Aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives, method for production thereof (variants), pharmaceutical composition containing the same and use thereof in drug manufacturing

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

 

The present invention relates to new compounds which are inhibitors of JAK3 kinases, methods for their preparation, intermediate compounds and pharmaceutical compositions containing them.

Janus kinase 3 (JAK3) is a member of the Janus family of protein kinases. Although other members of this family are expressed in essentially all tissues, the expression of JAK3 is limited to hematopoietic cells. This is consistent with their essential role in transmitting signals through the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 by non-covalent Association of JAK3 with gamma-chain common to those mnogosetochnykh receptors. All of these cytokines have the common feature that they are involved in differentiation and proliferation of lymphocytes. Were identified groups of patients with XSCID (X-linked form of severe combined immunodeficiency) with significantly reduced levels of JAK3 protein or genetic defects common gamma-chain, suggesting that the cause of immunosuppression should be blocking the transmission of signals by JAK3 way. Animal studies suggest that JAK3 not only plays a critical role in the maturation of b - and T-lymphocytes, but also JAK3 constantly required to maintain the function of T cells. Modulation of immune activity via this new mechanism may be useful in the treatment of T-is gunning proliferative disorders, such as transplant rejection and autoimmune diseases.

The role of JAK3 in mast cells described in knocked out mice. So, IgE/antigen-induced degranulation and release of mediators was significantly decreased in the fat cells, resulting in mice with deficiency of JAK3. The JAK3 deficiency has no effect on the proliferation of fat cells in vitro, it was also shown that the levels of IgE receptors and content of mediators same in JAK3-/- JAK3+/+ mast cells. Therefore, JAK3 is essential for the full response of mast cells stimulated by IgE. The role of JAK3 in the activation of mast cells has been well established in the system in mice, however, there is no published data about the function of fat cells in patients with AR-SCID (autosomal recessive form of severe combined immunodeficita). Targeting JAK3 provides the basis for a new and effective treatment of allergic reactions, mediated by fat cells.

To the present time has been described a number of JAK3 inhibitors, which include hintline (Sudbeck, E.A. et al. Clinical Cancer Res. 5 (1999) 1569-82, WO 00/0202) and pyrrolo[2,3-d]pyrimidine (Blumenkopf, T.A. et al. WO 99/65909).

In this application as JAK3 inhibitors of the claimed compounds, representing a 4-anilinophenol-3-carboxamide. Structurally related compounds have been previously described as inhibitors of kinases; for example, in WO 00/18761 and WO 98/43960 OPI is the Ana quinoline-3-carbonitrile derivatives. In a recent publication (Boschelli, D.H. et al. J. Med. Chem. 44 (2001) 822-33) it was shown that one connection of the present invention has no inhibitory ability in relation to the activity of the Src protein-tyrosine kinase. JAK3 is not mentioned in any of the above literary example.

Two compounds and their synthesis related to this invention, have been described previously (Boschelli, D.H. et al. J. Med. Chem. 44 (2001) 822-33 and Wissner et al. WO 98/43960).

Therefore, in the present invention an aromatic derivatives of 6,7-disubstituted 3-chinainternational formula (I) and their pharmaceutically acceptable salts for use in the manufacture of drugs for the treatment of diseases mediated JAK3:

where:

n is 0 or 1;

X represents NR3or;

Ar is selected from phenyl, tetrahydronaphthyl, indolyl, pyrazolyl, dihydroindole, 1-oxo-2,3-dihydroindole or indazole, each of which can be possibly substituted by one or more than one group selected from halogen, hydroxy, cyano, C1-C8alkoxy, CO2R8, CONR9R10C1-C8alkyl-O-C1-C8of alkyl, C1-C8alkyl-NR8-C1-C8of alkyl, C1-C8alkyl-CONR9R10, NR8COC -C8of alkyl, C1-C8alkylthio or C1-C8the alkyl (possibly substituted by one or more than one hydroxy or cyano or fluorine atoms);

groups R are independently hydrogen or C1-C8by alkyl;

R1and R2independently selected from hydrogen, halogen, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, hydroxy, phenyl, Y(CR112)pNR4R5, Y(CR112)pCONR4R5, Y(CR112)pCO2R6, Y(CR112)pOR6, Y(CR112)pR6;

or R1and R2joined together as co2O -, or-OCH2CH2O-;

group R11are independently hydrogen, C1-C8alkyl, hydroxy or halogen;

p is 0, 1, 2, 3, 4 or 5;

Y represents oxygen, CH2or NR7;

R3represents hydrogen or C1-C8alkyl;

R4and R5each independently represent hydrogen, C1-C8alkyl, or R4and R5together with the nitrogen atom to which they are attached, form a 4-7-membered saturated or aromatic heterocyclic ring system may contain an additional oxygen, sulphur or the group NR6or one of R4and R 5is hydrogen or C1-C8the alkyl and the other represents a 5 - or 6-membered heterocyclic ring system may contain additional atom of oxygen, sulfur or nitrogen;

R6represents hydrogen, C1-C8alkyl, phenyl or benzyl;

R7represents hydrogen or C1-C8alkyl;

R8represents hydrogen or C1-C8alkyl;

R9and R10each independently represent hydrogen or C1-C8alkyl,

provided that the compound is not 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-hyalinobatrachium, 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-hyalinobatrachium, 4-(2-bromoaniline)-6,7-dimethoxy-3-chinainternational and 4-(1,5-dichloroaniline)-6,7-dimethoxy-3-chinainternational.

Preferably both R groups are hydrogen.

Preferably X represents NR3.

Also preferably, Ar is represented phenyl, possibly substituted by one or more than one group selected from halogen, hydroxy, cyano, C1-C8alkoxy, CO2R8, CONR9R10C1-C8alkyl-O-C1-C8of alkyl, C1-C8alkyl-NR8-C1-C8of alkyl, C1-C8alkyl-CONR9R10, NR8COC1-C8of alkyl, C1 -C8alkylthio or C1-C8the alkyl (possibly substituted by one or more than one hydroxy or cyano or fluorine atoms).

R1preferably represents methoxy, ethoxy, OCH2CONH2, O(CH2)2OMe, O(CH2)2NR4R5or O(CH2)3NR4R5where R4and R5both are hydrogen or stands, or together with the nitrogen to which they are attached, form piperidino or morpholino ring, or R1represents NH(CH2)3NR4R5where R4and R5together with the nitrogen to which they are attached, form an imidazole ring.

R2preferably represents methoxy, ethoxy, O(CH2)2OMe, O(CH2)3HE, O(CH2)3CO2IU, O(CH2)2NR4R5, O(CH2)3NR4R5or O(CH2)4NR4R5where one of R4or R5is stands, and the other is pyridium, or R4or R5selected from hydrogen or methyl, or together with the nitrogen to which they are attached, they form thiomorpholine, piperidine, morpholino, imidazole, triazole or 2,6-dimethylmorpholine group.

The most preferred compounds according to the invention are the following:

6-Benzyloxy-4-3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

6-Hydroxy-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-(2-methoxyethoxy)-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-octyloxy-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(4-morpholinyl)ethoxy]-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-piperidinyl)ethoxy]-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-pyrrolidinyl)ethoxy]-3-chinainternational;

6-[2-(Dimethylamino)ethoxy]-4-(3-(hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

6-[2-(Dimethylamino)-2-oksidoksi]-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

6-(2-Amino-2-oksidoksi)-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

6-Methoxy-4-(2-(methylsulfonyl)aniline]-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-(1H-Indol-4-ylamino)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

Methyl-4-{[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-chinoline]oxy}is tanout;

4-(2-Ethylaniline)-7-(3-hydroxypropoxy)-6-methoxy-3-chinainternational;

6-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(2-toluidino)-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-(2-methoxyethoxy)-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-[4-(4-morpholinyl)butoxy]-3-chinainternational;

7-(3-Chloropropoxy)-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

7-{3-[(CIS)-2,6-Dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

7-{3-[(TRANS)-2,6-Dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(1-piperidinyl)propoxy]-3-chinainternational;

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-thiomorpholine)propoxy]-3-chinainternational;

6-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

4-(2-Ethylaniline)-6-[3-(1H-imidazol-1-yl)propoxy]-7-methoxy-3-chinainternational;

4-(2-Ethylaniline)-7-methoxy-6-(3-teenrotica)-3-chinainternational;

6-[2-(Dimethylamino)ethoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

6-(3-Aminopropoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

4-(2-Ethylaniline)-7-methoxy-6-[2-(methylamino)ethoxy]-3-fineliner is the oksamid;

6-(2-Aminoethoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

7-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-[2-(methylamino)ethoxy]-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-7-[2-(1-piperazinil)ethoxy]-3-chinainternational;

4-(2-Ethylaniline)-7-[3-(1H-imidazol-1-yl)propoxy]-6-methoxy-3-chinainternational;

4-(2-Ethylaniline)-7-[2-(1H-imidazol-1-yl)ethoxy]-6-methoxy-3-chinainternational;

7-(3-Aminopropoxy)-4-(2-ethylaniline)-6-methoxy-3-chinainternational;

7-Hydroxy-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

6-{[3-(1H-imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinainternational;

7-Methoxy-6-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational;

7-Methoxy-6-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational;

7-Methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational;

6-Methoxy-7-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational;

6-Methoxy-7-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational;

7-{[3-(1H-imidazol-1-yl)propyl]amino}-6-methoxy-4-(2-toluidino)-3-healingherbs is d;

