-(3,4-differenl)ethylamine (0,81 g). MS: 170 (M+H);1H NMR (300 MHz, CDCl3): δ 6,9-7 (3H, m); 2,95 (2H, t); 2,7 (2H, t).

Stage 3. A solution of 4,6-dichloro-2-methoxypyridine (0.7 g), 2-(3,4-differenl)ethylamine (0.66 g) and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated to 80°C for three hours, poured into water (400 ml), the solid is filtered, air-dried and receive (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-differenl)ethyl]amine (1.1 g). MS: 312 (M+H);1H NMR (300 MHz, CDCl3): δ 6,9-7 (3H, m); 6,05 (1H, s); of 3.95 (3H, s); 3,6-3,7 (2H, m); 2,95 (2H, t).

Stage 4. A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(3,4-differenl)ethyl]amine (1.6 g), 3-cyanophenylacetic acid (1.5 g), Cs2CO3(8,3 g) and tetrakis(triphenylphosphine)palladium(0) (45 mg) in water (8 ml) and dimethyl ether (32 ml) is heated at 90°C for 16 hours. The solution was poured into water and extracted with EtOAc (2×200 ml). The mixture of the extracts dried over sodium sulfate, filtered evaporated under vacuum and chromatographic on silica gel with elution EtOAc, getting 3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenol (1.1 g). MS: 379 (M+H);1H NMR (300 MHz, CDCl3): δ 8,3 (1H, s); 8,2 (1H, d, J=5,1 Hz); 7,9 (1H, d, J=5,1 Hz)); and 7.6 (1H, t); 7-7,2 (4H, m); at 6.4 (1H, s); 5 (1H, m); of 3.95 (3H, s); 3,7 (2H, t); 3 (2H, t).

Stage 5. The solution methylglyoxal (11 g) and hydrazine hydrate is added (4.7 g) in MeOH (10 ml) was stirred at room temperature for 16 hours. The solution is concentrated and placed under high vacuum for 3 hours. The residue weighed in THF (200 ml) and add utilizationa (8.5 ml). The mixture is stirred at room temperature for 16 hours. The solid is filtered and washed with diethyl ether, obtaining N-(2-hydroxyacyl)-N-ethylcarbodiimide (19 g).1H NMR (300 MHz, DMSO-d6): δ 9,2 (m, 1H); and 8.6 (s, 1H); 6,3 (m, 1H); 3.9 to (d, 2H, J=0.3 Hz); 3 (kV, 2H); 1 (d, 3H, J=0.4 Hz).

Stage 6. N-(2-hydroxyacyl)-N-ethylcarbodiimide (19 g) was stirred in a solution of NaOH (5.32 g) in water (60 ml) and EtOH (240 ml). The suspension is heated at 82°C for 20 hours. The solution is acidified to pH 6 with concentrated HCl (22 ml) and concentrated to oil. Part of the oil (1.51 g) was stirred in acetonitrile (60 ml) and added dropwise thionyl chloride (0,94 ml). The solution was stirred at room temperature for 20 hours and concentrated to a solid which is triturated in a mixture of Et2O/heptane and filtered in a nitrogen atmosphere, receiving 5-chloromethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-one(1.52 g). 1H NMR (300 MHz, CDCl3): δ 9,9 (m, 1H); 4.5 m (s, 2H); 3,8 (t, 3H); 1,4 (d, 3H, J=0.3 Hz).

Stage 7. A mixture of 3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}phenol (0.4 g) and K2CO3(0,46 g) in MeOH (25 ml) is heated under reflux for 30 minutes. The suspension is cooled to 0°C, add 5-chloromethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-one (0.12 g) and the solution stirred at 0°C for 30 minutes. The solution is acidified to pH 6 glacial acetic acid and extracted with EtOAc (3×100 ml). The combined organic layer is dried over Na2SO4, filtered and evaporated under vacuum. The remainder chromatographic on silica gel with elution with 5% MeOH in EtOAc, receiving 5-(3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]triazole-3-one (185 mg, example 69). MS: 483 (M+H);1H NMR (300 MHz, DMSO-d6): δ 11.8 in (s, 1H); 7.5 to about 7.8 (m, 3H); 7,2-7,4 (m, 2H); 7-7,2 (m, 2H); and 6.6 (s, 1H); from 5.1 (s, 2H); from 3.9 (s, 3H); 3,7 (q, 2H); 3,5 (m, 2H); 2,9 (t, 2H); 1,2 (d, 3H). IC50=143 nm.

Example 70

2-(2-Fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. To a solution of 5-bromo-2-florfenicol acid (5 g) in MeOH (200 ml) is added concentrated sulfuric acid (2 ml) and the solution heated at 64°C for 16 hours. The solution is evaporated under vacuum, the residue is transferred into EtOAc, washed with 10% bicarbonate the sodium, saline solution and dried over sodium sulfate. The solution is filtered and evaporated under vacuum, obtaining the methyl ester of (5-bromo-2-forfinal)acetic acid (5.1 g).1H NMR (300 MHz, CDCl3): δ 7.3 to 7.5 (m, 2H); to 6.9 (m, 1H); from 3.9 (s, 3H).

Stage 2. A solution of methyl ester (5-bromo-2-forfinal)acetic acid (3.5 g) in THF (50 ml) cooled to -70°C and added dropwise KOtBu (36 ml, 1M in THF), keeping the temperature below -65°C. At -78°C in one portion add logmean (2.5 ml) and added 18-crown-6 (0.45 g). The solution was stirred at -78°C for 30 minutes and warmed to room temperature for 16 hours. The solution was poured into water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic extracts washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum. The remainder chromatographic on silica gel with elution with 20% EtOAc in heptane, receiving the methyl ester of 2-(5-bromo-2-forfinal)-2-methylpropionic acid (3.7 g). MS: 276 (M+H);1H NMR (300 MHz, CDCl3): δ 7.3 to 7.5 (m, 2H); to 6.9 (m, 1H); 3,85 (s, 3H); 1,6 (s, 6H).

Stage 3. A solution of methyl ester of 2-(5-bromo-2-forfinal)-2-methylpropionic acid (5,15 g), bis-(pinacolato)Debora (5,24 g), Pd-dppf (0.3 g) and KOAc (3,67 g) in DMSO (2 ml) and THF (200 ml) is heated at 84°C for 16 hours. The solution is cooled to 5°C and add a solution of potassium hydroxide (16.6 g) in water (150 ml). The solution was stirred at room temperature in those which begins 30 minutes and filtered. The filtrate is acidified to pH 6 glacial acetic acid (19 ml) and extracted with EtOAc (2×200 ml). The combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum, obtaining the methyl ester of 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-2-methylpropionic acid (5.3g). MS: 323 (M+H);1H NMR (CDCl3): δ 7.3 to 7.5 (m, 2H); to 6.9 (m, 1H); 3,85 (s, 3H); 1,6 (s, 6H); 1,4 (s, 12H).

Stage 4. A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine (1.6 g), methyl ester 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-2-methylpropionic acid (0,63 g), Cs2CO3(11.6 g) and tetrakis(triphenylphosphine)palladium(0) (0.33 mg) in water (8 ml) and dimethyl ether (32 ml) is heated at 90°C for 16 hours. The solution was poured into water and extracted with EtOAc (2×200 ml). The combined extracts dried over sodium sulfate, filtered, evaporated under vacuum and chromatographic on silica gel with elution EtOAc, receiving the methyl ester of 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid (300 mg). MS: 508 (M+H);1H NMR (300 MHz, CD3OD): δ 7,8 (d, 1H, J=0.3 Hz), and 7.7 (m, 1H); to 7.4 (d, 2H, J=0.4 Hz); 7,2-7,3 (m, 4H); and 6.6 (s, 1H); 4,2 (s, 3H); 4 (s, 3H); 3.9 to (m, 2H); 3,05 (t, 2H); of 1.65 (s, 6H).

Stage 5: a Mixture of methyl ester of 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropyl the OIC acid (1.9 g) and sodium hydroxide (2,46 g) in water (19 ml), MeOH (19 ml) and THF (19 ml) was stirred at 40°C for 40 hours. The solution is evaporated under vacuum and acidified to pH 6 with concentrated HCl (1.6 ml). The solid is filtered, air-dried and chromatographic on silica gel with elution with 50% EtOAc in heptane, obtaining 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid (1.12 g, example 70). MS: 494 (M+H);1H NMR (300 MHz, CD3OD): δ 7,8 (d, 1H, J=0.3 Hz), and 7.7 (m, 1H); to 7.4 (d, 2H, J=0.4 Hz); 7,2-7,3 (m, 4H); and 6.6 (s, 1H); 4,2 (s, 3H); 3.9 to (m, 2H); 3,05 (t, 2H); of 1.65 (s, 6H). IC50=193 nm.

Example 71

2-(3-{2-Methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. By a method similar to that described in example 1, step 3, but replacing the C-thiophene-3-ylmethylamino 2-(3-fluoro-4-methoxyphenyl)ethylamine, get (6-chloro-2-methoxypyridine-4-yl)thiophene-3-ylmethylamino.

Stage 2. Through a mixture of (6-chloro-2-methoxypyridine-4-yl)thiophene-3-ylmethylamino (216 mg, 0.84 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [312 mg, 1.5 mmol, see example 49(b), stage 2], Cs2CO3(821 mg, 2,52 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol) in dimethyl ether of ethylene glycol (2.5 ml) and water (0.5 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 6 hours pre heated remaut and the mixture is cooled to ambient temperature within 24 hours. The mixture was diluted with water (40 ml) and twice extracted with EtOAc (25 ml). The organic extracts are mixed, dried over magnesium sulfate, filtered, concentrated and receive 2-(3-{2-methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid [15 mg, 4.6%, for example 71] in the form of solids. LC/MS RT=1,94 minutes, MS: 384 (M+H). IC50=393 nm.

Example 72

2-(3-{6-[(Benzo[b]thiophene-2-ylmethyl)amino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionate acid

Stage 1. By a method similar to that described in example 1, step 3, but substituting benzo[b]thiophene-2-ylmethylamino 2-(3-fluoro-4-methoxyphenyl)ethylamine, get benzo[b]thiophene-2-ylmethyl-(6-chloro-2-methylpyrimidin-4-yl)amine.

Stage 2. Through a mixture of benzo[b]thiophene-2-ylmethyl-(6-chloro-2-methylpyrimidin-4-yl)amine [247 mg, 0.81 mmol], 3-(1-carboxy-1-methylethyl)phenylboronic acid [304 mg of 1.46 mmol, see example 49(b), stage 2], Cs2CO3(792 mg, 2,43 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol) in dimethyl ether of ethylene glycol (2.5 ml) and water (0.5 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 6 hours the heating is stopped and the mixture was allowed to cool to ambient temperature within 24 hours. The mixture was diluted with water (20 ml) and twice extracted with EtOAc (30 ml). Organic is such extracts are mixed, dried over magnesium sulfate, filtered, concentrated and receive 2-(3-{6-[(benzo[b]thiophene-2-ylmethyl)amino]-2-methylpyrimidin-4-yl}phenyl)-2-methylpropionic acid [of 51.6 mg, 14.7 per cent, example 72] in the form of solids. LC/MS RT=2,27 minutes, MS: 434 (M+H).

Example 73

1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid

In a vessel mix (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [200 mg, 0.6 mmol, intermediate compound (44)], nicotinebuy acid (194 mg, 1.5 mmol), K2CO3(249 mg, 1.8 mmol) and 1-methyl-2-pyrrolidinone (2.5 ml). The vessel is sealed, heated to 140°C and stirred for 5 hours. The mixture is cooled to ambient temperature, leave it for 12 hours, diluted with water (20 ml) and acidified with 3M HCl. The resulting precipitate is collected by filtration and dried under high vacuum, obtaining 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid [121 mg, 47%, example 73] in the form of solids. LC/MS RT=2,15 minutes, MS: 425 (M+H). IC50=0.8 nm.

Example 74

Hydrochloride of 1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarboxylic acid

Stage 1. HCl drawn through a solution of 3-bromoferrocene acid (10.5 g, 46.5 mmol) in EtOH (70 is l) and cooled to 0°C for 5 minutes. Stoppered flask and the solution stirred at ambient temperature for 5 hours. The mixture is concentrated. The residue is transferred into water (80 ml) and twice extracted with EtOAc (70 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining the ethyl ester of (3-bromophenyl)acetic acid [10,55 g, 93.4%are] in the form of oil, which is used without further purification.

Stage 2. Sodium hydride (60% in oil, 1.07 g, 26.8 mmol) is added to a solution of ethyl ester (3-bromophenyl)acetic acid [2,59 g of 10.7 mmol] and 18-crown-6 (catalytic amount) in N,N'-dimethylformamide (50 ml). The mixture is stirred for 25 minutes and added dropwise via syringe 1,4-dibromobutane (1,41 ml of 11.8 mmol). After 18 hours stirring at room temperature the mixture was diluted with water (100 ml) and thrice extracted with EtOAc (60 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining the ethyl ester of 1-(3-bromophenyl)cyclopentanecarboxylic acid [2.9 g, 91%] in the form of oil, which is used without further purification.

Stage 3. A mixture of ethyl ester of 1-(3-bromophenyl)cyclopentanecarboxylic acid [3,42 g, 11,51 mmol], lithium hydroxide (579 mg, 13,81 mmol), THF (13 ml), MeOH (13 ml) and water (13 ml) was vigorously stirred for 18 hours. The mixture is concentrated and the residue diluted with water (50 ml). Water is mesh acidified with concentrated HCl to pH 1 and twice extracted with EtOAc (50 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining 1-(3-bromophenyl)cyclopentanecarbonyl acid [2.5 g, 80.6%of] in the form of a solid substance, which is used without further purification.

Stage 4. A solution of n-utility (2.5m in hexane, 5 ml, 12,48 mmol) in THF (30 ml) cooled to -78°C and added dropwise via syringe add a solution of 1-(3-bromophenyl)cyclopentanecarboxylic acid [1,05 g, 3.9 mmol] in THF (10 ml). The solution is stirred for 45 minutes and treated with tributyrate (3.2 ml, 11.7 mmol). The reaction mixture is stirred for 2.5 hours and then diluted with water (60 ml), acidified with 3M HCl and twice extracted with EtOAc (50 ml). The organic extracts are mixed, dried over magnesium sulfate, filtered and concentrated, obtaining 3-(1-carboxylatomethyl)phenylboronic acid in the form of a solid substance, which is used without further purification.

Stage 5. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [330 mg, 0,99 mmol], 3-(1-carboxylatomethyl)phenylboronic acid [580 mg, 2.48 mmol] and Cs2CO3(808 mg, 2.48 mmol) in dimethyl ether of ethylene glycol (4 ml) and water (1 ml), rinsed with argon for 5 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol), a reaction chamber is sealed and heated to 90°C. After stirring for 8 hours with the ect diluted with water (30 ml), acidified to pH 1 with concentrated HCl and three times extracted with EtOAc (30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and receive 1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarbonyl acid in the form of a solid substance, which is treated with HCl in ethyl acetate. Then the substance is dissolved in acetone (5 ml), add heptane (15 ml) and left at ambient temperature for 16 hours. With crystals decanted solvent and dried under high vacuum, obtaining the hydrochloride of 1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarbonyl acid [48 mg, 9%, example 74] in the form of solids. LC/MS RT=2,54 minutes, MS: 486 (M+H). IC50=0.5 nm.