7-[(1-Benzyl-4-piperidinyl)amino}-6-methoxy-4-(2-toluidino)-3-chinainternational;

6-Methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational;

4-[3-(Hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(4-Hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(4-Fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[(1-Ethyl-1H-pyrazole-5-yl)amino]-6,7-dimethoxy-3-chinainternational;

4-(3-Aminocarbonyl-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(2,3-dimethylaniline)-3-chinainternational;

6,7-Dimethoxy-4-(5,6,7,8-tetrahydro-1-naphthaleneamine)-3-chinainternational;

4-(4-Carboxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(1H-Indol-4-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(3-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(Aminocarbonyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-Hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(3-methoxy-2-methylaniline)-3-chinainternational;

6,7-Dimethoxy-4-[(1-methyl-1H-indol-4-yl)amino]-3-chinainternational;

6,7-Dimethoxy-4-[(1-oxo-2,3-dihydro-1H-inden-4-yl)amino]-3-chinainternational;

4-(1-Hydroxy-2,3-dihydro-1H-inden-4-yl)amino-6,7-dimethoxy-3-chinainternational;

4-(4-Carbon and-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(4-methoxycarbonyl-2-methylaniline)-3-chinainternational;

4-(4-Hydroxymethyl-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(2-propylaniline)-3-chinainternational;

4-(2-Isopropylaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(sec-Butyl)aniline]-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-[3-(methoxymethyl)-2-methylaniline]-3-chinainternational;

4-[3-(ISO-Butoxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-[3-(Cyanomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-{3-[(Ethylamino)methyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational;

4-{3-[2-(Ethylamino)-2-oxoethyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational;

Ethyl-2-(3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-were)acetate;

4-[3-(2-Amino-2-oxoethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-[3-(2-Hydroxyethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(3-{2-[(2-Hydroxyethyl)amino]-2-oxoethyl}-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

tert-Butyl 3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-methylbenzylamine;

4-[3-(Aminomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(4-Fluorescent-2-methylaniline)-6-methoxy-3-chinainternational;

4-(4-Bromo-2-methylaniline)-6-methoxy-3-chinainternational;

4-(4-Chloro-2-meth is anilino)-6-methoxy-3-chinainternational;

4-(2,4-Dimethylaniline)-6-methoxy-3-chinainternational;

6-Methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(4-Hydroxy-2-methylaniline)-6-methoxy-3-chinainternational;

4-(2-Bromoaniline)-6-methoxy-3-chinainternational;

4-(2,4-Dimethoxyaniline)-6-methoxy-3-chinainternational;

6-Methoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(2-Ethoxyaniline)-6-methoxy-3-chinainternational;

4-(2-Ethylaniline)-6-methoxy-3-chinainternational;

6-Methoxy-4-(2-toluidino)-3-chinainternational;

6-Methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(4-Bromo-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,4-Dimethylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(2-Bromo-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-Bromo-4-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2,4-Dimethoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-Fluorescent-2-methylaniline)-7-methoxy-3-chinainternational;

4-(4-Bromo-2-methylaniline)-7-methoxy-3-chinainternational;

4-(4-Chloro-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2,4-Dimethylaniline)-7-methoxy-3-chinainternational;

7-Methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(4-Hydrox the-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2-Bromoaniline)-7-methoxy-3-chinainternational;

4-(2-Bromo-4-methylaniline)-7-methoxy-3-chinainternational;

4-(2-Bromo-4-foranyone)-7-methoxy-3-chinainternational;

4-(2,4-Dimethoxyaniline)-7-methoxy-3-chinainternational;

6,7-sodium dichloro-4-(4-methoxy-2-methylaniline)-3-chinainternational;

6,7-sodium dichloro-4-(2,4-dimethoxyaniline)-3-chinainternational;

4-(2-Ethylaniline)-3-chinainternational;

4-(2-Toluidino)-3-chinainternational;

4-[2-(Methylsulfonyl)aniline]-3-chinainternational;

4-(2-Ethoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(Hydroxymethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(2-Ethylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(2-toluidino)-3-chinainternational;

6,7-Dimethoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(2,4-Dibromoanisole)-6,7-dimethoxy-3-chinainternational;

7-Methoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(2-Ethoxyaniline)-7-methoxy-3-chinainternational;

4-[2-(Aminocarbonyl)aniline]-7-methoxy-3-chinainternational;

4-(2-Ethylaniline)-7-methoxy-3-chinainternational;

7-Methoxy-4-(2-toluidino)-3-chinainternational;

7-Methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

6,7-sodium dichloro-4-(2-methoxyaniline)-3-chinainternational;

6,7-sodium dichloro-4-(2-ethylaniline)-3-chinainternational;

6,7-sodium dichloro-4-[2-(metals hanil)aniline]-3-chinainternational;

4-(2,5-Dimethylaniline)-6,7-dimethoxy-3-chinainternational;

4-(5-Fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(5-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(3-fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-Hydroxy-2,5-dimethylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-Hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-Aniline-6,7-dimethoxy-3-chinainternational;

4-(4-Chloro-2-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2,6-Diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(3-foranyone)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(4-methoxyaniline)-3-chinainternational;

4-(3-Chloroanilino)-6,7-dimethoxy-3-chinainternational;

4-(2-Chloroanilino)-6,7-dimethoxy-3-chinainternational;

4-[3-(Acetylamino)aniline]-6,7-dimethoxy-3-chinainternational;

4-(2,5-Diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(1H-Indol-5-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(1H-Indazol-5-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(1H-Indazol-6-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(2,4-Diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,5-Dichloroaniline)-6,7-dimethoxy-3-healingherbs the amide;

4-[2-(2-Hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-Chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-[3-(methylsulfonyl)aniline]-3-chinainternational;

6,7-Dimethoxy-4-(2-methoxy-5-methylaniline)-3-chinainternational;

4-[4-(Dimethylamino)aniline]-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-[4-(methylsulfonyl)aniline]-3-chinainternational;

4-[4-(2-Hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-Hydroxy-4-methoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,3-Dichloroaniline)-6,7-dimethoxy-3-chinainternational;

6,7-Dimethoxy-4-(2,3,4-triptoreline)-3-chinainternational;

6,7-Dimethoxy-4-(3-toluidino)-3-chinainternational;

4-(2-Hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-4-hydroxyanisole)-6,7-dimethoxy-3-chinainternational;

4-[2-(Hydroxymethyl)-4-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(2-chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-5-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[(2-Cyanophenyl)amino]-6,7-dimethoxyquinazolin-3-carboxamide;

4-[(2,5-Defloriani)amino]-6,7-dimethoxyquinazolin-3-carboxamide;

4-(1H-indol-5-ylamino)-6,7-dimethoxyindole-3-carboxamide;

6,7-sodium dichloro-4-(2-methylaniline)-3-chinainternational;

4-(2,3-Dihydro-1H-inden-1-ylamino)-6,7-dimethoxy--chinainternational;

6,7-Dimethoxy-4-{[2-(trifloromethyl)benzyl]amino}-3-chinainternational;

6,7-Dimethoxy-4-[(1-phenylethyl)amino]-3-chinainternational;

4-(3-Hydroxymethyl-2-methylaniline)-3-chinainternational;

9-(3-Hydroxymethyl-2-methylaniline)-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxamide;

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[2-(propylamino)ethoxy]quinoline-3-carboxamide;

6-[2-(Ethylamino)ethoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide;

6-[2-(Isopropylamino)ethoxy]-7-methoxy-4-[(3-methoxy-2-were)amino]quinoline-3-carboxamide;

6-[2-(Dimethylamino)ethoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide;

6-[3-(Diethylamino)propoxy]-4-{[3-(hydroxymethyl)-2-were]amino}-7-methoxyquinoline-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxy-6-[2-(methylamino)ethoxy]quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-4-ylamino)propoxy]quinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-[(2-amino-2-oxoethyl)amino]propoxy]-quinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-(1H-pyrazole-3-ylamino)propoxy]quinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-2-ylamino)propoxy]quinoline-3-carboxamide;

Ethyl-4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-7-yl)oxy]butanoate;

7-[3-(Diethylamino)propoxy]-6-methoxy-4-[2-methoxyphenyl)amino]quinoline-3-carboxamide;

7-[3-(Ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino}quinoline-3-carboxamide;

7-[3-(Ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide;

7-[3-(Ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide;

7-[3-(Dimethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

7-[3-(Diethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

7-[3-(Dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide;

7-[3-(Diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-thiomorpholine-4-ylpropionic)quinoline-3-carboxamide;

4-{[3-(Hydroxymethyl)-2-were]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

7-[3-(1,1-Diocletianopolis-4-yl)propoxy]-4-[(2-ethylphenyl)amino]-6-meth is chinolin-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

4-{[3-(Hydroxymethyl)-2-were]amino}-7-[3-(3-hydroxypiperidine-1-yl)propoxy]-6-methoxyquinoline-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]quinoline-3-carboxamide;

7-(3-Azepin-1 ipropose)-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

6,7-Dimethoxy-4-{[2-(methylthio)phenyl]amino}quinoline-3-carboxamide triptorelin;

6,7-Dimethoxy-4-[(4-methoxy-2-were)amino]quinoline-3-carboxamide;

4-{[2-Bromo-3-(hydroxymethyl)phenyl]amino}-6,7-Dimethoxyindole-3-carboxamide;

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6,7-dimethoxyindole-3-carboxamide;

or their pharmaceutically acceptable salts.