Example 75

2-Morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

4-Dimethylaminopyridine (4.4 mg, being 0.036 mmol) is added to stirred solution of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid (100 mg, 0.24 mmol), N-(2-hydroxyethyl)research (29,07 μl, 0.24 mmol) and 1,3-dicyclohexylcarbodiimide (0,31 ml, 1M solution in DCM) in dry mixture of THF/DCM (6 ml, 1:1) and the reaction mixture is stirred for 5.5 hours at room the temperature in nitrogen atmosphere. The mixture is filtered che the ez layer cellite and the filtrate concentrated under reduced pressure. The residue is dissolved in EtOAc (30 ml), washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, receiving 2-morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid (56 mg, example 75). LC/MS: RT=2,07 minutes, MS: 534 (M+H);1H NMR (300 MHz, CDCl3): δ to 8.62 (1H, s), and 8.3 (1H, d, J=3.5 Hz)and 8.1 (1H, d, J=3.5 Hz), 7,55 (1H, t, J=3.5 Hz), 7,42 (1H, s), 7,2 (2H, s), 6.48 in (1H, s), 5,04 (1H, ush.), 4,5 (2H, t, J=2 Hz), of 4.05 (3H, s), and 3.72 (6H, t, J=2 Hz), 3,1 (2H, t, J=2 Hz), 2,8 (2H, t, 2 Hz), and 2.6 (4H, t, 2 Hz).

Example 76

2-(4-Methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

By a method similar to that described in example 75, but replacing 1-(2-hydroxyethyl)-4-methylpiperazin N-(2-hydroxyethyl)morpholine, get 2-(4-methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid (47 mg, example 76). LC/MS: RT=2,04 minutes, MS: 545 (M+H);1H NMR (300 MHz, CDCl3): δ 8,6 (1H, s), and 8.3 (1H, d, J=3.5 Hz)and 8.1 (1H, d, J=3.5 Hz), 7,55 (1H, t, J=3.5 Hz), 7,42 (1H, s), 7,2 (2H, s), 6.48 in (1H, s), 5,15 (1H, ush.), 4,5 (2H, t, J=2 Hz), of 4.05 (3H, s), and 3.72 (2H, ush.), 3,1 (2H, t, J=2 Hz), 2,85 (2H, t, 2 Hz), and 2.7 (4H, ush.), 2,5 (4H, ush.), 2,3 (3H, s). IC50 =7 nm.

Example 77

Ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid

Solution Cs2CO3(407 mg, 1.25 mmol in 2 ml water) is added to stirred solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (166 mg, 0.5 mmol) and ehtilkarbodiimidom acid (br135.8 mg, 0.7 mmol) in 1,2-dimethoxyethane (5 ml). The mixture Tegaserod nitrogen for 10 minutes, add tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) and the reaction mixture is heated under reflux at 90°C for 6 hours. The reaction mixture is cooled to room temperature, diluted with water (10 ml), filtered through cellit and remove the volatiles under reduced pressure. The acidity of the aqueous phase adjust to neutral pH (0.1 N. HCl) and extracted twice with ethyl acetate. The combined extracts washed with brine and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of 5-15% ethyl acetate in DCM, obtaining the ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid (48 mg, example 77). LC/MS: RT=2,95 minutes, MS: 447 (M+H);1H NMR (300 MHz, CDCl3): δ 8,65 (1H, s), and 8.3 (1H, d, J=3.5 Hz), 8,15 (1H, d, J=3.5 Hz), 7,55 (1H, t, J=3.5 Hz), 745 (1H, C)to 7.25 (2H, s), and 6.5 (1H, s), of 4.95 (1H, ush.), of 4.45 (2H, q, J=3.5 Hz), of 4.05 (3H, in), 3.75 (2H, ush.), 3,1 (2H, t, J=3.5 Hz), a 1.45 (3H, t, 3.5 Hz). IC50=149 nm.

Example 78

(a)(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol

(b)(3'-Chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol

In a flask made of refractory glass solution (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (250 mg, 0.75 mmol), 3-(hydroxymethyl)phenylboronic acid (137 mg, 0.9 mmol) and Na2CO3(79,7 mg, 0.75 mmol) in a mixture of acetonitrile/water (6 ml, 2:1) Tegaserod nitrogen for 10 minutes. Add tetrakis(triphenylphosphine)palladium(0) (43,5 mg, 0.04 mmol), the flask is sealed and placed in a microwave for 25 minutes at 130°C. the Reaction mixture is diluted with 25 ml of water and extracted twice with ethyl acetate. The combined organic extracts washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (column with silica gel SiO2) with elution with mixture of EtOAc/DCM, getting (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol [165 mg, example 78(a)]. LC/MS: RT=2,24 minutes, MS: 405 (M+H);1H NMR (300 MHz, CDCl3): δ with 8.05 (1H, s), 7,95 (1H, ush.), of 7.48 (3H, ush.), 7,42 (1H, s), 7,2 (1H, s), of 6.45 (1H, s), 4.95 points (1, ush.), 4,78 (2H, ush.), of 4.05 (3H, s), and 3.72 (2H, ush.), 3,1 (2H, t, J=3.5 Hz); get (3'-chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol [110 mg, example 78(b)]. LC/MS: RT=2,12 minutes, MS: 477 (M+H).

Example 79

Methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid

Hydrochloric acid (81,46 μl, 4M solution in 1,4-dioxane, 0.33 mmol) is added to stirred solution of 2-(3-{6-[2-(2,4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [100 mg, 0.22 mmol, example 49(b)] in MeOH (8 ml) and the reaction mixture was stirred overnight at 65°C. the Reaction mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by chromatography and receive the methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid (34 mg, example 79). LC/MS: RT=2,79 minutes, MS: 475 (M+H);1H NMR (300 MHz, CDCl3): δ 7,98 (1H, s), 7,88 (1H, ush.), 7,42 (3H, d, J=2 Hz), 7,2 (2H, s)of 6.4 (1H, s)5,08 (1H, ush.), of 4.05 (3H, s), 3,7 (2H, ush.), the 3.65 (3H, s), 3,1 (2H, t, J=2 Hz), of 1.65 (6H, s).

Example 80

(a)4-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid

Stage 1. Hydrogen chloride is blown through MeOH (80 ml) and the solution stirred at 0oC in accordance with the ie 10 minutes. Added in several portions (3-bromophenyl)acetic acid (30 g, 139,5 mmol) and the reaction mixture was stirred overnight, warming to room temperature. The solution was concentrated in vacuo, the residue is dissolved in EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate and brine, filtered and concentrated, obtaining methyl ether (3-bromophenyl)acetic acid (32 g)used in the next stage without additional purification. MS: 230 (M+H);1H NMR (300 MHz, CDCl3): δ was 7.45 (2H, m), 7,25 (2H, m), and 3.72 (3H, s), 3,6 (2H, s).

Stage 2. A solution of methyl ester (3-bromophenyl)acetic acid (0.6 g, 2,62 mmol) in dry N,N'-dimethylformamide added to stir a suspension of sodium hydride (60% in mineral oil, 0.26 g, 6,55 mmol) in dry N,N'-dimethylformamide at 0°C and continue stirring for 20 minutes. Added dropwise a solution of bis(2-bromacil)ether (0,39 ml, 3.14 mmol) in N,N-dimethylformamide and the reaction mixture was stirred overnight, warming to room temperature. The reaction mixture was quenched with water, extracted twice with ethyl acetate, the combined extracts washed with brine and water, dried over sodium sulfate, filtered and concentrated in vacuo, obtaining the methyl ester of 4-(3-bromophenyl)tetrahydropyran-4-carboxylic acid (610 mg), used in the next stage without additional purification. LC/MS: R T=2,81 minutes, MS: 299, 301 (M+H).

Stage 3. The lithium hydroxide (0.21 g, 5,01 mmol) is added to a solution of methyl ester 4-(3-bromophenyl)tetrahydropyran-4-carboxylic acid (0.5 g, to 1.67 mmol) in methanol/water (8 ml, 3:1) and the reaction mixture is stirred for 5 hours at 65°C. the Mixture is diluted with water and the volatiles removed under vacuum. The aqueous phase is once extracted with diethyl ether, acidified to pH 2 and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filter and concentrate under vacuum, obtaining 4-(3-bromophenyl)tetrahydropyran-4-carboxylic acid (445 mg), used in the next stage without additional purification. LC/MS: RT=1.9 minutes, MS: 283 (M-H).

Stage 4. n-Utility (2M in pentane, 3,18 ml) is added in dry pentane (25 ml) at -78°C, under nitrogen atmosphere, and then added dropwise a solution of 4-(3-bromophenyl)tetrahydropyran-4-carboxylic acid (0.7 g, 2.45 mmol) in THF and the mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched by tributyrate (1.97 ml of 7.35 mmol) and continue stirring for another 1.5 hours, heating the mixture to -20°C. the Reaction mixture was diluted with water and the volatiles removed under vacuum. The aqueous phase is once extracted with diethyl ether, acidified to pH 2 (1 N. HCl) and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filter the display, and concentrate under vacuum. The residue is dissolved in DCM (15 ml), added dropwise heptane (200 ml) and the mixture is stirred for 1.5 hours. The precipitate is filtered by suction and dried in the air, getting 3-(4-tetrahydropyran-4-carboxylic acid)phenylboronic acid (420 mg). LC/MS: RT=1.16 min, MS: 249 (M-H).

Stage 5. Solution Cs2CO3(1.5 g, 4.6 mmol in 15 ml water) is added to stirred solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0,61 g of 1.84 mmol) and 3-(4-tetrahydropyran-4-carboxylic acid)phenylboronic acid (0.6 g, 2.4 mmol) in 1,2-dimethoxyethane (45 ml). The mixture Tegaserod nitrogen for 10 minutes, add tetrakis(triphenylphosphine)palladium(0) (64 mg, 0.03 mmol) and the reaction mixture is heated under reflux at 90°C during the night. The reaction mixture is cooled to room temperature, diluted with water (150 ml), filtered through cellit and remove volatiles under vacuum. The aqueous solution was slowly acidified (pH 4-5, HCl 0.1 N.) under vigorous stirring, which is continued for 2 hours. The formed precipitate is filtered by suction and dried in the air, getting 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid [605 mg, example 80(a)] LC/MS: RT=2.26 and minutes, MS: 502, 504 (M+H), H1NMR [300 MHz, (CD3SO)2SO]: δ was 12.75 (1H, ush.), 8 (1H, s), and 7.8 (1H, ush.), at 7.55 (2H, ush.), was 7.45 (2H, s), 7,35 (2H, s), 6,55 (1H, s), 3,85 3H, C), 3,82 (2H, m), 3,5 (4H, m), 2,95 (2H, t, J=2 Hz), 2,4 (2H, m), of 1.85 (2H, m). IC50=0,05 nm.

(b)N-[4-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (60,4 mg, 0.31 mmol) is added to stir at ice temperature a solution of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid [150 mg, 0.3 mmol, example 80(a)], methanesulfonamide (30 mg, 0.31 mmol) and 4-dimethylaminopyridine (a 38.5 mg, 0.3 mmol) in dry DCM under nitrogen atmosphere and the reaction mixture was stirred overnight, warming to room temperature. The mixture is concentrated under vacuum, the residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried over sodium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, receiving N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide [65 mg, example 80(b)]. LC/MS: RT=2,54 minutes, MS: 579, 581 (M+H);1H NMR (300 MHz, CDCl3): δ 8 (1H, s), a 7.85 (1H, d, J=3.5 Hz), was 7.45 (3H, m), 7,2 (2H, s)of 6.4 (1H, s)5,38 (1H, ush.), 4 (3H, s), 3,65 to-3.9 (6H, m), and 3.2 (3H, s), is 3.08 (2H, t, J=3.5 Hz), a 2.45 (2H, ush.), to 2.18 (2H, m). IC50<1 nm.

(c)Ethyl ester of 4-(3-{6-[2-(2,4-is chlorphenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid

Hydrochloric acid (4M solution in 1,4-dioxane, 20 μl, 0.08 mmol) is added to a solution of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid [(20 mg, 0.04 mmol, example 80(a)] in ethanol (4 ml) and the reaction mixture was stirred overnight at 75°C. the Reaction mixture is cooled to room temperature, quenched with water and extracted twice with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, obtaining the ethyl ester of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid [16 mg, example 80(c)]. LC/MS: RT=2,74 minutes, MS: 530, 532 (M+H);1H NMR (300 MHz, CDCl3): δ with 8.05 (1H, s), and 7.9 (1H, d, J=3.5 Hz), 7,4-of 7.55 (3H, m), 7,2 (2H, s)of 6.4 (1H, s), 5 (1H, ush.), 4,18 (2H, q, J=2 Hz), of 4.05 (3H, s), 3,98 (2H, m in), 3.75 (2H, ush.), the 3.65 (2H, t, J=3.5 Hz), 3,1 (2H, t, J=2 Hz), and 2.6 (2H, d, J=4 Hz), and 2.1 (2H, m), 1,2 (3H, t, J=2 Hz). IC50=223 nm.

Example 81

(a)(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid

Stage 1. By a method similar to that described in example 80(a), stage 1, but replacing ethyl alcohol methyl alcohol, get ethyl ester (3-bromophenyl)acetic acid is you. LC/MS: RT=1,82 minutes, MS: 243, 245 (M+H).

Stage 2. Bis(trimethylsilyl)amide, sodium (1M in THF, 27,14 ml, 27,14 mmol) are added dropwise to ethyl ester (3-bromophenyl)acetic acid (3 g, 12,34 mmol) in dry THF at -78°C under nitrogen atmosphere and the solution stirred for 20 minutes. Added dropwise a solution of N-forbindelseshastighed (8,56 g, 27,14 mmol) in THF and the reaction mixture stirred at -78°C for 3.5 hours. The reaction mixture was quenched with HCl (0,02 N., 150 ml) and twice extracted with DCM. The combined extracts washed with water, dried over magnesium sulfate, filter and concentrate under vacuum, obtaining the ethyl ester of (3-bromophenyl)DIPEROXY acid (2.7 g), used in the next stage without additional purification. LC/MS: RT=3,07 minutes, MS: 279, 281 (M+H);1H NMR (300 MHz, CDCl3): δ of 7.95 (1H, s), the 7.65 (1H, d, J=3.5 Hz), 7,55 (1H, d, J=3.5 Hz), 7,35 (1H, t, J=3.5 Hz), 4,35 (2H, q, J=2,5 Hz)of 1.32 (3H, t, J=2,5 Hz).

Stage 3. The lithium hydroxide (0,13 g of 3.12 mmol) is added to a solution of ethyl ester (3-bromophenyl)DIPEROXY acid (0.29 grams, 1.04 mmol) in methanol/water (8 ml, 3:1) and the reaction mixture was stirred over night at room temperature. The mixture is diluted with water and the volatiles removed under vacuum. The aqueous phase is once extracted with diethyl ether, acidified to pH 2 and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filter, the comfort, and concentrate under vacuum, receiving (3-bromophenyl)DIPEROXY acid (250 mg)used in the next stage without additional purification. LC/MS: RT=2.26 and minutes, MS: 249, 251(M-H).

Stage 4. n-Utility (2M in pentane, 5,18 ml, 10,35 mmol) is added in dry pentane (30 ml) at -78°C, under nitrogen atmosphere, and then added dropwise a solution of (3-bromophenyl)DIPEROXY acid (1 g, 3,98 mmol) in THF and the mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched by tributyrate (3.2 ml, 11,94 mmol) and stirred for 1.5 hours, heating the mixture to -20°C. the Reaction mixture was diluted with water and the volatiles removed under vacuum. The aqueous phase is once extracted with diethyl ether, acidified to pH 2 (1 N. HCl) and extracted twice with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is dissolved in DCM (15 ml), added dropwise heptane (200 ml) and the mixture is stirred for 1.5 hours. The precipitate is filtered by suction and dried in the air, getting 3-(DIPEROXY acid)phenylboronic acid (310 mg). LC/MS: RT=0.68 min, MS: 215 (M-H).

Stage 5. Solution Cs2CO3(0,41 g, 1.25 mmol in 4 ml water) is added to stirred solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.17 g, 0.5 mmol) and 3-(DIPEROXY acid)phenylboronic acid (of 0.13 g, 0.6 mmol) in 1,2-dimethoxyethane (20 ml). See the camping Tegaserod nitrogen for 10 minutes, add tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) and the reaction mixture is heated under reflux at 90°C during the night. The reaction mixture is cooled to room temperature, diluted with water (150 ml), filtered through cellit and remove volatiles under vacuum. The aqueous phase is slowly acidified (pH 4-5, 0.1 G. of HCl) and the mixture is stirred for 2 hours. The formed precipitate is filtered by suction and dried in the air, getting (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid [160 mg, example 81(a)]. LC/MS: RT=2,19 minutes, MS: 468, 470 (M+H);1H NMR [300 MHz, (CD3)2SO]: δ 8,08 (2H, ush.), to 7.7 (2H, m), 7,55 (1H, s), 7,35 (2H, s), of 6.65 (1H, s)to 3.92 (3H, s), the 3.65 (2H, ush.), 3 (2H, t, J=2 Hz). IC50=0,02 nm.

(b)[2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide econsultancy acid

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (43 mg, 0.22 mmol) is added to stir at ice temperature a solution of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid [100 mg, 0.21 mmol, example 81(a)], acanaloniidae (24.5 mg, 0.22 mmol) and 4-dimethylaminopyridine (26.1 mg, 0.21 mmol) in dry DCM under nitrogen atmosphere. The reaction mixture was stirred over night at 60°C. the Mixture is concentrated under vacuum, the residue solution is between ethyl acetate, washed with 0.1 N. HCl, brine and water, dried over sodium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography and receive [2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide econsultancy acid [35 mg, example 81(b)]. LC/MS: RT=2,31 minutes, MS: 559, 561 (M+H);1H NMR [300 MHz, CD3OD]: δ 8,18 (1H, ush.), with 8.05 (1H, ush.), of 7.75 (1H, d, J=4 Hz), and 7.5 (1H, t, J=4 Hz), 7,42 (1H, s), 7,28 (2H, q, J=4 Hz), 6,55 (1H, s), of 3.95 (3H, s), 3,7 (2H, ush.), 3,18 (2H, q, J=4 Hz), is 3.08 (2H, t, J=3.5 Hz)and 1.15 (3H, t, J=4Hz). IC50=0.1 nm.

(c)Ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid

Hydrogen chloride (4M in 1,4-dioxane, 52 μl, 2.1 mmol) is added to a solution of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid [65 mg, 0.14 mmol, example 81(a)] in ethanol (6 ml) and the reaction mixture was stirred overnight at 65°C. the Reaction mixture is cooled to room temperature, quenched with water and extracted twice with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography and get ethyl ester (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid [18 mg, example 81(c)] LC/MS: RT=3,19 minutes, MS: 496, 498 (M+H);1H NMR (30 MHz, CDCl3): δ 8,18 (2H, d, J=3.5 Hz), and 7.7 (1H, d, J=3.5 Hz), 7,55 (1H, t, J=3.5 Hz), and 7.4 (1H, s), 7,42 (1H, s), 7,18 (2H, s), of 6.45 (1H, s)5,08 (1H, ush.), the 4.3 (2H, q, J=4 Hz), of 4.05 (3H, s), and 3.72 (2H, ush.), is 3.08 (2H, t, J=3.5 Hz)and 1.3 (3H, t, J=4 Hz).

Example 82

(a)(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile

Solution Cs2CO3(1.63 g, 5 mmol in 4 ml water) is added to stirred solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.66 g, 2 mmol) and cyanomethylphosphonate acid (0.68 g, 2.8 mmol) in 1,2-dimethoxyethane (8 ml). The mixture Tegaserod nitrogen for 10 minutes, add tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and the reaction mixture is heated under reflux at 90°C during the night. The reaction mixture is cooled to room temperature, diluted with water (100 ml) and stirred for 45 minutes. The resulting precipitate filtered. The solid is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, getting (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile [585 mg, example 82(a)]. LC/MS: RT=2,47 minutes, MS: 413, 415 (M+H).

(b)(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital

Bis(trimethylsilyl)amide, sodium (1M in THF, of 0.53 ml of 0.53 mmol) are added dropwise in peremeshivanii solution of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile (0.1 g, 0.24 mmol) in dry THF at -78°C under nitrogen atmosphere and the solution stirred for 20 minutes. Added dropwise a solution of N-forbindelseshastighed (0.17 g, of 0.53 mmol) in THF and the reaction mixture stirred at -78°C for 3 hours. The mixture is diluted with water and extracted twice with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated under vacuum. The solid is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, getting (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital [15 mg, example 82(b)]. LC/MS: RT=3,34 minutes, MS: 449, 451 (M+H).

(c)[2-(2,4-Dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)Amin

Sodium azide (10 mg, 0.15 mmol) is added to stirred solution of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital (50 mg, 0.11 mmol) in N,N'-dimethylformamide (4 ml) and the reaction mixture is stirred for 4 hours at 80°C. the Reaction mixture was quenched with water, acidified to pH 2 (0,05 N. HCl) and extracted twice with ethyl acetate. The combined extracts dried over sodium sulfate, filtered and concentrated under vacuum. The residue is diluted with toluene and concentrated under vacuum, obtaining [2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)m is Teal]phenyl}-2-methoxypyridine-4-yl)amine [45 mg, example 82(c)]. LC/MS: RT=2,29 minutes, LC/MS: 492, 494 (M+H). IC50=0.1 nm.

Example 83

(a)2-{3-[6-(Indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionate acid

Stage 1. A solution of 4,6-dichloro-2-methoxypyridine (1 g, 5,59 mmol), 2-aminoindane (to 0.72 ml, 5,59 mmol) and sodium bicarbonate (0.7 g, scored 8.38 mmol) in EtOH (25 ml) is heated under reflux during the night. The reaction mixture is cooled to room temperature, quenched with water (100 ml) and stirred for one hour. The formed precipitate is filtered by suction and dried in the air, getting (6-chloro-2-methoxypyridine-4-yl)indan-1-ylamine (1.5 g). LC/MS: RT=3,35 minutes, LC/MS: 276, 278 (M+H).

Stage 2. Solution Cs2CO3(0.32 g, 1 mmol in 2 ml water) is added to stirred solution of (6-chloro-2-methoxypyridine-4-yl)indan-1-ylamine (0.11 g, 0.4 mmol) and 3-(2-methylpropenoic acid)phenylboronic acid (0.1 g, 0.48 mmol) in 1,2-dimethoxyethane (8 ml). The mixture Tegaserod nitrogen for 10 minutes, add tetrakis(triphenylphosphine)palladium(0) (be 18.49 mg, 0.02 mmol) and the reaction mixture is heated under reflux during the night. The reaction mixture is cooled to room temperature, diluted with water (60 ml), filtered through a layer of cellite and remove volatiles under vacuum. The aqueous phase is acidified (pH 4-5, 0.1 G. of HCl and twice extracted with ethyl what cetecom. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/DCM, receiving 2-{3-[6-(indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid [74 mg, example 83(a)]. LC/MS: RT=2,27 minutes, LC/MS: 404 (M+H). IC50=83 nm.

(b)2-{3-[6-(Indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionate acid

Stage 1. By a method similar to that described in example 83(a), stage 1, but replacing 1-aminoindan 2-aminoindan receive (6-chloro-2-methoxypyridine-4-yl)indan-2-ylamine. LC/MS: RT=3,35 minutes, MS: 276, 278 (M+H).

Stage 2. By a method similar to that described in example 83(a), step 2, but replacing (6-chloro-2-methoxypyridine-4-yl)indan-2-ylamine (6-chloro-2-methoxypyridine-4-yl)indan-1-ylamine, get 2-{3-[6-(indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid. LC/MS: RT=2,53 minutes, MS: 404 (M+H).

Example 84

(a)N-[4-(3-{2-Methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (39 mg, 0.2 mmol) is added to stir at ice temperature a solution of N-[4-(3-{2-methoxy-6-[2-(4-triptime xifei)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid (100 mg, 0,19 mmol), methanesulfonamide (19.3 mg, 0.2 mmol) and 4-dimethylaminopyridine (23,6 mg, 0,19 mmol) in dry DCM under nitrogen atmosphere. The reaction mixture was stirred over night at room temperature and concentrate under vacuum. The residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried over sodium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, receiving N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide [86 mg, example 84(a)]. LC/MS: RT=2,52 minutes, LC/MS: 595 (M+H). IC50=0.7 nm.

(b)Methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid

Hydrogen chloride (4M in 1,4-dioxane, to 43.5 μl, 0,17 mmol) is added to a solution of N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid (45 mg, 0.09 mmol) in methyl alcohol (4 ml) and the reaction mixture was stirred overnight at 70°C. the Reaction mixture is cooled to room temperature and quenched with water. Volatiles are removed under vacuum. The aqueous phase is extracted twice with ethyl acetate. The combined extracts dried over sulfate NAT the Oia, filter and concentrate under vacuum. The residue is purified by chromatography (column with silica gel SiO2) with elution with a mixture of ethyl acetate/heptane, receiving the methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid [86 mg, example 84(b)]. LC/MS: RT=2,48 minutes, MS: 532 (M+H). IC50=70 nm.

Example 85

2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-ethoxymethyleneamino-4-yl}phenyl)-2-methylpropionate acid

Stage 1. Gaseous hydrogen chloride is bubbled through a solution of methoxyacetanilide (26 g, and 0.37 mol) in EtOH (22 ml) and diethyl ether (118 ml), cooled to -10°C for twenty minutes. The capacity of the clog and the reaction mixture stirred for 17 hours at ambient temperature. The mixture is cooled to -10°C. the Resulting solid is collected by filtration, washed with diethyl ether and dried in the air, getting hydrochloride ethyl ester 2-methoxyacetophenone acid (49,3 g, 87%) as a solid.

Stage 2. Gaseous ammonia is bubbled through a solution of the hydrochloride of the ethyl ester of 2-methoxyacetophenone acid (49,3 g, 0.32 mol) in EtOH (240 ml), cooled to -10°C for twenty minutes. The container is sealed and the reaction mixture stirred for 17 hours at the temperature of environment is the first environment. The mixture is concentrated under vacuum, obtaining hydrochloride 2-methoxyacetanilide (35 g, 88%) as a solid.

Stage 3. Into a solution of the hydrochloride of 2-methoxyacetanilide (20,18 g, 0.16 mol) and diethylmalonate (24.6 ml, 0.16 mol) in EtOH (150 ml) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The reaction mixture is heated under reflux and stirred for 16 hours. The mixture is concentrated under vacuum, the residue diluted with water (100 ml) and extracted with EtOAc (75 ml). The aqueous layer was acidified to pH 3 with hydrochloric acid and three times extracted with EtOAc (75 ml). Organic extracts from acid solution combine, dried over magnesium sulfate, filtered and concentrated, obtaining 2-ethoxymethyleneamino-4,6-diol (20 g, 80%) as oil.

Stage 4. A solution of 2-ethoxymethyleneamino-4,6-diol (2.3 g, 14.7 mmol), triethylamine (2.9 ml, 20,58 mmol) and phosphorus oxychloride (8,8 ml, 94,08 mmol) is heated under reflux for 1.5 hours. The mixture is concentrated under vacuum, the residue was poured on ice (100 ml) and thrice extracted with EtOAc (75 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining 4,6-dichloro-2-methoxyethylamine (2 g, 70%) as oil.

Stage 5. A solution of 4,6-dichloro-2-methoxypiperidine (250 mg, 1.3 mmol), 2-(2,4-dichlorophenyl)ethylamine (196 μl, 1.3 mmol) and sodium bicarbonate (218 mg, 2.6 mmol) in EtOH (5 is l) is heated at 80°C for three hours, poured into water (20 ml) and thrice extracted with EtOAc (30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of 30% ethyl acetate/heptane, receiving (6-chloro-2-ethoxymethyleneamino-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (200 mg, 44%) as a solid.

Stage 6. Through a mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (200 mg, of 0.58 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [266 mg, 1.28 mmol, see example 49(b), stage 2], Cs2CO3(1.56 g, 2,52 mmol) and tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol) in dimethyl ether of ethylene glycol (4 ml) and water (1 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 16 hours the mixture was diluted with water (40 ml) and twice extracted with EtOAc (25 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of 40% ethyl acetate in heptane and get 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-ethoxymethyleneamino-4-yl}phenyl)-2-methylpropionic acid [165 mg, 60%, example 85] in the form of solids. LC/MS RT=2,59 minutes, MS: 474 (M+H). IC50=2,7 nm.

Example 86

2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-hydroxyethylpyrrolidine-4-yl}phenyl)-2-mate the propionic acid

Stage 1. A mixture of 4,6-dichloro-2-methylsulfonylamino (2.66 g, to 13.6 mmol), 2-(2,4-dichlorophenyl)ethylamine (and 2.26 ml, 15 mmol) and sodium bicarbonate (to 2.29 g of 27.2 mmol) in EtOH (35 ml) is heated at 85°C for 1 hour and poured into water (100 ml). The solid precipitate is collected by filtration and dissolved in hot EtOH (75 ml). After cooling overnight the resulting crystals are collected by filtration and dried, obtaining (6-chloro-2-methylsulfonylamino-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (3,43 g, 72%) as a solid.

Stage 2. A mixture of (6-chloro-2-methylsulfonylamino-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (3,36 g, for 9.64 mmol) in DCM (100 ml) cooled to 0°C and added in several portions 70% 3-chloroperoxybenzoic acid (of 5.99 g, 24,29 mmol). The mixture is stirred at 0°C for 3 hours and warmed to room temperature for 15 hours. The mixture is filtered to remove the precipitate and washed with DCM (100 ml). The filtrate is washed twice 3 N. NaOH (40 ml), dried over magnesium sulfate, filtered and evaporated, obtaining (6-chloro-2-methanesulfonamido-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (3.04 from g, 83%) as a solid.

Stage 3. A solution of (6-chloro-2-methanesulfonamido-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (821 mg, of 2.16 mmol) in THF (15 ml) cooled to 0°C. Add a 1M solution of vinylmania in THF (5.4 ml, 5.4 mmol) and the mixture is stirred for 30 minutes, and then add in the (30 ml) and thrice extracted with EtOAc (50 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of 30% ethyl acetate/heptane, receiving (6-chloro-2-vinylpyridin-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (600 mg) as a solid.