According to the invention also proposed compound of formula (I)as defined above, for the inhibition of JAK3.

According to the invention proposed 4-anilinophenol-3-carboxamide formula (IA):

where

Ar represents phenyl, substituted ethyl, propylene, hydroxymethyl or CO2N or disubstituted by stands and hydroxymethyl;

R1represents methoxy, ethoxy or group OCH2CONH2The co2SN 2Och3or O(CH2)pNR4R5where p is 2 or 3, and R4and R5represent hydrogen, methyl, ethyl or propyl, or R4and R5together form a pyrolidine, imidazole or morpholine ring;

R2represents methoxy, ethoxy or O(CH2)pNR4R5where p is 2, 3 or 4, and R4and R5represent hydrogen, methyl or ethyl, or one of R4or R5is stands, and the other is pyridium or pyrazole, or R4and R5form piperidino, hydroxypiperidine, thiomorpholine, morpholine, pyrolidine, 2,6-dimethylmorpholine, imidazole or triazole ring;

or their pharmaceutically acceptable salt or solvate,

provided that when a represents a phenyl, substituted with ethyl or propylene or disubstituted by stands, then R1and R2are not both methoxy, R1and R2are not both ethoxy, or one of R1/R2is not methoxy when another is ethoxy.

The most preferred compounds of formula (IA) are the following:

4-(2-ethylaniline)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-thiomorpholine)propoxy]-3-chinainternational,

4-[3-(GI is roximity)-2-methylaniline]-6-methoxy-7-[3-(1-piperidinyl)propoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational,

7-[3-(dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational,

7-{3-[(2R,6S)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[4-(4-morpholinyl)butoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-chinainternational,

4-(2-ethylaniline)-7-methoxy-6-[2-(methylamino)ethoxy]-3-chinainternational,

7-{3-[(2S,6S)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational,

4-(2-ethylaniline)-7-[3-(1H-imidazol-1-yl)propoxy]-6-methoxy-3-chinainternational,

6-(2-aminoethoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[2-(methylamino)ethoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-(2-methoxyethoxy)-3-chinainternational,

4-(2-ethylaniline)-7-(3-hydroxypropoxy)-6-methoxy-3-chinainternational,

6-methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(2-toluidino)-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[2-(1-pyrrolidinyl)ethoxy]-3-unlinkability,

4-[3-(hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

4-(2-ethylaniline)-7-[2-(1H-imidazol-1-yl)ethoxy]-6-methoxy-3-chinainternational,

4-[3-(2-hydroxyethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

7-methoxy-6-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational,

4-(2-ethylaniline)-6-[3-(1H-imidazol-1-yl)propoxy]-7-methoxy-3-chinainternational,

7-(3-aminopropoxy)-4-(2-ethylaniline)-6-methoxy-3-chinainternational,

methyl-4-{[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-chinoline]oxy}butanoate,

4-[3-(aminomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

6-{[3-(1H-imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-(2-methoxyethoxy)-3-chinainternational,

6-[2-(dimethylamino)ethoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-[3-(cyanomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

4-[3-(2-amino-2-oxoethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

6-(3-aminopropoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[2-(4-morpholinyl)ethoxy]-3-chinainternational,

and their pharmaceutically acceptable salts.

Makeproductfile compounds of formula (IA) are compounds chosen from:

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-4-ylamino)propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-[(2-amino-2-oxoethyl)amino]propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(1H-pyrazole-3-ylamino)propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-2-ylamino)propoxy]quinoline-3-carboxamide,

ethyl-4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-7-yl)oxy]butanoate,

7-[3-(diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)amino]quinoline-3-carboxamide,

7-[3-(ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino}quinoline-3-carboxamide,

7-[3-(ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide,

7-[3-(ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide,

7-[3-(dimethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide,

7-[3-(diethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-is propoxy)quinoline-3-carboxamide,

7-[3-(dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

7-[3-(diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

7-{3-[(2-ethoxyethyl)amino]propoxy}-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-ipropose)quinoline-3-carboxamide,

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-thiomorpholine-4-ylpropionic)quinoline-3-carboxamide,

4-{[3-(hydroxymethyl)-2-were]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide,

4-{[3-(hydroxymethyl)-2-were]amino}-7-[3-(3-hydroxypiperidine-1-yl)propoxy]-6-methoxyquinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]quinoline-3-carboxamide,

and their pharmaceutically acceptable salts.

According to the proposed invention the compounds of formula (IA) for use as inhibitors of JAK3 kinase.

The invention also relates to pharmaceutical compositions inhibiting JAK3 kinase containing a compound of formula (IA) or its pharmaceutically acceptable salt together with pharmacy is is automatic acceptable carrier.

According to the proposed invention is also the use of compounds of formula (I)as defined above, or its pharmaceutically acceptable salt for the manufacture of drugs for the treatment of a disease or condition mediated JAK3.

Preferably the disease or condition is a asthma, rejection/transplantation graft-versus-host or rheumatoid arthritis.

In the invention, a method for obtaining compounds of formula (I)in which:

the compound of formula (II):

where R1and R2such as defined in formula (I)or are protected derivatives, and R20represents a leaving group, is subjected to the interaction with the compound of the formula (III):

where Ar and R such as defined in formula (I)or are protected derivatives,

and maybe then

- remove any protective groups,

- turn the compound of formula (I) into another compound of formula (I),

- carry out the formation of pharmaceutically acceptable salts.

In this way, the group R20is a leaving group such as halogen, in particular chloro. The reaction can be performed in an inert solvent, such as DMF (dimethylformamide), at elevated temperature, for example at approximately 100°C.

in Addition, according to the invention a method for obtaining compounds of formula (I)in which:

for compounds of formula (I), where R1and/or R2are the groups Y(CH2)pNR4R5, Y(CH2)pCONR4R5, Y(CH2)pCO2R6, Y(CH2)pOR6or Y(CH2)pR6where Y is oxygen, the compound of formula (IV):

where R1'or R2'subject to transformation in group Y(CH2)pNR4R5, Y(CH2)pCONR4R5Y(CH2)pCO2R6, Y(CH2)pOR6or Y(CH2)pR6represents hydroxy and the other R1or R2and Ar are as defined in the previous method, is subjected to the interaction with the compound of the formula (V):

where R21represents NR4R5, CONR4R5, CO2R6, OR6or R6, a R4, R5and R6such as defined in formula (I)or are protected derivatives,

and maybe then

- remove any protective groups,

- turn the compound of formula (I) into another compound of formula (I),

- carry out the formation of pharmaceutically acceptable salts.

In this way leaving group L site which preferably represents halogen, in particular chloro. The reaction can be performed in the presence of a base such as cesium carbonate, in an inert solvent, such as DMF or ethanol.

The compounds of formula (II) can be obtained by reacting compounds of the formula (VI):

where R1, R2and R20such as defined in the formula (II), with gloriouse agent such as thionyl chloride, and the interaction of the corresponding acid chloride with ammonia.

The compounds of formula (VI) can be obtained using the information from the chemical literature.

The term "alkyl" when used by itself or as part of another group, such as alkoxy, means any alkyl group with straight or branched chain. The term "aryl" includes phenyl and naftalina group.

Groups R are preferably hydrogen or methyl, and most preferably both groups R are hydrogen.

X represents NR3or O. Preferably X represents NR3where R3is1-4the alkyl, more preferably X represents NH.

n is 0 or 1, preferably n is 0.

p is 0, 1, 2, 3, 4 or 5, preferably p is 1 to 4, more preferably p is 2 or 3.

The substituents in the group Ar may be present in any suitable position. Can prists who participate in more than one Deputy, and they may be the same or different. Preferably Ar represents an indolyl or phenyl, most preferably phenyl.

More preferably, the group Ar is unsubstituted or has one or more than one Deputy, including the substituents in the compounds described in this description as examples, such as methyl, ethyl, propyl, butyl, thiomethyl, hydroxymethyl, bromo, fluorescent, hydroxy, CO2H, CONH2, CF3methoxymethyl, butoxymethyl, cyanomethyl, ethylaminomethyl, aminomethyl, ethylamino-2-oxoethyl, hydroxyethyl, 2-amino-2-oxoethyl, CO2CH3, methoxy or ethoxy. When Ar is phenyl, then preferred are one or two substituting groups. Even more preferred substituents include ethyl, n-propyl, isopropyl, hydroxymethyl, hydroxyethyl, thiomethyl, aminomethyl, bromo and CO2N. The most preferred substituents are methyl, ethyl and hydroxymethyl.

Accordingly, R1and R2independently selected from hydrogen, halogen, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, hydroxy, Y is(CH2)pNR4R5, Y(CH2)pCONR4R5, Y(CH2)pCO2R6, Y(CH2)pOR6, Y(CH2)pR6; or R1and R2joined together as co2O - or-sub> 2CH2O-. Preferably R1and R2represent hydrogen, chloro, methoxy, ethoxy, C(CH2)2NR4R5, O(CH2)3NR4R5, NH(CH2)2NR4R5or NH(CH2)2NR4R5where R4and R5are hydrogen or stands, or one is stands, and the other is pyridium, or R4and R5form morpholino, 3,5-dimethylmorpholine, thiomorpholine, pyrolidine, pieperazinove (possibly substituted), piperidino, triazole or imidazolidine ring, or R4and R5are independently O(CH2)3CO2CH3, O-benzyl, 1-benzyl-4-piperidylamine, O(CH2)2NMe2, OCH2CONH2, O(CH2)2NHMe, - O(CH2)3NH2, nitro or cyano; or R1and R2joined together as co2O -, or-och2CH2O-.