Stage 4. To a solution of (6-chloro-2-vinylpyridin-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (240 mg, 0.73 mmol) in THF (2 ml), acetone (2 ml) and water (2 ml) is added N-oxide 4-methylmorpholine (342 mg, of 2.92 mmol), and then osmium tetroxide (153 μl, 0.015 mmol). After stirring the mixture at room temperature for 17 hours, add a solution of sodium bisulfite (728 mg, 7 mmol) in water (15 ml) and twice extracted with EtOAc (25 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated and receive 1-{4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-yl}-ethane-1,2-diol (320 mg) as a solid.

Stage 5. In a mixture of 1-{4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-yl}-ethane-1,2-diol (320 mg, 0.88 mmol) in MeOH (5 ml) and water (5 ml) add metaperiodate sodium (567 mg, to 2.65 mmol) and the mixture is stirred for 16 hours, and then add water (50 ml) and the mixture is twice extracted with EtOAc (30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated and receive 4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-carbaldehyde (270 mg, 93%) in the form of solid substances is A.

Stage 6. To a solution of 4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-carbaldehyde (70 mg, 0.21 mmol) in MeOH (4 ml) is added sodium borohydride (24 mg, to 0.63 mmol). The mixture is stirred for 4 hours at ambient temperature. Add water (20 ml) and the mixture is extracted three times with ethyl acetate (25 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated and receive {4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-yl}methanol (67 mg) as a solid.

Stage 7. Through a mixture of {4-chloro-6-[2-(2,4-dichlorophenyl)ethylamino]pyrimidine-2-yl}methanol (67 mg, 0.2 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [92 mg, 0.44 mmol, see example 49(b), stage 2], Cs2CO3(197 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (16,3 mg, 0.014 mmol) in dimethyl ether of ethylene glycol (1.6 ml) and water (0.4 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 16 hours the mixture was diluted with water (25 ml), acidified to pH 4 with HCl and three times extracted with EtOAc (25 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated and receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-hydroxyethylpyrrolidine-4-yl}phenyl)-2-methylpropionic acid [16,5 mg, 18%, example 86] in the form of solids. LC/MS RT=2,47 minutes, MS: 460 (M+H). IC50=71 nm.

<> Example 87

5-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}thiophene-2-carboxylic acid

Stage 1. 5-(Dihydroxyaryl)-2-thiencarbazone acid (527 mg, 3.1 mmol) and 2,2-DIMETHYLPROPANE-1,3-diol (361 mg, 3.4 mmol) stirred in THF (10 ml) for 19 hours and concentrated under vacuum, obtaining 5-(5,5-dimethyl-[1,3,2]dioxaborolan-2-yl)thiophene-2-carboxylic acid (748 mg) as a solid. LC/MS: RT=1.15 minutes;1H NMR [300 MHz, (CD3)2SO]: δ 13,15 (1H, s), and 7.7 (1H, m); 7,45 (1H, m); of 3.75 (4H, s); of 0.95 (6H, s).

Stage 2. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [277 mg, 0.83 mmol, intermediate compound (44)], 5-(5,5-dimethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid (300 mg, 1.25 mmol), cesium fluoride (378 mg, 2.5 mmol) and tetrakis(triphenylphosphine)palladium (77 mg, 0.07 mmol) in water (2 ml) and dimethyl ether of ethylene glycol (8 ml) Tegaserod by blowing nitrogen for 5 minutes and heated at 85°C for 16 hours. The reaction mixture is cooled, diluted with water (150 ml) and brine (50 ml)and thrice extracted with EtOAc (150 ml) and concentrate the extracts under vacuum. The residue is purified flash chromatography on a column of silica gel (10 g) with elution with a mixture of from 0 to 15% MeOH in ethyl acetate. The product is twice triturated in heptane (5 ml) and twice in ether (5 ml) and dried, obtaining 5-{6-[2-(2,4-dichlorophenyl)e is ylamino]-2-methoxypyridine-4-yl}thiophene-2-carboxylic acid (189 mg, example 87) in the form of solids. MS: 424 (M+H);1H NMR [300 MHz, (CD3)2SO]: δ 13,2 (1H, s), and 7.7 (3H, m); and 7.6 (1H, s); to 7.35 (2H, s); and 6.6 (1H, s); 4,85 (3H, s); 3,6 (2H, m); 3 (2H, t). IC50=0.16 nm.

Example 88

Hydrochloride 5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid

Stage 1. To a solution of 2,3-dihydrobenzofuran-2-carboxylic acid (510 mg, 3.11 mmol) in glacial acetic acid (4 ml) was added dropwise bromine (497 mg, 3.11 mmol). After 16 hours the reaction mixture was quenched with water (100 ml) and sodium bisulfite (1 g, 9.6 mmol) and twice extracted with EtOAc (100 ml). The extracts are concentrated under vacuum and dried under high vacuum, receiving 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid (811 mg) as a solid. MS: 241 (M+H);1H NMR [300 MHz, (CD3)2SO]: δ of 13.05 (1H, s); 7,4 (1H, s); of 7.25 (1H, d); 6,8 (1H, m); 5.25-inch (1H, HF); 3,55 (1H, DD); to 3.25 (1H, m).

Stage 2. A mixture of 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid (0.74 g, and 2.83 mmol), bis(pinacolato)Debora (1.51 g, 5,94 mmol), potassium acetate (1.47 g, 15 mmol) and complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM (115 mg, 0.14 mmol) in dimethyl sulfoxide (10 ml) Tegaserod by blowing nitrogen for 5 minutes. The mixture is heated at 90°C for 16 hours. The reaction mixture is cooled, diluted with water (200 ml) and brine (25 ml), filter the t through cellit, and then add water (200 ml) and EtOAc (200 ml). The filtrate is twice extracted with EtOAc (200 ml) and the extracts are concentrated under vacuum. The residue is purified flash chromatography on a column of silica gel (4 g) with elution with a mixture of from 80 to 100% EtOAc in heptane, receiving 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylic acid (715 mg) in the form of oil. MS: 289 (M-H);1H NMR [300 MHz, (CD3)2SO]: δ of 13.05 (1H, s); 7,5 (2H, m); 6,8 (1H, m); and 5.2 (1H, m); 3,6 (1H, m); 3,3 (1H, m); of 1.05 (12H, s).

Stage 3. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(4-trifloromethyl)ethyl]amine [475 mg of 1.36 mmol, intermediate compound (13)], 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylic acid (266 mg, of 0.91 mmol), Cs2CO3(1.19 g, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.13 mmol) in water (2 ml) and dimethyl ether of ethylene glycol (8 ml) Tegaserod by blowing nitrogen for 5 minutes and heated at 60°C for 23 hours. The reaction mixture is cooled, diluted with water (200 ml) and brine (50 ml) and acidified with 1 N. hydrochloric acid to pH 5. The mixture was thrice extracted with EtOAc (150 ml) and concentrate the extracts under vacuum. The residue is purified flash chromatography on a column of silica gel (5 g) with elution with a mixture of from 0 to 20% MeOH in ethyl acetate. The product is dissolved in ether and treated with hcl 1M in ether, receiving hydrochloride 5-{2-methoxy-6-[2-(4-t is eformatexif)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid (148 mg, example 88) in the form of solids. MS: 476 (M+H); LC/MS: RT=2,78 minutes, MS: 474 (M-H). IC50=3,1 nm.

Example 89

2,3-Dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid

To a solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [145 mg, 0,315 mmol, example 49(b)] N,N'-dimethylformamide (4 ml) is added (2,2-dimethyl-[1,3]dioxolane-4-yl)methanol [62 mg, 0,472 mmol] and TBTU (151 mg, 0,472 mmol)and then triethylamine (1 ml). The reaction mixture is stirred for 16 hours at room temperature, quenched by addition of water (200 ml) and brine (25 ml) and twice extracted with EtOAc (200 ml). The extracts are concentrated under vacuum and the residue is stirred in MeOH (4 ml). Add 1 N. hydrochloric acid (4 ml). After one hour the reaction mixture was poured into water (150 ml) and twice extracted with EtOAc (150 ml). The extracts are concentrated and the residue purified column flash chromatography on silica gel (4 g) with elution with a mixture of from 60 to 80% EtOAc in heptane and receive 2,3-dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [135 mg, example 89] in the form of oil. MS: 534 (M+H);1H NMR [300 MHz, (CD3)2SO]: δ is 7.9 (1H, s); 7,8 (1H, s); and 7.6 (2H, s); coefficient 7.45 (2H, m), 7,35 (2H, s); and 6.6 (1H, s); 4,8 (1H, d); 4,55 (1H, t); of 4.05 (1H, is); of 3.9 (1H, m); of 3.85 (3H, s); 3,6 (3H, m); of 3.25 (2H, t); 2,95 (2H, t); 1,5 (6H, s). IC50=18 nm.

Example 90

2-(3-{6-[(2,3-Dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. In the mixture of (2,3-dihydrobenzofuran-2-yl)methanol (1.65 g, 11 mmol), phthalimide (3,24 g, 22 mmol) and triphenylphosphine (5,77 g, 22 mmol) in THF (40 ml) add diethylazodicarboxylate (of 3.46 ml, 22 mmol) at -10°C and the mixture is heated to room temperature. After 20 hours at room temperature the mixture is concentrated under vacuum and the residue chromatographic on SiO2(40% EtOAc in heptane)to give 2-(2,3-dihydrobenzofuran-2-ylmethyl)isoindole-1,3-dione (3.58 g). LC/MS: RT=2,64 minutes, MS: 280 (M+H).

Stage 2. To a solution of 2-(2,3-dihydrobenzofuran-2-ylmethyl)isoindole-1,3-dione (0.97 g, 3,47 mmol) in MeOH (15 ml) and CH2Cl2(5 ml) is added hydrazine (0,55 ml of 17.4 mmol). After 20 hours at room temperature the mixture is filtered and the filtrate concentrated. The residue was diluted with water (50 ml) and extracted with CH2Cl2(2×50 ml). The extracts are dried (MgSO4), filtered and concentrated, obtaining C-(2,3-dihydrobenzofuran-2-yl)methylamine, which is used in the next stage without additional purification. LC/MS: RT=1.25 minutes, MS: 150 (M+H).

Stage 3. A mixture of 4,6-dichloro-2-methoxypyridine (0,41 g, 2.3 mmol), C-(2,3-dihydrobenzofuran-2-yl)methylamine (0.5 g, 3,47 mmol) and NaHCO3(0.97 g, 12 mmol) in EtOH (7 ml) is heated under reflux for 3 hours. The mixture is diluted with water (8 ml), filtered and washed (water). The solid is dissolved in EtOAc, dried (MgSO4), filtered and concentrated under vacuum, obtaining (6-chloro-2-methoxypyridine-4-yl)-(2,3-dihydrobenzofuran-2-ylmethyl)amine (0.5 g) as a solid. LC/MS: RT=2,59 minutes, MS: 292 (M+H).

Stage 4. A mixture of (6-chloro-2-methoxypyridine-4-yl)-(2,3-dihydrobenzofuran-2-ylmethyl)amine (167 mg, or 0.57 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid (155 mg, 0.75 mmol) and Cs2CO3(0,46 g of 1.43 mmol) in dimethyl ether of ethylene glycol (8 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.03 mmol) at room temperature. The mixture is heated at 85°C for 3 hours, diluted with water (20 ml) and twice extracted with EtOAc (10 ml). The aqueous layer was separated, acidified to pH 2.5 solution of 1M HCl and extracted with EtOAc (2×10 ml). The extracts are dried (MgSO4), filtered through a short column with SiO2and get 2-(3-{6-[(2,3-dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid (139 mg, example 90). LC/MS: RT=2,05 minutes, MS: 420 (M+H);1H NMR (300 MHz, DMSO-d6): δ 12,4 (1H, s), 8,05-7,8 (2H, m), 7.5 to a 7.1 (5H, m), 6,8-of 6.75 (2H, m), 5 (1H, s), 4 (3H, USS), the 3.65 (2H, USS), 3,4-2,95 (2H, m)to 1.48 (6H, s

Example 91

2-(3-{6-[(Isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. A mixture of 4,6-dichloro-2-methoxypyridine (0.45 g, 2.5 mmol), C-isochroman-1-ylmethylamino (0,53 g, 3.2 mmol) and NaHCO3(0,63 g, 7.5 mmol) in EtOH (5 ml) is heated under reflux for 4 hours. The mixture is diluted with water and concentrated under vacuum. The remainder is divided between EtOAc and water and extracted with EtOAc. The extracts are dried (Na2SO4) and concentrated, obtaining (6-chloro-2-methoxypyridine-4-yl)isochroman-1-ylmethylamino (0.84 g). LC/MS: RT=2,94 minutes, MS: 306 (M+H).

Stage 2. A mixture of (6-chloro-2-methoxypyridine-4-yl)isochroman-1-ylmethylamino (141 mg, 0.46 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid (125 mg, 0.6 mmol) and Cs2CO3(0,37 g, 1.15 mmol) in dimethyl ether of ethylene glycol (8 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (27 mg, is 0.023 mmol) at room temperature. The mixture is heated at 85°C for 3 hours, diluted with water (20 ml) and twice extracted with EtOAc (20 ml). The aqueous layer was separated, acidified to pH 2.5 solution of 1M HCl and extracted with EtOAc (2×30 ml). The extracts are dried (MgSO4), filtered through a short column with SiO2and get 2-(3-{6-[(isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-mate the propionic acid (189 mg, example 91). LC/MS: RT=2,03 minutes, MS: 434 (M+H);1H NMR (300 MHz, CDCl3): δ of 9.8 (1H, s), 8,02 (1H, s), 7,82 (1H, d, J=6 Hz), 7.5 to a 7.1 (6H, m), to 6.43 (1H, s), 5 (1H), 4 (3H, s), 3,85 of 3.75 (1H, m), 3,65-3,55 (1H, m), 3.04 from-2,95 (1H, m)of 2.75 (1H), and 1.8 (6H, s). IC50=23 nm.

Example 92

2-(3-{2-Methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. A mixture of 4,6-dichloro-2-methoxypyridine (0.27 g, 1.48 mmol), C-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)methylamine (0,22 g of 1.23 mmol) and NaHCO3(0,62 g, 7.4 mmol) in EtOH (7 ml) is heated under reflux for 5 hours. The mixture is concentrated under vacuum. The remainder is divided between EtOAc and water and extracted with EtOAc. The extracts are dried (Na2SO4) and concentrated, obtaining (6-chloro-2-methoxypyridine-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amine (0.39 g). LC/MS: RT=3,27 minutes, MS: 321 (M+H).

Stage 2. A mixture of (6-chloro-2-methoxypyridine-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amine (200 mg, of 0.62 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid (190 mg, of 0.94 mmol) and Cs2CO3(0.51 g, 1.6 mmol) in dimethyl ether of ethylene glycol (10 ml) and water (2 ml) Tegaserod by blowing argon for 5 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) at room temperature. The mixture is heated at 85°C for 6 hours, RA is billaut water (20 ml) and extracted with EtOAc (20 ml). The aqueous layer was separated, acidified to pH 3 with a solution of 1M HCl and extracted with EtOAc (2×30 ml). The extracts are dried (MgSO4), filtered and concentrated. The remainder chromatographic on SiO2(70% EtOAc in heptane)to give 2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid (190 mg, example 92). LC/MS: RT=2,59 minutes, MS: 449 (M+H). IC50=278 nm.