When R4and R5form a 4-7-membered saturated or aromatic heterocyclic ring system, suitable examples of such rings include morpholine, 3,5-dimethylmorpholine, 2,6-dimethylmorpholine, thiomorpholine, pyrrolidine, piperazine (possibly substituted C1-C8the alkyl, piperidine, triazole or imidazole.

If one of R4and R5is hydrogen or C1-C8the alkyl, and others who Goy is a 5 - or 6-membered heterocyclic ring system, may contain additional atom of oxygen, sulfur or nitrogen, then examples of such rings include thienyl, furyl, pyrimidyl, imidazolyl, pyridyl and pyrazole.

The most preferred compounds are those in which R1and/or R2are both methoxy or ethoxy, or one is methoxy and the other is ethoxy.

Particularly preferred compounds according to the invention include compounds shown here as examples, both in the free base form and in the form of pharmaceutically acceptable salts.

Compounds according to the invention can form pharmaceutically acceptable solvate or salt. The compounds of formula (I) can form salts accession acids with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, Hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, almond, wine, triperoxonane and methansulfonate acid.

Compounds of the present invention include all stereoisomers, pure and mixed racemates and mixtures thereof. The tautomers of the compounds of formula (I) and (IA) also form an aspect of the present invention.

Obviously, for some functional groups may need to be protected using conventional protective groups. Protection and removal the protection of functional groups is described, for example, in "Protective Groups in Organic Chemistry", edited by J. W. F. McOmie, Plenum Press (1973) and ' Protective Groups in Organic Chemistry", 3rdedition, T.W.Greene & P.G.M.Wuts, Wiley-lnterscience (1999).

Diseases mediated JAK3, include inflammatory, immunological and pulmonary disorders, including the following: rejection organtransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications from diabetes, cancer, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases.

The dose of a compound that should be introduced depends on the relevant readings, age, weight and sex of the patient, and it can be determined by a doctor. The dosage is preferably will be in the range from 0.1 mg/kg to 100 mg/kg

These compounds can be entered locally, for example in the lung and/or Airways, in the form of solutions, suspensions, HFA (hydrofluroalkane) aerosols or dry powder drugs, such as drugs in the device for inhalation, known as the Turbuhaler®or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration, for example in the form of sterile parenteral solutions or suspensions, or by rectal administration, e.g. is in the form of suppositories.

Compounds according to the invention can be entered by themselves or in the form of a pharmaceutical composition containing the compound according to the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions that do not contain substances that can cause side-effects such as allergic reaction.

Dry powder drugs and pressurized HFA aerosol compounds according to the invention can be administered by oral or intranasal inhalation. For inhalation, it is desirable that the connection has been finely dispersed. Finely dispersed compound preferably has a mass median diameter less than 10 microns and may be suspended in a mixture of propellants using a dispersing agent such as8-C20fatty acid or its salt (for example, oleic acid), salt of the bile acid, phospholipid, alkylchloride, perfluorinated or polyethoxyethanol surfactant, or other pharmaceutically acceptable dispersing agent.

Compounds according to the invention can also be entered using the dry powder inhaler. This inhaler can be a single or mnogorazovyj inhaler and may be an inhaler for dry powder, activated breath.

One possibility is the mixing of finely dispersed connection with substance carrier, for example mono-, di - or polysaccharide, a sugar alcohol or another polyol. Suitable carriers are sugars, such as lactose, glucose, raffinose, melezitose, lactic, ▫ maltitol, trehalose, sucrose, mannitol; starches. Alternative finely dispersed connection can be covered with a shell of another substance. The powder mixture can also be distributed in hard gelatin capsules, each containing the desired dose of the active connection.

Another possibility is the processing of finely dispersed powder in areas that are destroyed during the process of inhalation. This spheronization powder, you can fill the reservoir for a drug, for example, is known as the Turbuhaler®where the metering device measures the required dose, which then is inhaled by the patient. Using this system active connection with a substance carrier, or without it delivered to a patient.

For oral administration the active compound can be mixed with an adjuvant or a carrier, for example lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; derivatives of cellulose; a binder such as gelatine or polyvinylpyrrolidone, and/or a lubricant such as magnesium stearate, calcium stearate, polietileno Olam, wax, paraffin and the like, and then pressed into tablets. If you need tablets, coated core obtained as described above, can be coated with a concentrated sugar solution which may contain, for example, gum Arabic, gelatin, talc, titanium dioxide and the like. Alternative tablet can be coated with a suitable polymer dissolved in a volatile organic solvent.

To obtain soft gelatin capsules, the compound can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules connection with any of the above mentioned excipients for tablets. Also hard gelatin capsules can be filled with liquid or semi-solid drugs drugs.

Liquid preparations for oral administration may be in the form of syrups or suspensions, for example solutions containing the compound, while the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. It is possible that such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to specialists in this field of technology.

Compounds according to the invention can also introduces the in combination with other compounds, used to treat the above conditions.

It is implied that the term "medical treatment" when used here includes preventive, diagnostic and therapeutic regimes, carried out in vivo or ex vivo in humans or other mammals.

The following examples illustrate the invention.

General methods. All reactions were carried out in dry glassware in an argon atmosphere at room temperature if not stated otherwise. All solvents and reagents used such as they were received. For preparative chromatography on silica gel used Merck silica gel 60 (0,040-0,063 mm). For preparative HPLC (high performance liquid chromatography) used column Kromasil KR-100-5-C18 (250×20 mm, Akzo Nobel) and a mixture of acetonitrile/water with a flow rate of 10 ml/min. Monitoring of reactions was carried out at 254 nm using an analytical HPLC using a Kromasil C18 column (150×4.6 mm) and a gradient containing 0.1% triperoxonane acid) from 5 to 100% acetonitrile in water with flow rate of 1 ml/min Evaporation of solvents was carried out under reduced pressure using a rotary evaporator with maximum a temperature of 40°C. the Products were dried under reduced pressure at 40°C.

1H-NMR (nuclear magnetic resonance) spectra were recorded on a Varian lnova-400 or Unity 500 + device. Central is the first peak of the solvent chloroform-d (δn7,27 ppm (millionths)), dimethyl sulfoxide-d6nof 2.50 ppm) or methanol-d4nat 3.35 ppm) were used as internal standards. Mass spectra of low resolution received in the system Hewlett Packard 1100 LC-MS (liquid chromatography - mass spectrometry)with APCI ionization chamber (chemical ionization at atmospheric pressure).

Silica gel Merck 60 (0,040-0,063) was used for preparative chromatography on silica gel. For preparative HPLC used a Kromasil KR-100-5-C18 column (250×20 mm, Akzo Nobel) and a mixture of acetonitrile/water with a flow rate of 10 ml/min. Monitoring of reactions was carried out at 254 nm using an analytical HPLC using a Kromasil C18 column (150×4.6 mm) and a gradient containing 0.1% triperoxonane acid) from 5 to 100% acetonitrile in water with flow rate of 1 ml/min Evaporation of solvents was carried out under reduced pressure using a rotary evaporator with a maximum temperature of 40°C. the Products were dried under reduced pressure at 40°C.

Example 1

6-(Benzyloxy)-4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-3-chinainternational

a) 1-(Benzyloxy)-2-methoxy-4-nitrobenzene

4-Nitroguaiacol potassium salt monohydrate (25 g, 111 mmol) and cesium carbonate (3.25 g, 10 mmol) was transferred into odnogolosy flask of 500 ml and add to dry dimetilan the amide (200 ml), was added dropwise benzylbromide (21,4 g, 125 mmol) at room temperature in an atmosphere of N2and the reaction mixture was intensively stirred for approximately 3 hours. The solvent and excess benzylbromide then removed under reduced pressure. To the crude product were added water (200 ml) and ethanol (100 ml) and boiled under reflux for 10-15 minutes. Yellowish crystals were filtered off from the cold mixture, washed with water and dried to obtain 29 g (100%yield) specified in the connection header.

1H NMR (CDCl3): δ 7.85 (1H, dd); 7.77 (1H, d); 7.46-7.32 (5H, m); 5.26 (2H, s); 3.97 (3H, s).

b) 4-(Benzyloxy)-3-methoxyaniline. To 1-(benzyloxy)-2-methoxy-4-nitrobenzene (26 g, 100 mmol)dissolved in ethanol (500 ml) in a 2-liter odnogolosy flask was added dropwise over 30 minutes a solution of dithionite sodium in water (500 ml), stirring was continued at ambient temperature for 2 hours and then the reaction mixture was heated at 70-80°C for approximately 4 hours, cooled and podslushivaet sodium carbonate. The precipitate was filtered, washed with water and dried. The combined water phases were extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was combined with the filtered precipitate with getting the 9.3 g (41%yield) of product.

1H NMR (DMSO-d6): δ 7.42-7.24 (5H, t); 6.67 (1H, d); 6.27 (1H, d); 6.02 (1H, dd); 4.86 (2H, s); 4.68 (2H, s); 3.67 (3H, s).