Example 93

2-(3-{6-[(Benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate acid

Stage 1. By a method similar to that described in example 1, step 3, but replacing the C-benzofuran-5-ylmethylamino 2-(3-fluoro-4-methoxyphenyl)ethylamine, get benzofuran-5-ylmethyl-(6-chloro-2-methoxypyridine-4-yl)amine.

Stage 2. Through a mixture of benzofuran-5-ylmethyl-(6-chloro-2-methoxypyridine-4-yl)amine (100 mg, 0.35 mmol), 3-(1-carboxy-1-methylethyl)phenylboronic acid [131 mg, 0,63 mmol, see example 49(b), stage 2], Cs2CO3(342 mg, 1.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) in dimethyl ether of ethylene glycol (1.7 ml) and water (0.3 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 6 hours the heating is stopped and the mixture is brought to ambient temperature for 24 hours. The mixture was diluted with water (20 ml) and twice EXT Airout EtOAc (30 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, concentrated and receive 2-(3-{6-[(benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid [50 mg, 34%, example 93] in the form of solids. LC/MS RT=2,05 minutes, MS: 418 (M+H).

Example 94

N-(6-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)ndimethylacetamide

Stage 1. To a solution of 2-amino-6-bromobenzimidazole (10 g, 43,65 mmol), triethylamine (12,2 ml of 87.3 mmol) and N,N-dimethylaminopyridine (269 mg) in THF (100 ml) add acetylchloride (4,7 ml). After stirring for 17 hours, add water (100 ml) and the mixture is twice extracted with EtOAc (75 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining N-(6-bromobenzimidazole-2-yl)ndimethylacetamide (8,79 g, 74%) as a solid.

Stage 2. Through a mixture of N-(6-bromobenzimidazole-2-yl)ndimethylacetamide (5 g, 0.018 mmol), bis(pinacolato)Debora (9.6 g, of 0.038 mol), potassium acetate (9.3 g, 0,095 mol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (816 mg, 1 mmol) in dimethylsulfoxide (60 ml) purge argon for 10 minutes. A reaction chamber is sealed and heated to 90°C. After stirring for 18 hours the mixture was diluted with water (200 ml) and twice extracted with EtOAc (100 ml). The organic extracts are combined, dried over self the volume of magnesium, filtered and evaporated. The remainder chromatographic on silica gel with elution with a mixture of 70% ethyl acetate/heptane, receiving N-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzothiazole-2-yl]ndimethylacetamide (of 5.06 g, 88,3%) as a solid.

Stage 3. Through a mixture of N-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzothiazole-2-yl]ndimethylacetamide (1.12 g, to 3.52 mmol), 2-methoxy-4,6-dichloropyrimidine (700 mg, 3,91 mmol), Na2CO3(625 mg, 5.9 mmol) and chloride bis(triphenylphosphine)palladium(II) (280 mg, 0.4 mmol) in dimethoxyethane (8 ml), water (3.4 ml) and EtOH (2.2 ml) purge argon for 10 minutes. The mixture is treated in a microwave oven at 160°C for 10 minutes, add water (20 ml) and the mixture extracted with EtOAc (40 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated, obtaining N-[6-(6-chloro-2-methoxypyridine-4-yl)benzothiazol-2-yl]ndimethylacetamide (160 mg) as a solid.

Stage 4. A mixture of N-[6-(6-chloro-2-methoxypyridine-4-yl)benzothiazol-2-yl]ndimethylacetamide (160 ml, 0.48 mmol), 2-(2,4-dichlorophenyl)ethylamine (362 μl, 2.4 mmol) and K2CO3(359 mg, 2.6 mmol) in N-methylpyrrolidinone (2,6 ml) heated to 140°C. After 1 hour heat add water (20 ml) and extracted with EtOAc (20 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated. The remainder chromatographic on silica gel with elution with 90% ethyl acetate in heptane, getting t ardoe substance, which is triturated in 1:1-mixture of methanol and ethyl acetate. The solid is collected and receive N-(6-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)ndimethylacetamide [31 mg, 13%, example 94]. LC/MS: RT=2,49 minutes, MS: 488 (M+H). IC50=11 nm.

Example 95

(a)[2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid

The hydrochloride of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (44 mg, 0.23 mmol) is added to stir at ice temperature a solution of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid (100 mg, 0.22 mmol), acanaloniidae (25 mg, 0.23 mmol) and 4-dimethylaminopyridine (27 mg, 0.22 mmol) in dry DCM under nitrogen atmosphere. The ice bath is removed and the reaction mixture was stirred over night at 60°C. the Volatiles removed under reduced pressure, the residue is dissolved in ethyl acetate, washed with 0.1 N. HCl, brine and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (column with silica gel SiO2) with elution with mixture of EtOAc/DCM, receiving [2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid [67 mg, example 95(a)]. LC/MS: RT=2,49 minutes, MS: 551, 553 (M+H).

(b)N-[2-(-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-C-phenylmethanesulfonyl

By a method similar to that described in example 95(a), but replacing phenylmethanesulfonyl on econsultant receive N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-C-phenylmethanesulfonyl [105 mg, example 95(b)]. LC/MS: RT=2,83 minutes, MS: 613, 615 (M+H). IC50=2 nm.

(c)2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he

By a method similar to that described in example 95(a), but replacing the morpholine in econsultant will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-[93 mg, example 95(c)]. LC/MS: RT=2,35 minutes, MS: 529, 531 (M+H). IC50=281 nm.

(d)2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide

By a method similar to that described in example 95(a), but replacing tetrahydropyran-4-ylamine to econsultant will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide [55 mg, example 95(d)]. LC/MS: RT=2,3 minutes, MS: 543, 545 (M+H). IC50=278 nm.

(e)2-(3-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide

By a method similar to the description of namu in example 95(a), but substituting 1H-tetrazol-5-ylamine to econsultant will receive 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide [106 mg, example 95(e)]. LC/MS: RT=2,02 minutes, MS: 527, 529 (M+H). IC50<1 nm.

Example 96

[2-(2,4-Dichlorophenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)piperidine-1-yl]pyrimidine-4-yl}Amin

Stage 1. In a mixture of benzyl ester 3-cyanopiperidine-1-carboxylic acid (1 g, 4.1 mmol), oxide dibutyrate (153 mg, 0.6 mmol) in toluene (8 ml) is added trimethylsilyl (1.1 ml, 8.2 mmol) at room temperature. After heating the mixture at 95oC for 15 hours add an additional amount trimethylsilane (2 ml, 15 mmol) and continue stirring for another 6 hours at 95°C. the Mixture is concentrated and the resulting solid is triturated in heptane (30 ml) and filtered, obtaining benzyl ester 3-(1H-tetrazol-5-yl)piperidine-1-carboxylic acid (1 g). LC/MS: RT=2,31 minutes, MS: 288 (M+H).

Stage 2. To a solution of benzyl ester 3-(1H-tetrazol-5-yl)piperidine-1-carboxylic acid (1 g, 3.5 mmol) in MeOH (20 ml) is added Pd on carbon (10%, 150 mg) at room temperature. The mixture is rinsed several times with argon, and then connect the tank with hydrogen. After 30 hours at 20°C the mixture is filtered and concentrated, obtaining 3-(1H-tetrazol-5-yl)piperidine. LC/MS: RT=0,54 m the chickpeas, MS: 154 (M+H).

Stage 3. A mixture of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine [300 mg, 0.9 mmol], 3-(1H-tetrazol-5-yl)piperidine [383 mg, 2.25 mmol] and K2CO3(373 mg, 2.7 mmol) in N-methylpyrrolidinone (5 ml) is heated at 140°C for 16 hours. The mixture was diluted with water (50 ml), acidified to pH 3 with 10% HCl and three times extracted with EtOAc (40 ml). Organic extracts of acid layers are combined, dried over magnesium sulfate, filtered and concentrated. The remainder chromatographic on silica gel with elution 15% atimetool in DCM and get the oil that is diluted with water (20 ml). The resulting solid is collected by filtration and receive [2-(2,4-dichlorophenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)piperidine-1-yl]pyrimidine-4-yl}amine [303 mg, 75%, example 96] in the form of solids. LC/MS: RT=1,95 minutes, MS: 449 (M+H). IC50=5 nm.

Example 97

1-{6-[2-(2,4-Dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid

Stage 1. A mixture of 2-methoxy-3,6-dichloropyrimidine (635 mg, 3,55 mmol), hydrochloride isonipecaine (706 mg, 4.26 deaths mmol) and sodium bicarbonate (895 mg, 10,65 mmol) in EtOH (12 ml) is heated at 90°C for 15 hours. The mixture is concentrated and the residue is placed in water (30 ml) and thrice extracted with EtOAc (25 ml). The aqueous solution is acidified to pH 3 with 10% citric acid and thrice extracted with EtOAc (25 m is). Organic extracts of acid layers are combined, dried over magnesium sulfate, filtered and concentrated, obtaining 1-(6-chloro-2-methoxypyridine-4-yl)piperidine-4-carboxylic acid [680 mg, 70%] in the form of solids.

Stage 2. In a solution of 1-(6-chloro-2-methoxypyridine-4-yl)piperidine-4-carboxylic acid [131 mg, 0.48 mmol] in MeOH (1 ml) and toluene (1 ml) add a solution of 2M diazomethane in diethyl ether (of 0.48 ml, 0.96 mmol). The solution is stirred for 2 hours at ambient temperature and concentrate. The remainder chromatographic on silica gel with elution with a mixture of 40% ethyl acetate/heptane, receiving methyl ester 1-(6-chloro-2-methoxypyridine-4-yl)piperidine-4-carboxylic acid [103 mg, 75%] in the form of solids.

Stage 3. In vitro mixed methyl ester 1-(6-chloro-2-methoxypyridine-4-yl)piperidine-4-carboxylic acid [103 mg, 0.36 mmol], 2-(2,4-dichlorophenyl)ethylamine (0,163 ml of 1.08 mmol), sodium bicarbonate (181 mg, of 2.16 mmol) and N-methylpyrrolidinone (2 ml). The mixture is heated at 140°C for 12 hours. Add another 2-(2,4-dichlorophenyl)ethylamine (0.2 ml, of 1.33 mmol) and heated at 140°C continued for a further 12 hours. The mixture was diluted with water (30 ml) and twice extracted with EtOAc (30 ml). The organic extracts washed twice with water (40 ml) and once with brine (30 ml)are pooled, dried over magnesium sulfate, filtered and concentrated. The rest of chromatogra irout on silica gel with elution with a mixture of 40% ethyl acetate in heptane and get methyl ester 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid [70 mg, 44%] in the form of solids.

Stage 4. A solution of methyl ester 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid [70 mg, 0.16 mmol] and a 2M solution of lithium hydroxide (1 ml, 2 mmol) in MeOH (1 ml) in THF (1 ml) was stirred at ambient temperature for 15 hours. The mixture is concentrated and the residue is placed in water, acidified to pH 2 by adding 10% HCl and twice extracted with EtOAc (20 ml). Organic extracts of acid layers are combined, dried over magnesium sulfate, filtered, concentrated and receive 1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid [26 mg, 38%, example 97] in the form of solids. LC/MS RT=2,02 minutes, MS: 425 (M+H). IC50=7 nm.

Example 98

2-(2-Chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol

Stage 1. To a suspension of 5-bromo-2-chlorbenzoyl acid (5 g) in MeOH (200 ml) is added concentrated sulfuric acid (2 ml) and the mixture is heated at 64°C for 16 hours. The solution is evaporated under vacuum. The residue is placed in EtOAc and washed with 10% sodium bicarbonate and brine and dried over sodium sulfate. The solution is filtered and evaporated under vacuum, obtaining the methyl ester of 5-bromo-2-chlorbenzoyl acid (5.1 g).1H NMR (300 MHz, CDCl3): δ 7.3 to 7.5 (m, 2H); to 6.9 (m, 1H); from 3.9 (s, 3H).

One hundred is s 2. To a solution of methyl ester 5-bromo-2-chlorbenzoyl acid (5 g) in diethyl ether (200 ml), cooled to -70°C, are added dropwise 3M methylacrylamide in THF (20 ml). The solution was stirred at -78°C for 2 hours and heated to room temperature for 16 hours. The solution is cooled to 0°C and added dropwise 1 N. HCl (100 ml). The mixture is extracted with EtOAc (2×150 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum. The remainder chromatographic on silica gel with elution with 20% EtOAc in heptane, receiving 2-(5-bromo-2-chlorophenyl)propan-2-ol (4,56 g). MS: 250 (M+H);1H NMR (300 MHz, CDCl3): δ 7,8 (m, 1H); 7.5 (m, 1H); to 7.2 (m, 1H); 4,4 (s, 1H); 1,6 (s, 6H).

Stage 3. A solution of 2-(5-bromo-2-chlorophenyl)propan-2-ol (1,72 g), bis-(pinacolato)Debora (1,94 g), Pd-dppf (10 g) and KOAc (1,33 g) in DMSO (30 ml) is heated at 90°C for 16 hours. The solution is cooled to 5°C and add a solution of KOH (16.6 g) in water (150 ml). The solution was stirred at room temperature for 30 minutes and filtered. The solution was diluted with water (200 ml) and extracted with EtOAc (2×200 ml). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum, obtaining 2-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]propan-2-ol.1H NMR (300 MHz, DMSO): δ 7,8 (m, 1H); 7.5 (m, 1H); to 7.2 (m, 1H); 4,4 (s, 1H); 1,6 (s, 6H); 1,4 (s, 12H).

Stage 4. Dissolve the (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0,58 g), 2-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]propan-2-ol (0,63 g), Cs2CO3(1,36 g) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in water (8 ml) and dimethyl ether (32 ml) is heated at 90°C for 16 hours. The solution was poured into water and extracted with EtOAc (2×200 ml). The organic layer is dried over sodium sulfate, filtered and evaporated under vacuum. The remainder chromatographic on silica gel with elution EtOAc, obtaining 2-(2-chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol (162 mg, example 98). MS: 466 (M+H);1H NMR (300 MHz, DMSO): δ 8,2 (m, 1H); 7,8 (d, 1H, J=0.3 Hz); of 7.5 to 7.7 (m, 2H); to 7.4 (d, 2H, J=0.4 Hz); and 7.3 (m, 1H); and 7.3 (s, 1H); and 6.6 (s, 1H); 4,2 (s, 3H); 4 (s, 3H); and 3.8 (m, 2H); 3,05 (t, 2H); 1.55V (s, 6H). IC50=110 nm.

Example 99

Hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid

A solution of (6-chloro-2-methoxypyridine-4-yl)-[2-(2,4-dichlorophenyl)ethyl]amine (0.24 g), 2-[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-2-methylpropionic acid (0.4 g), Cs2CO3(1.01 g) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in water (20 ml) and dimethyl ether (80 ml) is heated at 90°C for 16 hours. The solution was poured into water and extracted with EtOAc (2×200 ml). The organic layer is dried over sodium sulfate, filtered and evaporated under vacuum. The remainder chromatographic on silica gel what elution EtOAc, getting 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid (100 mg)which was dissolved in THF (4 ml) and treated with 4 N. HCl in 1,4-dioxane (1 ml). The mixture is concentrated under vacuum and the residue was stirred in ether (25 ml). The formed solid is filtered in a nitrogen atmosphere and receive hydrochloride 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid (67 mg, example 99). MS: 478 (M+H);1H NMR (300 MHz, CD3OD): δ 7,8 (d, 1H, J=0.3 Hz); to 7.4 (m, 2H); to 7.35 (s, 1H); 7-7,15 (m, 4H); and 6.6 (s, 1H); 4,2 (s, 3H); 3,6 (m, 2H); 3,05 (t, 2H); of 1.65 (s, 6H). IC50=0.5 nm.

PHARMACOLOGICAL TESTS

The inhibitory action of the compounds according to the invention is evaluated by using functional analysis on the DP of the person. Applied analysis of camp using a cell line of human LS174T expressing endogenous receptor DP. A Protocol similar to that described previously (Wright D.H., Ford-Hutchinson A.W., Chadee K., Metters C.M., The human prostanoid DP receptor stimulates mucin secretion in LS174T cells, Br. J. Pharmacol. 131(8): 1537-45 (2000)).

The SPA Protocol-analysis of camp in cells LS174 T person

Materials

- PGD2 (Cayman Chemical, cat. No. 12010)

- IBMX (Sigma cat. No. 5879)

- Direct screening SPA-analysis of camp (code Amersham RPA 559)

- 96-hole plates to cell cultures (Wallac cat. No. 1450-516)

- Scintillation counter Wallac 1450 Trilux Microplate (PerkinElmer)

- Cap tablets

- In saline phosphate buffer (PBS) Dulbecco (Invitrogen cat. No. 14040-133)

- Distilled water

- Shaker

- Magnetic stirrer and a set of anchors

Reagent preparation

Before dilution, all reagents should be brought to room temperature.

Analytical buffer 1X

Transfer the contents of the bottle 500 ml beaker repeated washing with distilled water. Bring total volume to 500 ml by adding distilled water, and mix thoroughly.

Lyse reagent 1 and 2

Dissolve each of the lytic reagents 1 and 2 in 200 ml of analytical buffer, respectively. Leave on for 20 minutes at room temperature to dissolve.

Granules of rabbit antibodies for SPA-analysis

Add in a bottle of 30 ml lyse buffer 2. Gently shake the bottle for 5 minutes.

Immune serum

Add 15 ml of lyse buffer 2 in each vessel and the contents gently mixed until dissolved.

Marker (I125-camp)

Add 14 ml of lyse buffer 2 in each vessel and the contents gently mixed until dissolved.

Preparation of immunoreactive

1) Add an equal volume marker of immune serum and SPA-reagent antibodies rabbit in a vessel, that was made obvious in the first volume for the desired number of holes (150 μl per well).

2) mix Thoroughly.

3) you Must prepare a fresh solution of immunoreactive before each analysis and are not reusable.

Standard

1) Add 1 ml of lyse buffer 1 and the contents gently mixed until dissolved.

2) the Final solution contains camp at a concentration of 512 pmol/ml

3) Mark 7 polypropylene or polystyrene tubes of 0.2 pmol, 0.4 pmol, 0.8 pmol, 1.6 pmol, 3.2 pmol, 6.4 and 12.8 pmol pmol.

4) Pipette add 500 ál lyse buffer 1 in all test tubes.

5) In a test tube "12.8 pmol" add by pipette 500 ál of standard mixture (512 pmol/ml) and mix thoroughly. Transfer 500 ál from tube "12.8 pmol" in the tube "6.4 pmol and mix thoroughly. Repeat the dilution procedure twice with the rest of the tubes.

6) portions of 50 μl in duplicate from each serial dilution and standard source solution allow you to get 8 standard camp levels in the range from 0.2 to 25.6 pmol.

Dilution buffer connection

Add 50 ál of 1 mm IBMX in 100 ml of PBS to obtain a final concentration of 100 μm, and treated with ultrasound at 30°C for 20 minutes.

Preparation PGD2

Dissolve 1 mg of PGD2 (FW, AZN 352.5) 284 μl DMSO to obtain the original solution of 10 mm, and stored at 20°C. Before each analysis must prepare the fresh solution. Add 3 ál of 10 mm initial solution in 20 ml of DMSO, mix thoroughly and transfer 10 ml to 40 ml PBS.

Dilution connection

The dilution of the compounds is carried out in Biomex 2000 (Beckman) using Method 11 points camp DP.

5 ál of each joint of 10 mm tablets of the standard solutions of the compounds are transferred into wells of 96-well plates, as described below.

tr>
123456789101112
A1
B2
C3
D4
E5
F6
G7
HControl

Fill the tablet 45 μl of DMSO, except column 7 where add 28 μl of DMSO. Carefully measure the pipette contents of columns 1 and transfer 12 ál in parallel in column 7. Perform sequence is the emotional dilution 1:10 from column 1 to column 6 and column 7 to column 11, transferring from 5 ál 45 ál DMSO to obtain the following concentrations:

The first tabletThe final concentration
Column 120
Column 110.03 µm
Column 100,3 ám
Column 93 microns
Column 80.03 mm
Column 70.3 mm
Column 60.01 µm
Column 50.1 ám
Column 41 micron
Column 30,01 mm
Column 20.1 mm
Column 11 mm

Add in a new 96-well plate of 247.5 μl of dilution buffer for the connection. Transfer of 2.5 μl of serially diluted compounds from cooked above tablet in new (Rabaul is the 1:100) as follows:

The first tabletThe second tabletThe final concentration
Column 12Column 10
Column 6Column 20.1 nm
Column 11Column 30.3 nm
Column 5Column 41 nm
Column 10Column 53 nm
Column 4Column 60.01 µm
Column 9Column 70.03 µm
Column 3Column 80.1 ám
Column 8Column 90,3 ám
Column 2Column 101 micron
Column 7Column 113 microns
Column 1Column 1210 µm

The growth of cells

1. LS174T always grown in MEM (ATCC cat. No. 30-2003), 10% FBS (ATCC cat. No. 30-2020) and an additional 2 mm L-glutamine, at 37°C and 5% CO2.

2. Warmed 0.05% trypsin, versine (Invitrogen cat. No. 25300-054) at 37°C in a water bath.

3. Remove environment for the growth of cells. The cells in the flask bulldozer t165 washed twice with 4 ml of trypsin, and then incubated at 37°C and 5% CO2within 3 minutes.

4. Add 10 ml of medium and pipette carefully separate and count the cells.

5. Bring the density of the cells to 2.25×105cells per ml and sow 200 ál of cells per well (45,000 cells per well) in 96-well tablet 1 day before analysis.

Order analysis

Day 1

Sow 45,000 cells per well in 200 μl of medium in 96-well plates. Incubated tablets with cells at 37°C, 5% CO2and 95% humidity during the night.

Day 2

WIPOnet dilution of the compounds.

2. Prepare analytical buffer lyse buffers 1 and 2, PGD2and the standard.

3. Remove the medium from the cells by aspiration and add 100 ál of a solution of the compound, following the Protocol of camp DP Zymark Sciclone-ALH/FD.

4. Incubate cells at 37°C, 5% CO2and 95% humidity in techenie minutes.

5. Add 5 ál of 300 nm PGD2 (20×15 nm final concentration) to each well using a Protocol Zymark camp DP PGD2 and incubated the cells at 37°C, 5% CO2and 95% humidity for another 15 minutes.

6. Remove the medium from the cells by aspiration, add 50 ál lyse buffer 1 using the Protocol Zymark camp DP lysis and incubated at room temperature with shaking for 30 minutes.

7. Add to the wells, 150 μl of immunoreagent (total volume 200 μl per well).

8. Seal tablet, shaken for 2 minutes and placed in a scintillation camera counter for microtiter tablets Wallac for 16 hours.

Day 3

Consider the number of [125I] camp for 2 minutes in a scintillation counter 1450 Trilux.

Data processing

Build standard dependence camp on the number of pulses per minute.

Table 1
Typical data analysis for standard
camp (pmol/ml)Imp./minCf. imp./min
0,2572557695530
0,45367 52596317
0,8469547966507
1,6425141786581
3,2343434296601
6,4275827166711
12,8209420546680
25,6153115736653

Concentration camp (pmol/ml) of unknown samples are calculated according to a standard based camp on the number of pulses per minute. The percentage inhibition is calculated according to the following formula:

Results

Compounds included in the scope of the present invention, give 50% inhibition in the SPA-analysis of camp in T-cells LS174 person at concentrations in the range from about 0.1 nm to about 10 μm. Preferred compounds included in the scope of the present invention,give 50% inhibition in the SPA-analysis of camp in T-cells LS174 person at concentrations in the range of from about 0.1 to about 100 nm. More preferable compounds included in the scope of the present invention, give 50% inhibition in the SPA-analysis of camp in T-cells LS174 person at concentrations in the range of from about 0.1 to about 30 nm.

1. The compound of formula (I)

where (A) Cy1To 6-membered heterocyclyl containing N as a heteroatom, 5,6-membered monocyclic or 9,10-membered bicyclic heteroaryl containing one to three heteroatoms selected from N, S and O, phenyl or phenyl fused with 5-membered heterocyclyl, containing O as the heteroatom, each of which optionally has from one to three identical or different substitute groups Cy1which are:
(C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)-alkylsulfonyl, (C3-C6-cycloalkyl, 6-membered heterocyclyl containing 1-2 heteroatoms selected from O and N, and phenyl, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O, Y1Y2N, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-;
(C1-C6-alkoxycarbonyl;
(C1-C6)-alkyl, which optionally contains from one to three identical or different substituents, which are the FDS is th halogen, carboxy, cyano, hydroxy, Y1Y2N, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-membered heterocyclyl containing N as the heteroatoms, a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O; or (C1-C6-alkoxycarbonyl; and
(C1-C6)-alkoxy, which optionally has one to three identical or different substituents, represents carboxy, (C1-C6-alkoxycarbonyl, cyano, 3-membered heterocyclyl, containing O as the heteroatom, or a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O;
where the phenyl or heteroaryl fragments in the replacement group Cy1optional independently have substituents, represents hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;
and where cycloalkyl fragments in the replacement group Cy1optional independently have deputies, representing (C1-C6)-alkoxy, carboxy;
(B) Cy2- 9-membered cycloalkenyl, phenyl, 5,6-membered monocyclic or 9,10-membered bicyclic heteroaryl containing one to three heteroatoms selected from N, S and O, or phenyl fused with 5,6-membered heterocyclyl is m, containing one or two heteroatoms, selected from N and O, each of which is independently optionally has from one to three identical or different substituents representing a (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-;
(C) L1- alkylen with a linear or branched chain containing from 1 to 6 carbon atoms, optionally substituted by carboxy; or
L1- -CH2-(C1-C5)halogenation;
(D) R1- (C1-C4)-alkoxy, which optionally has one to three substituents as halogen;
(E) L2- bond, -O - or-CH2-O-;
and where R2, R3, R4and R5each independently represents H or (C1-C6)-alkyl,
R6- (C1-C6)-alkyl;
R7- N or (C1-C6)-alkyl;
R8- (C1-C6)-alkyl, phenyl-(C1-C6)-alkyl;
Y1and Y2each independently represent hydrogen or (C1-C6)-alkyl, which optionally has one to three identical or different substituents, represents carboxy, (C1-C6)-alkoxy; or
Y1and Y2together with the nitrogen atom to which they are bound, form a nitrogen-containing six-membered saturated courtesans who were cilil, which optionally contains one heteroatom selected from O or NY3where Y3is hydrogen or (C1-C6)-alkyl;
provided that if R1- methoxy, L1- -CH2-CH2-L2communication and Cy2is 2,4-dichlorophenyl, Cy1is not 1-methyl-2-ethoxycarbonylmethyl-5-yl;
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1- methoxy, ethoxy or 2,2,2-triptoreline; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where Cy1- phenyl, benzimidazolyl, benzothiazolyl, benzo[b]thiophenyl, 1H-benzotriazolyl, 2,3-dihydrobenzofuranyl, furanyl, imidazolyl, 1H-indazole, indolyl, ethenolysis, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridyl, thiazolyl, chinoline, thienyl or piperidinyl, each of which is optionally independently has from one to three identical or different substitute groups Cy1; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

4. The compound according to claim 1, where Cy1- phenyl, benzimidazole-2-yl, benzimidazole-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzofuran-5-yl, FSD is n-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups Cy1; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

5. The compound according to claim 1, where Cy2- phenyl, benzo[1,3]dioxole, benzofuranyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[b]thiophenyl, imidazolyl, indolyl, isopropanol, pyridyl or thienyl, each of which optionally has from one to three identical or different substituents, which are (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N -, or N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

6. The compound according to claim 1, where Cy2- phenyl, benzo[1,3]dioxol-5-yl, benzofuran-6-yl, 2,3-dihydrobenzofuran-2-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-2-yl, benzo[b]thiophene-2-yl, imidazol-4-yl, 1H-indol-3-yl, 1H-indol-5-yl, isochroman-1-yl, pyridine-2-yl, pyridin-3-yl, pyridin-yl or Tien-2-Il, each of which optionally has from one to three identical or different substituents, which are (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N -, or N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

7. The compound according to claim 1, where L1- -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH(CH3)-, -CH2- (CH3)2-, -CH(CH3)-CH2-, -CH(CO2H)-CH2-, -CH2-CF2-or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

8. The compound according to claim 1, where L1and Cy2together represent indan-1-yl or indan-2-yl; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

9. The compound according to claim 1, where L1- -CH2-CH2-; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

10. The compound according to claim 1, where L1- -CH2-CF2-; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

11. The compound according to claim 1, where Cy1- asamese the hydrated phenyl or phenyl, having from one to three same or different substitute groups, which are:
(C1-C6)-acyl, (C1-C6)-alkylsulfonyl, carboxy, cyano, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O, hydroxy, Y1Y2N, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, (C1-C6)-alkyl-NH-C(=O)-NH-;
(C1-C6)-alkoxy, which optionally has one to three identical or different substituents, which are carboxyl group or a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O; or
(C1-C6)-alkyl, which optionally has one to three identical or different substituents which are halogen, carboxy, 5-membered heteroaryl containing 1-3 heteroatom selected from N and O, cyano, hydroxy, Y1Y2N-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-;
where the phenyl or heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;
or its N-oxide, or (C1-C6)-alkilany Konyagin, or its pharmaceutically acceptable salt.

12. The compound according to claim 1, where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzofuran-5-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-Il or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups, which are (C1-C4-alkanoyl, (C1-C4)-alkoxy, carboxy, cyano, Y1Y2N, Y1Y2NC(=O)-, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O; or (C1-C4)-alkyl, which optionally has from one to three identical or different substitute groups, which are halogen, carboxy, 5-membered heteroaryl containing 1-3 heteroatom selected from N and O, hydroxy, or Y1Y2N-; where the heteroaryl fragments in foster groups is independently optionally substituted by hydroxy, (C1-C6)-alkyl or (C1-C6)-alkoxy; or its N-oxide, or (C1-C6)-alkilany complex EF the R, or its pharmaceutically acceptable salt.