C) Diethyl-2-(4-benzyloxy-3-methoxyaniline)metromont

A mixture of 4-(benzyloxy)-3-methoxyaniline (9.3 g, 40 mmol) and diethylethoxymethylenemalonate (9,65 g, 45 mmol) was heated at 120°C for 1-1 .5 hours, the resulting ethanol was removed under reduced pressure to obtain 16 g (100%yield) specified in the connection header.

1H NMR (CDCl3): δ 11.0 (1H, d); 8.43 (1H, d); 7.45-7.29 (5H, m); 6.87 (1H, d); 6.67 (1H, d); 6.64 (1H, dd); 5.14 (2H, s); 4.31 (2H, q); 25 (2H, q); 3.91 (3H, s); 1.39 (3H, t); 1.32 (3H, t).

d) Ethyl-6-benzyloxy-4-chloro-7-methoxy-3-chinainternational

A mixture of diethyl-2-(4-benzyloxy-3-methoxyaniline)metromont (16 g, 40 mmol), toluene (100 ml) and phosphorus oxychloride (25 ml) was heated to boiling under reflux in nitrogen atmosphere for 5 hours. After cooling, the solution was evaporated to remove solvent and excess phosphorus oxychloride. The residue was treated with aqueous sodium bicarbonate, water and a small amount of ethanol was heated to boiling under reflux for several minutes. After cooling, the precipitate was filtered, washed three times with water and dried in vacuum at 50°obtaining 12 g (81%yield) specified in the connection header.

1H NMR (DMSO-d6): δ 8.97 (1H, s); 7.68 (1H, s); 7.55 (2H, bd); 7.53 (1H, s); 7.46-7.35 (3H, m); 5.3 (2H, s); 4.40 (2H, q); 4.00 (3H, s); 1.37 (3H, t).

e) 6-(Benzyloxy)-4-chloro-7-methoxy-3-quinoline-carboxylic acid

Ethyl-6-(benzyloxy)-4-chloro-7-methoxy-3-chinainternational (11.9 g, 32 mmol) was dissolved in a mixture of tetrahydrofuran (THF) and methanol (300 ml) in a 1:1 ratio. Was added aqueous sodium hydroxide (2.0 M, 65 ml, 130 mmol) and the mixture was stirred at room temperature for 2 hours. Organic solvents were removed by evaporation on a rotary evaporator and the resulting solution was diluted with more water (200 ml), cooled on ice and acidified to pH 2-3 with hydrochloric acid under vigorous stirring. The precipitate was filtered, washed twice with water, twice with ethanol and diethyl ether and finally dried in vacuum at 50°during the night to obtain white solids, of 11.0 g (100%yield).

1H NMR (DMSO-d6): δ 13.66 (1H, bs); 8.97 (1H, s); 7.68 (1H, s); 7.54 (2H, bd); 7.52 (1H, s); 7.46-7.34 (3H, m); 5.34 (2H, s); 4.00 (3H, s).

e) 6-(Benzyloxy)-4-chloro-7-methoxy-3-chinainternational

A mixture of 6-benzyloxy-4-chloro-7-methoxy-3-quinoline-carboxylic acid (11,0 g, 32 mmol), thionyl chloride (30 ml) and toluene (100 ml) was boiled under reflux for 2 hours in an atmosphere of N2.

After cooling, the toluene and excess thionyl chloride was removed by evaporation on a rotary evaporator and the residue is suspended in acetone (250 ml) and the resulting suspend the Yu was cooled in an ice bath. Little was added aqueous ammonia (25%, 20 ml), keeping the temperature below 10°C. the Stirring was continued for 3 hours and then the acetone was removed by evaporation on a rotary evaporator. The residue is suspended in water (200 ml) and was stirred for one hour, was filtered, washed twice with water, twice with ethanol and diethyl ether and finally dried in vacuum at 50°during the night with obtaining not off-white solids, 10.4 g (95%yield).

1H NMR (DMSO-d6): δ 8.65 (1H, s); 8.10 (1H, s); 7.83 (1H, s); 7.59 (1H, s); 7.54 (2H, bd); 7.50 (1H, s); 7.46-7.34 (3H, m); 5.33 (2H, s); 3.98 (3H, s).

g) 6-Benzyloxy-4-3-(hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational. A mixture of 6-benzyloxy-4-chloro-7-methoxy-3-chinainternational (1,72 g, 5 mmol), 3-amino-2-methylbenzylamino alcohol (0,82 g, 6 mmol), acetic acid (1.2 ml) in DMF (20 ml) was heated at 100°C for two hours. After cooling, the reaction mixture was poured into ice water (500 ml) and podslushivaet to pH 9 with diluted sodium hydroxide. The resulting precipitate was filtered, washed with water, dried in air, washed twice with diethyl ether and then dried in vacuum at 50°to obtain 2.15 g (97%yield) specified in the title compound as a white solid.

1H NMR (CDCl3): δ at 10.82 (1H, s); 8.87 (1H, s); 8.26 (1H, s); 7.59 (1H, s); 7.37-7.20 (5H, m); 7.14-7.04 (3H, m); 6.73(1H, s); 6.65 (1H, d); 5.22 (1H, t); 4.61 (2H, d); 4.50 (2H, s); 3.91 (3H, s); 2.20 (3H, s).

Example 2

6-Hydroxy-4-3-(hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational

A mixture of 6-benzyloxy-4-3-(hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational (2.1 g, 4.7 mmol) and 10%palladium on coal (of 0.44 g) in methanol (50 ml), DMF (40 ml), ethyl acetate (40 ml) and acetic acid (0.5 ml) was subjected to hydrogenolysis at atmospheric pressure at 25°C. After 24 hours the reaction mixture was filtered through a bed of celite, which is then washed with DMF. The combined filtrates were podslushivaet the addition of an aqueous ammonia and the solvent was removed under reduced pressure. The residue is suspended in methanol (10 ml), was filtered and washed with methanol and diethyl ether, dried in vacuum at 50°during the night to obtain 1.1 g (66%yield) specified in the title compound as a yellow solid.

1H NMR (DMSO-d6): δ 10.43 (1H, s); 9.53 (1H, s); 8.85 (1H, s); 8.27 (1H, s); 7.60 (1H, s); 7.27 (1H, s); 7.08 (1H, d); 6.95 (1H, t); 6.78 (1H, s); 6.40 (1H, d); 5.13 (1H, t); 4.57 (2H, d); 3.92 (3H, s); 2.29 (3H s).

Example 3

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-chinainternational

A mixture of 6-hydroxy-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational (0,071 g, 0.20 mmol), 4-(3-chlorpropyl)of the research (0.036 g, 0.22 mmol), cesium carbonate (of 0.13 g, 0.40 mmol) and DMF (2.5 ml) was heated at 100°t is an increase of two hours. After cooling, the reaction mixture was poured into water and was extracted three times with dichloromethane, the solvent was removed under reduced pressure and the residue was chromatographically on silica, using a mixture of dichloromethane/methanol/ammonia (200:10:1) as eluent.

The fractions containing the product (slightly polluted), were combined and evaporated. The residue is triturated with eluent to obtain 40 mg (38%yield) specified in the title compound as a white solid.

1H NMR (DMSO-d6): δ 10.91 (1H, s); 8.76 (1H, s); 7.26 (1H, s); 7.16 (1H, dd); 7.14 (1H, t); 7.04 (1H, dd); 6.74 (1H, s); 6.15 (2H, bs); 4.69 (2H, bs); 3.95 (3H, s); 3.79 (4H, bt); 3.54 (2H, bt); 3.49 (1H, s); 2.46 (4H, m); 2.32 (2H, m); 2.30 (3H, s); 1.63 (2H, qv).

Example 4

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-(2-methoxyethoxy)-3-chinainternational

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.81 (1H, s); 8,87 (1H, s); 8.26 (1H, s); 7.59 (1H, s); 7.25 (1H, s); 7.19 (1H, d); 7.07 (1H, t); 6.67 (1H, d); 6.65 (1H, s); 5.15 (1H, t); 4.56 (2H, d); 3.89 (3H, s); 3.47 (2H, bt); 3.40 (2H,, bt); 3.20 (3H, s); 2.26 (3H, s).

Example 5

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-octyloxy-3-chinainternational

received according to the method described in Example 3.

1H NMR (DMSO-d6): δ at 10.89 (1H, s); 8.86 (1H, s); 8.25 (1H, s); 7.58 (1H, s); 7.22 (1H, s); 7.18 (1H, d); 7.07 (1H, t); 6.70 (1H, d); 6.65 (1H, s); 5.14 (1H, t); 4.55 (2H, d); 3.88 (3H, s); 3.32 (2H, bt); 2.24 (3H, s); 1.45 (2H, m); 1.33-1.15 (10H, m); 0.87 (3H, t).

Example 6

4-(3-Hydroxymethyl-2-methyl is iLine)-7-methoxy-6-[2-(4-morpholinyl)ethoxy]-3-chinainternational

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.86 (1H, s); 8.87 (1H, s); 8.26 (1H, br s); 7.59 (1H, br s); 7.24 (1H, s); 7.18 (1H, d); 7.07 (1H, t); 6.68 (1H, d); 6.67 (1H, s); 5.15 (1H, t); 4.55 (2H, d); 3.88 (3H, s); 3.54 (4H, m); 3.45 (2H, bit); 2.43 (2H, t); 2.30 (4H, m); 2.24 (3H, s).