13. The compound according to claim 1, where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzofuran-5-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-Il or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups are formyl, acetyl, methoxy, carboxy, cyano, methyl, oxazol-5-yl, HO2C-CH2-NON2-BUT-CH(CH3)-, H2N-CH2-, CH3NHCH2-, CH3OCH2CH2NHCH2-, CH3NH-C(=O)-,,oror its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

14. The compound according to claim 1, where Cy1is phenyl or phenyl having one to three identical or different substituents, which are the formyl, acetyl, methoxy, hydroxy, cyano, carboxy, CH3SO2-, CH3CH2SO2-, HO2C-CH2-O-, HO2C-With(With the 3)2-O-, 3-methylisoxazol-5-yl, 3-methyl-[1,2,4]oxadiazol-5-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 5-methyl-2H-[1,2,4]triazole-3-yl, oxazol-5-yl, H2N - (CH3)2N-CH3OCH2CH2NH-,,, HO2C-CF2-, CH3CH2SO2NHC(=O)-(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-, H2N-C(=O) -, - CH3NHC(=O)-, (CH3)2NC(=O)-, HO2CCH2NH-C(=O)-, HO2CCH(CH3)NH-C(=O)-, HO2CCH(CH{CH3}2)NH-C(=O), HO2CCH(CH2CH{CH3}2)NH-C(=O)-,H2N-SO2-, CH3NHSO2-, CH3CH2NHSO2-, (CH3)2CHNH-SO2-, CH3CH2NH-C(=O)-CH2-O-CH3-SO2-NH-C(=O)-, CH3-SO2-N(CH3)-C(=O) -, - CH3-C(=O)-NH-,
HO2C-CH2CH2-, HO2C-CH(CH3)-, HO2C-C(CH3)2-, NC-CH2-NON2-NON2CH2-BUT-CH(CH3)-BUT-(CH3)2-, H2NCH2-, (CH3)2NCH2CH2NHCH2-,CH3-C(=O)-NH-CH2-, CH3-C(=O)-NH-CH2-CH2-,or; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically priemel who may salt.

15. The compound according to claim 1, where Cy2is phenyl, which optionally has one to three identical or different substituents, which are (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen (C1-C6)-alkoxy, nitro, Y1Y2N -, or N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

16. The compound according to claim 1, where Cy2is phenyl, which optionally has one to three identical or different substituents, which are the methoxy, ethoxy, methyl, ethyl, bromine, chlorine, fluorine, F2HCO-, F3CO-, amino, hydroxy, nitro, or N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

17. The compound according to claim 1, where Cy2- benzo[1,3]dioxol-5-yl, 1H-indol-3-yl, 1H-indol-5-yl, imidazol-4-yl, 1H-indol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl or Tien-2-yl, each of which optionally has from one to three identical or different substituents, which are (C1-C6)-alkoxy, halogen or hydroxy; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

18. The compound according to claim 1, where L2communication; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable Sol is.

19. The compound according to claim 1, where the compound has formula (II)

or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

20. The connection according to claim 19, where Cy1is phenyl or phenyl having from one to three identical or different substitute groups, which are:
(C1-C6)-acyl, (C1-C6)-alkylsulfonyl, carboxy, cyano, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O, hydroxy, 6-membered heterocyclyl containing 1-2 heteroatoms selected from O and N, Y1Y2N, Y1Y2NC(=O)-, Y1Y2N-SO2-, R6-C(=O)-N(R5)-, (C1-C6)-alkyl-NH-C(=O)-NH-;
(C1-C6)-CNS group, which is optionally substituted by a carboxyl group or a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O; or
(C1-C6)-alkyl, which is optionally substituted with halogen, carboxy, cyano, 5-membered heteroaryl containing 1-3 heteroatom selected from N and O, hydroxy, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-;
where heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R 8-SO2-N(R5)-C(=O)-;
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

21. The connection according to claim 19, where Cy1is phenyl or phenyl having from one to three identical or different substitute groups, kotorii are formyl, acetyl, cyano, methoxy, hydroxy, carboxy, 3-methylisoxazol-5-yl, 3-methyl-[1,2,4]oxadiazol-5-yl, 5-methyl-[1,3,4]oxadiazol-2-yl, 5-methyl-2H-[1,2,4]triazole-3-yl, oxazol-5-yl, H2N-CH3-NHC(=O) -, - CH3SO2-, CH3CH2SO2-, HO2C-CH2-O-, HO2C-C(CH3)2-O-CH3OCH2CH2NH-, H2N-SO2-, CH3NHSO2-, CH3CH2NHSO2-, (CH3)2CHNH-SO2-, CH3-SO2-NH-C(=O)-, CH3-SO2-N(CH3)-C(=O) -, - CH3-C(=O)-NH-, CH3CH2NH-C(=O)-NH-, HO2C-CH2CH2-, HO2C-CH(CH3)-, HO2C-C(CH3)2-NON2-BUT-CH(CH3)-BUT-(CH3)2-, NC-CH2-, HO2C-CF2-, CH3CH2SO2NHC(=O)-(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-,or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

22. The connection according to claim 19, where Cy1- benzimidazole-2-yl, benzimidazol the-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzofuran-5-yl, furan-2-yl, furan-3-yl, imidazol-1-yl, 1H-indazol-6-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which is optionally has from one to three identical or different substitute groups, which are:
(C1-C6)-acyl, carboxy, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O, Y1Y2NC(=O)-; or
(C1-C6)-alkyl, which is optionally substituted by carboxyl group, a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O, or a hydroxyl group;
where heteroaryl fragments in foster groups can be independently substituted by hydroxy, (C1-C6)-alkyl or (C1-C6)-alkoxy;
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

23. The connection according to claim 19, where Cy1- benzimidazole-2-yl, benzimidazole-5-yl, benzothiazol-6-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, 1H-benzotriazol-6-yl, 2,3-dihydrobenzofuran-5-yl, furan-2-yl, furan-yl, imidazol-1-yl, 1H-indazol-6-yl, indolin-5-yl, indol-3-yl, indol-5-yl, indol-6-yl, isoquinoline-5-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, oxazol-5-yl, phenyl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrid-3-yl, pyrid-4-yl, thiazol-2-yl, quinoline-3-yl, quinoline-6-yl, quinoline-8-yl, Tien-2-yl, Tien-3-yl or piperidine-1-yl, each of which optionally has from one to three identical or different substitute groups are formyl, acetyl, methyl, methoxy, carboxy, oxazol-5-yl, HO2C-CH2-NON2-, CH3NH-C(=O)-,; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

24. The connection according to claim 19, where Cy2is phenyl, which optionally has one to three identical or different substituents, which are (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen (C1-C6)-alkoxy, nitro, Y1Y2N -, or N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

25. The connection according to claim 19, where Cy2is phenyl, which optionally has one to three identical or different substituents, which are the methoxy, methyl, ethyl, cyano, bromine, chlorine, fluorine, F2HCO-, F3CO-, nitro; or its N-oxide, or (C1-C6and what of Kilby ester, or its pharmaceutically acceptable salt.

26. The connection according to claim 19, where Cy2- benzo[1,3]dioxol-5-yl, benzofuran-6-yl, 2,3-dihydrobenzofuran-2-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-2-yl, benzo[b]thiophene-2-yl, imidazol-4-yl, 1H-indol-3-yl, 1H-indol-5-yl, isochroman-1-yl, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl or Tien-2-yl; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

27. The connection according to claim 19, where Cy2- benzo[1,3]dioxol-5-yl, 2,2-debtorrent[1,3]dioxol-5-yl, pyridine-4-yl or Tien-2-yl; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

28. The connection according to claim 19, where Cy1is phenyl, which optionally has from one to three identical or different substitute groups, which are:
(C1-C6)-acyl, carboxy, cyano, 5-membered heteroaryl containing one to three heteroatoms selected from N, S and O, 6-membered heterocyclyl containing 1-2 heteroatoms selected from O and N, hydroxy, Y1Y2NC(=O)-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-;
(C1-C6)-CNS group, which is optionally substituted by a carboxyl group or a 5-membered heteroaryl containing 1-3 heteroatom selected from N and O; or
(C1-C6)-alkyl, which is optionally substituted with halogen, carboxy, -membered heteroaryl, containing 1-3 heteroatom selected from N and O, hydroxy, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-;
where heteroaryl fragments in foster optional groups independently have the substituents are hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-;
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

29. The connection according to claim 19, where Cy1is phenyl, which optionally has from one to three identical or different substitute groups are formyl, methoxy, carboxy, cyano, HO2C-CH2-O-, HO2C-C(CH3)2-O-CH3NHC(=O)-, CH3-SO2-NH-C(=O)-, BUT2C-CH(CH3)-, HO2C-C(CH3)2-NON2-, HO2C-CF2-, CH3CH2SO2NHC(=O)-C(CH3)2-, PhCH2SO2NHC(=O)-C(CH3)2-, CH3CH2SO2NHC(=O)-CF2-; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

30. The connection according to claim 19, where Cy1is:
,,,
,, ,
,,,,
,,,
,,,
,,,; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

31. The connection according to claim 19, where Cy1- 1H-benzotriazol-6-yl, 1H-indazol-6-yl, indol-5-yl, indol-6-yl, quinoline-6-yl, quinoline-3-yl, Tien-2-yl, Tien-3-yl or 1-piperidine-1-yl, each of which optionally has from one to three identical or different substituents, which are (C1-C6)-acyl, carboxy, Y1Y2NC(=O)-; or (C1-C6)-alkyl, which is optionally substituted by carboxyl or hydroxyl group; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

32. The connection according to claim 19, where Cy1- 1H-benzotriazol-6-yl, 1H-indazol-6-yl, indol-5-yl, indol-6-yl, quinoline-6-yl, quinoline-3-yl, Tien-2-yl, Tien-3-yl or 1-piperidine-1-yl, each of which optionally has from one to three identical or different substituents, which are the Xia formyl, carboxy CH3-NH-C(=O)-, HO2C-CH2-or BUT-CH2-; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

33. The connection according to claim 19, where Cy1is:
,,,
,,,
,,,
,,,;
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

34. The connection according to claim 19, where su2- 4-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-differenl, 2-fluoro-6-chlorophenyl, 3-fluoro-4-methoxyphenyl, 4-forfinal, 4-methoxyphenyl, 4-nitrophenyl, 2,2-debtorrent[1,3]dioxol-5-yl; or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

35. The connection, which is a
3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile,
[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,
3-{2-methoxy-6-2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide,
N-ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,
N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide,
[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine,
N-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)acetamide", she
N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetamide", she
ethyl ester of (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid,
3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,
4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,
[6-(3,5-dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-yl)pyrimidine-4-yl]amine,
(6-isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,
(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol,
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol,
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamine is]pyrimidine-4-yl}phenyl)methanol,
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol,
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine,
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine,
[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
N-(2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide,
4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide,
[2-methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
(6-benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,
1-(4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon,
[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[6-(2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[6-(4-dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[6-(5-deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmatieteen-2-yl)pyrimidine-4-yl]amine,
6-{4-fluoro-3-[(2-methoxyethylamine)is ethyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,
4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol,
N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N,N'-dimethylated-1,2-diamine,
[6-(1H-benzimidazole-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-yl]amine,
[6-(3,4-acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine,
2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,
[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]amine,
ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid,
methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid,
methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid,
methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid is,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile,
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile,
2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid,
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid,
(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid,
2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,
[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine,
[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine,
{2-methoxy-6-[4-methoxy-3-(1-N-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,
N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide,
3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamid,
the reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
the reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
the oxime of 3-{2-methoxy-6-[2-(4-shall ethoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,
the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone,
the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl }thiophene-2-carbaldehyde,
[6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-methylpropyl]Amin,
5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-it,
5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-it,
3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-he,
3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-he,
3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-he,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,
3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid,
[2-(3,4-acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl)amine,
[2-(3,4-acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl)amine,
(6-biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine,
3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}ensinou acid,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide,
1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon,
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol,
2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde,
1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone,
3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
[2-methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol,
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-4-Yeremey-4-yl)amine,
2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol,
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile,
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde,
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
[2-methoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
2-methoxy-5-{2-methoxy-6-[2-(methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde,
ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid,
{2-methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,
{2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,
{2-methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,
{2-methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine,
[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine,
1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea,
ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid,
[2-(4-chlorophenyl)-1-methylethyl]-[6-(3,4-acid)-2-methoxypyridine-4-yl]amine,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine,
[2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-ileti]Amin,
3-{2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol,
[2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
[2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
[2-is ethoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)amine,
[2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
(4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)amine,
[2-(1H-imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine,
(2S)-2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid,
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
[2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
(2-methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine,
3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine,
N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetamide", she
[2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine,
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol,
[2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylprop the new acid 1-ethoxycarbonylmethyl ester,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid 2-dimethylaminoethyl ester,
(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid,
[6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium,
[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine,
3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile,
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid,
ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid,
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,
methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid,
methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid,
N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate,
N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)e is ylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]acetamide", she
[2-(2-fluoro-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]amine,
2-{3-[6-(2,2-debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,
2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionic acid,
5-(3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]triazole-3-one,
2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{2-methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-3-carboxylic acid
1-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarbonyl acid,
2-morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
2-(4-methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl) methanol,
(3'-chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol,
methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypurine the Jn-4-yl }phenyl)-2-methylpropionic acid,
4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,
N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide,
ethyl ester of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)deferoxamine econsultancy,
ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile,
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)differenital,
[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine,
2-{3-[6-(indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,
2-{3-[6-(indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid,
N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide,
methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid,
5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxyp rimidine-4-yl}thiophene-2-carboxylic acid,
5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid,
2,3-dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{6-[(2,3-dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{6-[(isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid,
2-(3-{6-[(benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid,
N-(6-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)acetamide", she
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid,
N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-phenylmethanesulfonyl,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide,
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic what islote,
2-(2-chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol,
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid, or
or its N-oxide, or (C1-C6)-alkilany ester, or its pharmaceutically acceptable salt.