Example 7

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-piperidinyl)ethoxy]-3-chinainternational

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.84 (1H, s); 8.86 (1H, s); 8.25 (1H, br s); 7.57 (1H, br s); 7.22 (1H, s); 7.17 (1H, d); 7.05 (1H, t); 6.67 (1H, d); 6.65 (1H, s); 5.13 (1H, br s); 4.54 (2H, s); 3.86 (3H, s); 3.41 (2H, brt); 2.39 (2H, t); 2.25 (4H, m); 2.23 (3H, s); 1.45 (4H, m); 1.35 (2H, m).

Example 8

4-(3-Hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-pyrrolidinyl)ethoxy]-3-chinainternational

received according to the method described in Example 3.

1H NMR (DMSO-d6): δ 10.83 (1H, s); 8.87 (1H, s); 8.26 (1H, br s); 7.58 (1H, br s); 7.24 (1H, s); 7.18 (1H, d); 7.06 (1H, t); 6.67 (1H, s); 6.66 (1H, d); 5.16 (1H, brt); 4.55 (2H, d); 3.88 (3H, s); 3.44 (2H, brt); 2.51 (2H, m); 2.35 (4H, m); 2.26 (3H, s); 1.65 (4H, m).

Example 9

6-[2-(Dimethylamino)ethoxy]-4-(3-(hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.87 (1H, s); 8.88 (1H, s); 8.27 (1H, br s); 7.60 (1H, br s); 7.26 (1H, s); 7.19 (1H, d); 7.08 (1H, t); 6.69 (1H, d); 6.68 (1H, s); 5.14 (1H, br s); 4.56 (2H, s); 3.89 (3H, s); 3.51 (2H, brt); 2.62 (2H, brt); 2.26 (6H, s); 2.25 (3H, s).

Example 10

6-[2-(Dimethylamino)-2-oksidoksi]-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-analysisbased

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.81 (1H, s); 8.89 (1H, s); 8.28 (1H, br s); 7.60 (1H, br s); 7.27 (1H, s); 7.17 (1H, d); 7.03 (1H, t); 6.58 (1H, d); 6.48 (1H, s); 5.18 (1H, brt); 4.57 (2H, d); 4.23 (2H, br s); 3.91 (3H, s); 2.74 (3H, s); 2.66 (3H, s); 2.22 (3H, s).

Example 11

6-(2-Amino-2-oksidoksi)-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational

received according to the method described in Example 3

1H NMR (DMSO-d6): δ 10.71 (1H, s); 8.88 (1H, s); 8.26 (1H, br s); 7.59 (1H, br s); 7.27 (1H, s); 7.26 (1H, s); 7.18 (1H, d); 7.05 (1H, s); 7.03 (1H, t); 6.62 (1H, s); 6.58 (1H, d); 5.11 (1H, t); 4.57 (2H, d); 3.91 (3H, s); 3.85 (2H, s); 2.26 (3H, s).

Example 12

4-(2-Ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational

a) 4-Chloro-7-hydroxy-6-methoxy-3-chinainternational

A mixture of 7-benzyloxy-4-chloro-6-methoxy-3-chinainternational (1.0 g, 2.9 mmol)obtained similarly to the method described in Example 1, and thioanisole (1.75 ml, 14.1 mmol) in TFA (triperoxonane acid (15 ml) was boiled under reflux for 3 hours. After cooling, the solvents were removed under reduced pressure and the residue was poured into water and podslushivaet aqueous ammonia. The precipitate was filtered, washed with water and dried to obtain 0.52 g (72%yield) specified in the connection header.

b)4-(2-Ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational

A mixture of 4-chloro-7-hydroxy-6-methoxy-3-chinainternational (0,056 g 0.22 mmol), 2-ethylaniline (32 μl, 0.26 mmol) and acetic acid (10 μl) in ethanol (5 ml) was heated under reflux for four hours. The solvents were removed under reduced pressure and the residue was chromatographically on silica using as eluent methanol. The product was dissolved in DMSO (dimethyl sulfoxide) (5 ml), was added morpholinopropan (0,018 g, 0.11 mmol) and Cs2CO3(0,090 g, 0.28 mmol) and the mixture was heated at 100°C for 20 hours. After cooling, the mixture was poured into water and the aqueous phase was extracted with methylene chloride. The residue was chromatographically on silica, using a mixture of methylene chloride/methanol (9/1-1/1) as the eluent, to obtain 9 mg (9%yield) specified in the connection header.

1H NMR (CDCl3): δ 11.05 (1H, s); 8.96 (1H, s); 7.35 (1H, s); 7.32 (1H, dd); 7.12 (2H, m); 6.91 (1H, dd); 6.74 (1H, s); 4.22 (2H, m); 3.68 (4H, m); 3.25 (3H, s); 2.80 (2H, m); 2.52 (2H, q); 2.44 (4H, m); 2.08 (2H,, t); 1.30 (3H, t).

The connections defined in the headers of examples 13-15 were obtained in a manner analogous to the one described in Example 12.

Example 13

6-Methoxy-4-[2-(methylsulfonyl)aniline]-7-[3-(4-morpholinyl)propoxy]-3-chinainternational

1H NMR (CDCl3): δ 10.76 (1H, s); 8.89 (1H, s); 7.34 (1H, s); 7.32 (1H, d); 7.11 (1H, dd); 7.02 (1H, dd); 6.79 (1H, d); 6.75 (1H, s); 4.21 (2H, t); 3.72 (4H, t); 3.39 (3H, s); 2.55-2.42 (6H, m); 2.49 (3H, s); 2.10-2.02 (2H, m).

Example 14

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-morpholinyl)about the oxy]-3-chinainternational

1H NMR (CDCl3): δ 10.81 (1H, s); 8.79 (1H, s); 7.26 (1H, s); 7.20 (1H, d); 7.16 (1H, dd); 6.84 (1H, d); 6.69 (1H, s); 4.74 (2H, s); 4.15 (2H, t); 3.68 (4H, t); 3.29 (3H, s); 2.48 (2H, t); 2.42 (4H, m); 2.32 (3H, s); 2.01 (2H, m).

Example 15

4-(1H-Indol-4-ylamino)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational

1H NMR (CD3OD): δ 8.82 (1H, s); 7.37 (1H, d); 7.23 (1H, d); 7.15 (1H, s); 7.14 (1H, t); 6.92 (1H, s); 6.88 (1H, d); 6.21 (1H, d); 4.21 (2H, t); 3.78 (4H, t); 2.98 (3H, s); 2.98-2.88 (6H,m); 2.18 (2H, m).

Example 16

Methyl-4-{[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-chinoline]oxy}of butanoate

A mixture of 7-hydroxy-6-methoxy-4-(2-toluidino)-3-chinainternational (0,026 g 0,080 mmol), DMSO (2.5 ml), K2CO3(of 0.017 g, 0.12 mmol) and methyl-4-chlorobutyrate (0,011 g 0,080 mmol) was boiled under reflux for 2 hours. The reaction mixture was filtered, evaporated and chromatographically on the silicon dioxide with obtaining specified in the connection header.

1H NMR (DMSO-d6): δ 10.72 (1H, s); 8.85 (1H, s); 8.25 (1H, br s); 7.58 (1H, br s); 7.28 (1H, d); 7.22 (1H, s); 7.10-6.97 (2H, m); 6.68 (1H, d); 6.67 (1H, s); 4.10 (2H, t); 3.57 (3H, s); 3.26 (3H, s); 3.28 (3H, s); 2.05-1.93 (4H, m).

APCI-MS m/z: 424,1 [MH+]

Example 17

4-(2-Ethylaniline)-7-(3-hydroxypropoxy)-6-methoxy-3-chinainternational

A mixture of 4-(2-ethylaniline)-7-hydroxy-6-methoxy-3-chinainternational (0.12 g, 0.35 mmol), DMSO (15 ml), Cs2CO3(0.34 g, 1.0 mmol) and 1,3-dibromopropane was stirred at 100°C for 2 hours. The reaction mixture was poured into NaHC 3(aq.) and was extracted with CH2Cl2. Substance chromatographically obtaining specified in the connection header (0,012 g, 9%).

1H NMR (CDCl3): δ at 10.82 (1H, s); 8.83 (1H, s); 7.34-7.26 (2H, m); 7.09 (1H, m); 6.83 (1H, dd); 6.70 (1H, s); 4.60 (2H, t); 3.93 (2H, t); 3.28 (3H, s); 2.77 (2H, q); 2.12 (2H, m); 1.22 (3H, t).

APCI-MS m/z: 396,1 [MH+]

Example 18

6-Methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(2-toluidino)-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 12.

1H NMR (CDCl3): δ 10.60 (1H, s); 8.72 (1H, s); 7.28-7.26 (2H, m); 7.07 (1H, m); 6.89 (1H, m); 6.75 (1H, s); 4.28 (2H, t); 3.72 (4H, t); 3.32 (3H, s); 2.88 (3H, t); 2.58 (4H, t); 2.36 (3H, s).

APCI-MS m/z: 437,2 [MH+]

Example 19

4-(2-Ethylaniline)-6-methoxy-7-(2-methoxyethoxy)-3-chinainternational

A mixture of 4-(2-ethylaniline)-7-hydroxy-6-methoxy-3-chinainternational (0,22 g, of 0.65 mmol), DMF (15 ml), Cs2CO3(0.64 g, to 1.98 mmol) and 2-pomatoleios ether was stirred at 100°C for 2 hours. The reaction mixture was evaporated and chromatographically obtaining specified in the connection header (0,045 g, 18%).