36. The compound or its pharmaceutically acceptable salt, which is:
3-{6-[2-(3-fluoro-4-methoxyphenyl)ethylamino]-2-methoxypyridine-4-yl}benzonitrile;
[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-N-methylbenzenesulfonamide;
N-ethyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide;
N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide;
[6-(3-AMINOPHENYL)-2-methoxypyridine-4-yl]-[2-(4-trifloromethyl)ethyl]amine;
N-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide;
N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)ndimethylacetamide;
ethyl ester of (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)carbamino acid;
3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl is)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid;
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl)thiophene-2-carbaldehyde;
4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
[6-(3,5-dimethylisoxazol-4-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-methoxy-6-(5-methylthiophene-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(1H-pyrazole-4-yl)pyrimidine-4-yl]amine;
(6-isoquinoline-5-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine;
(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol;
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol;
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanol;
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol;
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine;
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine;
[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
N-(2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanesulfonamide;
4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide;
[2-methoxy-6-(1-methyl-1H-indol-5-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
(6-benzo[b]thiophene-2-yl-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine;
1-(4-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}f the Nile)Etalon;
[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[6-(2,3-dihydrobenzofuran-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-methoxy-6-(4-(morpholine-4-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[6-(4-dimethylaminophenyl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-methoxy-6-(5-oxazol-5-althofen-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-methoxy-6-(3-oxazol-5-ylphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[6-(5-deformalities-2-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-(4-methoxyphenyl)ethyl]-[2-methoxy-6-(5-pyrrolidin-1-ilmatieteen-2-yl)pyrimidine-4-yl]amine;
the hydrochloride of 6-{4-fluoro-3-[(2-methoxyethylamine)methyl]phenyl}-2-methoxypyridine-4-yl)-[2-(4-methoxyphenyl)ethyl]amine;
hydrochloride 4-[2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoylamino)ethyl]phenol;
the hydrochloride of N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-N',N'-dimethylated-1,2-diamine;
[6-(1H-benzimidazole-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
6-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}-3H-benzoxazol-2-he;
hydrochloride 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-the l}benzoic acid;
hydrochloride 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
[2-(3,4-acid)ethyl]-[6-(3,4-acid)-2-isopropoxypyridine-4-yl]amine;
[6-(3,4-acid)-2-ethoxypyridine-4-yl]-[2-(3,4-acid)ethyl]amine;
2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-[2-methoxy-6-(1-oxypyridine-3-yl)pyrimidine-4-yl]amine;
ethyl ester of 2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid;
methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid;
methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid;
methyl ester of (5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetonitrile;
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypurine is n-4-yl}phenoxy)acetonitrile;
2-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)-2-methylpropionic acid;
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid;
(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic acid;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid;
hydrochloride of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine;
hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine;
{2-methoxy-6-[4-methoxy-3-(1-N-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide;
3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}-N-(2-pyrrolidin-1-retil)benzamide;
the reaction of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
the reaction of 2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}tiof the h-2-yl)ethanone;
the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
hydrochloride [6-(3-aminomethyl-4-forfinal)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
the hydrochloride of N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzyl)-2-methoxyacetate;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)-2-methylpropyl]amine;
5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1H-pyridine-2-he;
5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-ylmethyl)-1H-pyridine-2-he;
hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it;
hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-it;
hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}benzoic acid;
[2-(3,4-acid)ethyl]-(2-methoxy-6-thiophene-2-Yeremey-4-yl)amine;
[2-(3,4-acid)ethyl]-(6-furan-2-yl-2-methoxypyridine-4-yl)amine;
(6-biphenyl-4-yl-2-methoxypyridine-4-yl)-[2-(3,4-acid)ethyl]amine;
hydrochloride 3-{6-[2-(4-forfinal)ethylamino]-2-methoxypyridine-4-yl}b is Noynoy acid;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzamide;
1-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)Etalon;
hydrochloride 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol;
2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)Etalon;
hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
[2-methoxy-6-(6-methoxypyridine-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol;
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-pyridin-4-Yeremey-4-yl)amine;
2-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol;
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)acetonitrile;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzaldehyde;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
[2-is ethoxy-6-(pyridin-3-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
ethyl ester of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
{2-methoxy-6-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
{2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
{2-methoxy-6-[3-(3-methylisoxazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
{2-methoxy-6-[3-(5-methyl-2H-pyrazole-3-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine;
1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)urea;
ethyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid;
[2-(4-chlorophenyl)-1-methylethyl]-[6-(3,4-acid)-2-methoxypyridine-4-yl]amine;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-trifloromethyl)ethyl]amine;
hydrochloride [2-(2-chloro-6-forfinal)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-thiophene-2-ileti]amine;
3-{2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]ethyl}-1H-indol-5-ol;
hydrochloride [2-(6-methoxy-1H-indol-3-yl)ethyl]-[2-methods the si-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
hydrochloride [2-(5-methoxy-1H-indol-3-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(2-pyridin-3-retil)amine;
hydrochloride [2-(4-AMINOPHENYL)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
hydrochloride (4-methoxybenzyl)-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
hydrochloride [2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-(3-phenylpropyl)amine;
[2-(1H-imidazol-4-yl)ethyl]-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]amine;
(2S)-2-[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-ylamino]-3-(4-methoxyphenyl)propionic acid;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
(2-methoxy-6-oxazol-5-Yeremey-4-yl)-[2-(4-methoxyphenyl)ethyl]amine;
3-{6-[2-(2,2-debtorrent[1,3]dioxol-5-yl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
hydrochloride [2-(2,2-debtorrent[1,3]dioxol-5-yl)ethyl]-(2-methoxy-6-pyridin-3-Yeremey-4-yl)amine;
the hydrochloride of N-(3-{6-[2-(4-deformational)ethylamino]-2-methoxypyridine-4-yl}phenyl)ndimethylacetamide;
hydrochloride [2-(4-deformational)ethyl]-[6-(3-methanesulfonyl)-2-methoxypyridine-4-yl]amine;
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenol;
hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}Hairdryer is l)propionic acid;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
hydrochloride of 1-ethoxycarbonylmethylene ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
the dihydrochloride of 2-dimethylaminoethanol ether 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid;
triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium;
[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine;
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile;
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionate sodium;
ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl }benzoylamine)acetic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoylamine)acetic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}fanilo the initial broadcast ethylcarbamate acid;
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid;
triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid;
hydrochloride [2-methoxy-6-(2-methoxybenzyloxy)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
methyl ether (3-{6-[2-(3,4-acid), ethylamino]-2-methoxypyridine-4-yloxy}benzoic acid;
N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]-2-methoxyacetate;
the hydrochloride of N-[2-(3-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}phenyl)ethyl]ndimethylacetamide;
[2-(2-fluoro-4-triptoreline)ethyl]-[2-methoxy-6-(3-oxiranylmethyl)pyrimidine-4-yl]amine;
2-{3-[6-(2,2-debtor-2-phenylethylamine)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid;
2-[3-(2-methoxy-6-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethylamino}pyrimidine-4-yl)phenyl]-2-methylpropionic acid;
5-(3-{6-[2-(3,4-differenl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-1-ethyl-2,4-dihydro-[1,2,4]triazole-3-one;
2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid;
2-(3-{2-methoxy-6-[(thiophene-3-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid;
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-3-carboxylic acid;
hydrochloride of 1-(3-{6-[2-(2,4-dichlorophenylamino]-2-methoxypyridine-4-yl}phenyl)cyclopentanecarboxylic acid;
2-morpholine-4-jatiluwih ester 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
2-(4-methylpiperazin-1-yl)ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
ethyl ester of 3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)methanol,
(3'-chloro-4'-{2-[6-(3-hydroxymethylene)-2-methoxypyridine-4-ylamino]ethyl}biphenyl-3-yl)methanol;
methyl ester of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid;
N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide;
ethyl ester of 4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid;
econsultancy acid [2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide;
ethyl ester of (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)acetonitrile;
(3-{6-[2-(2,4-dichlorophenyl)ethyl) - Rev. Ino]-2-methoxypyridine-4-yl}phenyl)differenital;
[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine;
2-{3-[6-(indan-1-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid;
2-{3-[6-(indan-2-ylamino)-2-methoxypyridine-4-yl]phenyl}-2-methylpropionic acid;
N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide;
methyl ester of 4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid;
5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}thiophene-2-carboxylic acid;
hydrochloride 5-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}-2,3-dihydrobenzofuran-2-carboxylic acid;
2,3-dihydroxypropyl ester 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
2-(3-{6-[(2,3-dihydrobenzofuran-2-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
2-(3-{6-[(isochroman-1-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)amino]pyrimidine-4-yl}phenyl)-2-methylpropionic acid;
2-(3-{6-[(benzofuran-5-ylmethyl)amino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
N-(6-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzothiazole-2-yl)acetone is d;
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid;
N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-phenylmethanesulfonyl;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tetrahydropyran-4-yl)isobutyramide;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide;
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-piperidine-4-carboxylic acid;
2-(2-chloro-5-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propan-2-ol; or
hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}-4-forfinal)-2-methylpropionic acid.

37. The compound or its pharmaceutically acceptable salt, which is a
N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzosulfimide;
3-{6-[2-(2,4-differenl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
triptorelin 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid;
5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)methanol; (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenyl)methanol;
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-6-Yeremey-4-yl)amine;
[2-(4-methoxyphenyl)ethyl]-(2-methoxy-6-quinoline-3-Yeremey-4-yl)amine;
[6-(1H-indol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
[6-(1H-benzotriazol-5-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
hydrochloride 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenol;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
hydrochloride 3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionic acid;
2-fluoro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
2-methoxy-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
methyl ether (3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid;
methyl ether (3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)acetic acid;
(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}phenoxy)acetic acid;
(5-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}-2-oxo-2H-pyridin-1-yl)acetic Ki the lot;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxy)-2-methylpropionic acid;
hydrochloride of 2-chloro-5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
[2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine;
hydrochloride [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidine-4-yl]amine;
{2-methoxy-6-[4-methoxy-3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}-[2-(4-methoxyphenyl)ethyl]amine;
N-(3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoyl)methanesulfonamide;
the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
the oxime of 3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
the oxime 1-(5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-yl)ethanone;
the reaction of 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
hydrochloride 3-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it;
hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyl)-4H-[1,2,4]oxadiazol-5-it;
hydrochloride 3-(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}phenoxymethyl)-4H-[1,2,4]oxadiazol-5-it;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzoic acid;
hydrochloride 3-{6-[2-(4-forfinal)ethylamino-2-methoxypyridine-4-yl}benzoic acid;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenol;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carbaldehyde;
hydrochloride 3-{6-[2-(4-chlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzonitrile;
3-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}benzaldehyde;
3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
[2-(3-fluoro-4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)phenyl]pyrimidine-4-yl}amine;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-nitrophenyl)ethyl]amine;
[2-methoxy-6-(3-methoxyphenyl)pyrimidine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
hydrochloride of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)propionic acid;
(5-{6-[2-(2-fluoro-4-triptoreline)ethylamino]-2-methoxypyridine-4-yl}-1H-indol-3-yl)acetic acid;
triptorelin [6-(1H-indol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]ammonium;
[6-(1H-indazol-6-yl)-2-methoxypyridine-4-yl]-[2-(4-methoxyphenyl)ethyl]amine;
3-{6-[2-(2,6-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}benzoic acid;
sodium salt of [2-(4-methoxyphenyl)ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)phenyl]pyrimidine-4-yl]amine;
(3-{6-[2-(2-chloro-6-forfinal)ethylamino]-2-methoxypyridine-4-yl}benzyloxy)acetic acid;
(3-{6-[2-(2,4-dichlorophenyl)atrami what about]-2-methoxypyridine-4-yl}benzoylamine)acetic acid;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl ether ethylcarbamate acid;
triptorelin methylamide 5-{2-methoxy-6-[2-(4-methoxyphenyl)ethylamino]pyrimidine-4-yl}thiophene-2-carboxylic acid;
1-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}piperidine-3-carboxylic acid;
4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carboxylic acid;
N-[4-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide;
(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)DIPEROXY acid;
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2,2-divercity]amide econsultancy acid;
[2-(2,4-dichlorophenyl)ethyl]-(6-{3-[debtor-(1H-tetrazol-5-yl)methyl]phenyl}-2-methoxypyridine-4-yl)amine;
N-[4-(3-{2-methoxy-6-[2-(4-trifloromethyl)ethylamino]pyrimidine-4-yl}phenyl)tetrahydropyran-4-carbonyl]methanesulfonamide;
[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]amide econsultancy acid;
N-[2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methylpropionyl]-phenylmethanesulfonyl;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-2-methyl-1-morpholine-4-improper-1-he;
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(tet gidropony-4-yl)isobutyramide; or
2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyridine-4-yl}phenyl)-N-(1H-tetrazol-5-yl)isobutyramide.

38. Pharmaceutical composition having the property of binding to receptors of prostaglandin D (DP), including a pharmaceutically effective amount of a compound according to any one of claims 1 to 37 or its N-oxide, or (C1-C6)-Olkiluoto of ester or its pharmaceutically acceptable salt, in a mixture with a pharmaceutically acceptable carrier.

39. A method of treating allergic disorders involving the introduction of a pharmaceutically effective amount of a compound according to any one of claims 1 to 37 or its N-oxide, or (C1-C6)-Olkiluoto of ester or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

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

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

9 cl, 106 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent which modulates PPARδ (peroxisome proliferator-activated receptor δ). In formula I

, p is equal to 1; L2 is selected from a group which includes -XOX- and -XSX-, where X is independently selected from a group which includes a bond and C1-C4alkylene; R13 is selected from a group which includes halogen, C1-C6alkyl; R14 is selected from a group which includes -XOXC(O)OR17 and -XC(O)OR17, where X denotes a bond or C1-C4alkylene and R17 denotes hydrogen; R15 and R16 are independently selected from a group which includes -R18 and -YR18, where Y is selected from a group which includes C2-C6alkenylene, and R18 is selected from a group which includes C6-C10aryl, pyridinyl, pyrimidinyl, quinolinyl, benzo[b]furanyl, benzoxazolyl, 1,5-benzodioxanyl, 1,4-benzodioxanyl and 3,4-dihydro-2H-benzo[b][1,4]dioxepin; where any of phenyl, pyridinyl, pyrimidinyl, benzoxazolyl in R18 is independently substituted with 1-2 radicals, independently selected from a group which includes halogen, C1-C6alkyl, C2-C7alkenyl, C1-C6alkoxy group, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy group, C3-C12cycloalkyl, phenyl, morpholinyl, pyrrolidinyl, piperidinyl, -XNR17R17, -XC(O)NR17R17, -XC(O)R19 and -XOXR19, where X denotes a bond or C1-C4alkylene; R17 is selected from a group which includes C1-C6alkyl, and R19 is selected from a group which includes C3-C12cycloalkyl, piperidinyl and phenyl. The invention also relates to use of the disclosed compounds to prepare a medicinal agent which modulates PPARδ activity, a pharmaceutical composition having PPARδ activity modulating properties, which contains a therapeutically effective amount of the disclosed compound and to use of the pharmaceutical composition in preparing a medicinal agent which modulates PPARδ activity.

EFFECT: improved properties of compounds.

10 cl, 1 tbl, 69 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole derivatives of the formula I: , where R1 and R2 independently denote Ph; mono- or disubstituted in different positions of the ring Ph, where substitute denotes -OCH3; C5-heteroaryl with one heteroatom selected from O or S; R2 denotes H, NO2, NH2, C(O)NH2; R4 denotes H, a straight or branched C1-C6-alkyl; n equals the number of methylene groups and is between 1 and 8 inclusively; X denotes O, S, NH; Y NH, -CH2-; Z denotes O, S; W denotes -OH, hydroxylamine, hydrazine, alkylhydrazine.

EFFECT: compounds can inhibit histone deacetylase, which enables their use in cancer treatment.

10 cl, 9 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopenta[b]benzofuranyl derivatives of formula wherein substitutes R1, R2, R3, R4, R5, R6 and R7 and n are specified in the patent clam. These compounds exhibit properties of NF-kB-activity and/or AP-1 inhibitor/modulator. Also, the inventive subject matter are methods for preparing intermediate compounds thereof, a pharmaceutical composition containing them, administration thereof for prevention and/or treatment of inflammatory and autoimmune diseases, neurodegenerative diseases and hyperproliferative diseases caused by NF-kB- and/or AP-1-activity, and a method for prevention and/or treatment of said diseases.

EFFECT: preparation of new cyclopenta[b]benzofuranyl derivatives.

21 cl, 3 tbl, 151 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 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: chemistry.

SUBSTANCE: invention relates to compounds of formula

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

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

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

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