1H NMR (CDCl3): δ 10.70 (1H, s); 8.72 (1H, s); 7.30 (1H, dd); 7.26 (1H, s); 7.08 (1H, m); 6.85 (1H, dd); 6.74 (1H, s); 4.28 (2H, t); 3.83 (2H, t); 3.45 (3H, s); 3.30 (3H, s); 2.80 (2H, q); 1.30 (3H, t).

APCI-MS m/z: 396,1 [MN+]

Example 20

4-(2-Ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational

a) Ethyl-3-(1H-1,2,4-triazole-1-yl)propanoate. To a solution of 1H-1,2,triazole (5 g, to 72.4 mmol), EtOH (36 ml) and Na (1.66 g, to 72.4 mmol) was added dropwise ethyl-3-bromopropionate (9,9 ml of 79.6 mmol). The reaction mixture was stirred over night, filtered, evaporated to 50 ml and subjected to distillation to obtain specified in the title compound (3.3 g, 30%) as a white solid.

1H NMR (DMSO-d6): δ 8.43 (1H, s); 7.90 (1H, s); 4.30 (2H, t); 3.94 (2H, q); 2.78 (2H, t); 1.05 (3H, t).

b) 3-(1H-1,2,4-triazole-1-yl)-1-propanol. To a solution of ethyl-3-(1H-1,2,4-triazole-1-yl)propanoate (2,95 g, 17.5 mmol) in diethyl ether (90 ml) was added LiAlH4(0.66 g, 17.5 mmol). After heating to boiling under reflux for 60 hours was added 10 ml of a mixture of 50%methanol-water. The reaction mixture was filtered and the filter was washed with 100 ml of methanol and twice with 100 ml of hot water. After evaporation and after purification using preparative HPLC has been specified in the header of the product.

1H NMR (CDCl3): δ 8.42 (1H, s); 7.98 (1H, s); 4.35 (2H, t); 3.47 (2H, t); 2.09 (2H, q).

C) 1-(3-Chloropropyl)-1H-1,2,4-triazole. 3-(1H-1,2,4-triazole-1-yl)-1-propanol (0,160 g, 1.3 mmol) was boiled under reflux in thionyl chloride (3 ml) for 2 hours. The reaction mixture was evaporated obtaining specified in the header of the product.

APCI-MS m/z: 146,1 [MN+]

g) 4-(2-Ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational

Specified in title product was obtained according to the method described the WMD in Example 17

1H NMR (CDCl3): δ 10.71 (1H, s); 8.70 (1H, s); 8.07 (1H, s); 7.94 (1H, s); 7.34-7.29 (1H, m); 7.20 (1H, s); 7.16-7.05 (2H, m); 6.90-6.85 (1H, m); 6.76 (1H, s); 4.44 (2H, t); 4.28 (2H, t); 3.62 (3H, s); 2.80 (2H, q); 2.46 (2H, m); 1.30 (3H, t).

APCI-MS m/z: 447,5 [MH+]

Example 21

4-(2-Ethylaniline)-6-methoxy-7-[4-(4-morpholinyl)butoxy]-3-chinainternational

4-(2-Ethylaniline)-7-hydroxy-6-methoxy-3-chinainternational (0,064 g 0,19 mmol) was dissolved in DMSO (4 ml), 1-bromo-4-chlorobutane (22 μl, 0,19 mmol) was added Cs2CO3(0.18 g, 0.55 mmol), the mixture was stirred at ambient temperature for three days. The mixture was poured into water and was extracted with methylene chloride. The residue was chromatographically on silica, using a mixture of ethyl acetate/methanol (1:0→1:1) as eluent. The resulting oil was dissolved in DME, morpholine (25 μl, 0.29 mmol) was added a catalytic amount of KI, the mixture was heated under reflux for four days. After cooling, the mixture was poured into water and was extracted with methylene chloride. The crude product was purified preparative HPLC to obtain 20 mg (22%yield) specified in the connection header.

1H NMR (CDCl3): δ 11.31 (1H, s); 9.02 (1H, s); 7.40 (1H, s); 7.34 (1H, d); 7.22-7.11 (2H, m); 6.95 (1H, d); 6.73 (1H, s); 4.18 (2H, t); 3.72 (4H, m); 3.29 (3H, s); 2.79 (2H, q); 2.5-2.40 (6H, m); 1.93 (2H, m); 1.69 (2H, m); 1.28 (3H, t).

Example 22

7-(3-Chloropropoxy)-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational

7-Hydroxy-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational (0,90 mg, 2.54 mmol) was dissolved in DMF (10 ml), 1-bromo-4-chlorobutane (of 0.28 ml, and 2.79 mmol) was added Cs2CO3(1.7 g, 5.2 mmol), the mixture was stirred at ambient temperature for three days. The mixture was poured into water and was extracted with methylene chloride. The residue was chromatographically on silica, using a mixture of ethyl acetate/methanol (1:0→5:1) as eluent, to obtain 550 mg (50%yield) specified in the connection header.

1H NMR (DMSO-d6): δ 10.85 (1H, s); 8.83 (1H, s); 8.22 (1H, s, br); 7.30 (1H, s, br); 7.22 (1H, s); 7.10 (1H, d); 7.02 (1H, t); 6.65 (1H, d); 6.62 (1H, s); 5.18 (1H, m); 4.58 (2H, d); 4.21 (2H, t); 3.78 (2H, t); 3.22 (3H, s); 2.23 (3H, s); 2.23-2.19 (2H, m).

Example 23(a)23(b)

7-{3-[(CIS)-2,6-Dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational and

7-{3-[(TRANS)-2,6-Dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational

7-(3-Chloropropoxy)-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational (50 mg, 0.12 mmol) was dissolved in DME (3 ml), 2,6-dimethylmorpholine (25 μl, 0.29 mmol) was added a catalytic amount of KI, the mixture was heated under reflux for four days. After cooling, the mixture was filtered and the crude product was purified preparative HPLC to obtain 14 mg (23%yield) of CIS-connect the deposits and 8 mg (13%yield) cross-connect.

7-{3-[(CIS)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational:

1H NMR (CD3CO): δ 8.89 (1H, s); 7.24 (1H, d); 7.20 (1H, s); 7.18 (1H, t); 6.95 (1H, d); 6.79 (1H, s); 4.68 (2H, s); 4.20 (2H, t); 3.75-3.65 (2H, m); 3.29 (3H, s); 3.0 (2H, d); 2.78 (2H, t); 2.38 (3H, s); 2.16 (2H, m); 1.95 (2H, m); 1.18 (6H, d).

7-{3-[(TRANS)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational:

1H NMR (CD3OD at 55°): δ 8.82 (1H, s); 7.52 (1H, d); 7.35 (1H, t); 7.29 (1H, s); 7.18 (1H, d); 6.85 (1H, s); 4.78 (2H, s); 4.30 (2H, t); 4.18 (2H, m); 3.35 (3H, s); 3.21 (4H, m); 2.93 (2H, m); 2.34 (2H, m); 2.35 (3H, s); 1.35 (6H, d).

The connections defined in the headers of examples 24-26, obtained by the method similar to that described in Example 23.

Example 24

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(1-piperidinyl)propoxy]-3-chinainternational

1H NMR (CD3OD): δ 8.82 (1H, s); 7.34 (1H, d); 7.25 (1H, s); 7.18 (1H, t); 6.89 (1H, d); 6.85 (1H, s); 4.75 (2H, s); 4.22 (2H, t); 3.35 (3H, s); 3.20-3.05 (6H, m); 2.40 (3H, s); 2.28 (2H, m); 1.85 (4H, m); 1.64 (2H, m).

Example 25

7-{3-[(2-Ethoxyethyl)amino]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational

1H NMR (CD3OD): δ 8.82 (1H, s); 7.30 (1H, d); 7.25 (1H, s); 7.18 (1H, t); 6.89 (1H, d); 6.82 (1H, s); 4.76 (2H, s); 4.22 (2H, t); 3.59 (2H, t); 3.53 (2H, q); 3.35 (3H, s); 2.89 (2H, t); 2.83 (2H, t); 2.40 (3H, s); 2.12 (2H, m); 1.18 (3H, t).

Example 26

4-[3-(Hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-thiomorpholine)propoxy]-3-chinainternational

1H NMR (CD 3CO): δ 8.81 (1H, s); 7.31 (1H, d); 7.22 (1H, s); 7.18 (1H, t); 6.86 (1H, d); 6.80 (1H, s); 4.75 (2H, s); 4.20 (2H, t); 3.38 (3H, s); 3.08 (2H, m); 2.80-2.60 (8H, m); 2.39 (3H, s); 2.08 (2H, m).

Example 27

6-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational

a) 6-(Benzyloxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 1(g).

APCI-MS m/z: 428 [MH+]

b)4-(2-Ethylaniline)-6-hydroxy-7-methoxy-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 2.

1H NMR (DMSO-d6): δ 10.52 (1H, s); 9.54 (1H, br s); 8.86 (1H, s); 8.29 (1H, br s); 7.62 (1H, br s); 7.28 (1H, s); 7.28 (1H, m); 6.98 (2H, m); 6.76 (1H, s); 6.45 (1H, m); 3.92 (3H, s); 2.75 (2H, q); 1.29 (3H, t).

APCI-MS m/z: 338 [MN+]

C) 6-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational

Associated with the polymer triphenylphosphine (0.15 g, 0.44 mmol) and 3-dimethylamino-1-propanol (26 μl, 0.22 mmol) suspended and dissolved in CH2Cl2and THF at -15°and was stirred for 30 minutes. Was added dropwise DEAD (diethylazodicarboxylate) (70 μl, 0.44 mmol) at -15°C. 4-(2-Ethylaniline)-6-hydroxy-7-methoxy-3-chinainternational (50 mg, 0.15 mmol) suspended in THF and then added to the reaction mixture. The reaction mixture was stirred overnight, allowing the temperature to rise to ˜10°C. the Polymer was filtered and the filtrate Ko is centered in a vacuum. The product was purified using preparative HPLC, to obtain 15 mg (24%) of white crystals.

1H NMR (CD3OD): δ 8.79 (1H, s); 7.37 (1H, m); 7.22 (1H, s); 7.15 (2H, m); 6.84 (1H, m); 6.78 (1H, s); 3.95 (3H, s); 3.42 (2H, t); 2.79 (2H, q); 2.35 (2H, t); 2.23 (6H,s); 1.74(2H,m); 1.29(3H,t).

APCI-MS m/z: 423 [MH+].

The connections defined in the headers of examples 28-33, obtained by the method similar to that described in Example 27.

Example 28

4-(2-Ethylaniline)-6-[3-(1H-imidazol-1-yl)propoxy]-7-methoxy-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.54 (1H, s); 7.29 (1H, m); 7.24 (1H, s); 7.06 (3H, m); 6.98 (1H, s); 6.80 (1H, m); 6.71 (1H, s); 3.99 (3H, s); 3.28 (2H, m); 2.75 (2H, q); 2.04 (2H, m); 1.27 (3H, t)

APCI-MS m/z: 446 [MH+]

Example 29

4-(2-Ethylaniline)-7-methoxy-6-(3-teenrotica)-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.37 (2H, m); 7.24 (1H, s); 7.16 (2H, m); 7.06 (1H, m); 6.91 (1H, m); 6.87 (1H, s); 6.83 (1H, m); 4.53 (2H, s); 3.97 (3H, s); 2.76 (2H, q); 1.29 (3H, t).

APCI-MS m/z: 434 [MH+].

Example 30

6-[2-(Dimethylamino)ethoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.37 (1H, m); 7.22 (1H, s); 7.15 (2H, m); 6.84 (1H, m); 6.78 (1H, m); 3.95 (3H, s); 3.50 (2H, brt); 2.80 (2H, q); 2.57 (2H, t); 2.24 (6H, s); 1.30 (3H, t)

APCI-MS m/z: 409 [MH+]

Example 31

6-(3-Aminopropoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational

This compound was synthesized as described above using Vos-aminosidine alcohol. After filtration of the resin and evaporation the residue was dissolved in CH2Cl2and TF (50:50) and was stirred at room temperature for 30 minutes. The solvent is evaporated and the product was purified preparative HPLC.

1H NMR (CD3OD): δ 8.82 (1H, s); 7.38 (1H, m); 7.23 (1H, s); 7.16 (2H, m); 6.86 (1H, m); 6.80 (1H, s); 3.97 (3H, s); 3.48 (2H, brt); 2.81 (2H, q); 2.71 (2H, t); 1.74 (2H, m); 1.31 (3H, t)

APCI-MS m/z: 395 [MH+].

Example 32

4-(2-Ethylaniline)-7-methoxy-6-[2-(methylamino)ethoxy]-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.36 (1H, m); 7.23 (1H, s); 7.15 (2H, m); 6.84 (1H, m); 6.80 (1H, s); 3.97 (3H, s); 3.50 (2H, brt); 2.79 (2H, q); 2.75 (2H, t); 2.37 (3H, s); 1.29 (3H, t)

APCI-MS m/z: 395 [MH+]

Example 33

6-(2-Aminoethoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.36 (1H, brd); 7.23 (1H, s); 7.14 (2H, m); 6.84 (1H, brd); 6.78 (1H, s); 3.96 (3H, s); 3.41 (2H, brt); 2.79 (4H, m); 1.29 (3H, t)

APCI-MS m/z: 381 [MH+]

Example 34

7-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational

a)4-(2-Ethylaniline)-7-benzyloxy-6-methoxy-3-chinainternational

Specified in the title compound was obtained as described in Example 27(a), starting from 7-benzyloxy-4-chloro-6-methoxy-3-chinainternational obtained by the method similar to that described in Example 1. Yield 4.4 g (89%) of light brown powder.

1H NMR (DMSO-d6): δ 11.85 (1H, br s); 8.98 (1H, s); 8.47 (1H, br s); 7.84 (1H, br s); 7.52-7.33 (7H, m); 7,29-7.17 (2H, m); 6.99 (1H, brd); 6.75 (1H, s); 5.26 (2H, s); 3.24 (3H, s); 2.70 (2H, q); 1.20 (3H, t)

APCI-MS m/z: 428 [MH+]

b) 4-(2-Ethylaniline)-7-hydroxy-6-methoxy-3-chinainternational

Specified in the title compound was obtained which, as described in Example 27(b).

Yield 0.3 g (90%) yellow oil, which crystallized after a few hours.

1H NMR (CD3OD): δ 8.70 (1H, s); 7.39 (1H, m); 7.19 (2H, m); 7.00 (1H, s); 6.94 (1H, m); 6.73 (1H, s); 2.78 (2H, q); 1.29 (3H, t)

APCI-MS m/z: 338 [MH+]

C) 7-[3-(Dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational

Specified in the title compound was obtained as described in Example 27(b).

1H NMR (CD3OD): δ 8.78 (1H, s); 7.35 (1H, m); 7.19 (1H, s); 7.13 (2H, m); 6.83 (1H, m); 6.77 (1H, s); 4.15 (2H, t); 3.28 (3H, s); 2.79 (2H, q); 2.57 (2H, t); 2.29 (6H, s); 2.05 (2H, m); 1.28 (3H, t).

APCI-MS m/z: 423 [MH+]

The connections defined in the headers of examples 35-37, obtained by the method similar to that described in Example 34.

Example 35

4-(2-Ethylaniline)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-chinainternational

1H NMR (CD3OD): δ 8.78 (1H, s); 7.93 (2H, brm); 7.37 (1H, m); 7.16 (2H, m); 7.13 (1H, s); 6.84 (1H, m); 6.79 (1H, s); 6.67 (2H, brd); 4.12 (2H, t); 3.65 (2H, t); 3.33 (3H, s); 3.01 (3H, s); 2.80 (2H, q); 2.13 (2H, m); 1.31 (3H, t)

APCI-MS m/z: 486 [MH+]

Example 36

4-(2-Ethylaniline)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-chinainternational

1H NMR (CDCl3): δ 11.11 (1H, s); 8.88 (1H, s); 8.20 (2H, br s); 7.33 (1H, d); 7.32 (1H, s); 7.15 (2H, m); 6.90 (1H, d); 6.75 (1H, d); 6.74 (1H, s); 4.36 (2H, t); 3.94 (2H, t); 3.23 (3H, s); 3.19 (3H, s); 2.78 (2H, q); 1.29 (3H, t)

APCI-MS m/z: 472 [MH+]

Example 37

4-(2-Ethylaniline)-6-methoxy-7-[2-(methylamino)ethoxy]-3-chinainternational

1H NMR (CD3OD): δ 8.80 (1H, s); 7.37 (1H, m); 7.23 (1H, s), 7.15 (2H, m); 6.86 (1H, m); 6.80 (1H, s); 4.24 (2H, t); 3.30 (3H, s); 3.04 (2H, t); 2.80 (2H, q); 2.47 (3H, s); 1.29 (3H, t)

APCI-MS m/z: 395 [MH+]

Example 38

4-(2-Ethylaniline)-6-methoxy-7-[2-(1-piperazinil)ethoxy]-3-chinainternational

Triphenylphosphine (0.12 g, 0.44 mmol) and 1-(2-hydroxyethyl)piperazine (25 MCP, 0.22 mmol) was dissolved in CH2Cl2and THF at -15°and was stirred for 30 minutes was added dropwise DEAD (70 μl, 0.44 mmol) at -15°C. 4-(2-Ethylaniline)-7-hydroxy-6-methoxy-3-chinainternational (0.50 g, 0.15 mmol) suspended in THF and then added to the reaction mixture. The reaction mixture was stirred overnight, allowing the temperature to rise to ˜10°C. the Solvent was removed under reduced pressure and the product was purified using preparative HPLC, to obtain 34 mg (24%) of a clear oil.

1H NMR (CD3OD): δ 8.80 (1H, s); 7.36 (1H, m); 7.21 (1H, s); 7.13 (2H, m); 6.83 (1H, m); 6.77 (1H, s); 4.28 (2H, t); 3.28 (3H, s); 2.86 (6H, m); 2.79 (2H, q); 2.62 (4H, br s); 1.29 (3H, t)

APCI-MS m/z: 450 [MH+]

The connections defined in the header of examples 39-41, obtained by the method similar to that described in Example 38.

Example 39

4-(2-Ethylaniline)-7-[3-(1H-imidazol-1-yl)propoxy]-6-methoxy-3-chinainternational

1H NMR (CD3OD): δ 8.79 (1H, s); 7.64 (1H, s); 7.37 (1H, m); 7.15 (3H, m); 6.95 (1H, s); 6.84 (1H, m); 6.79 (1H, s); 4.26 (2H, t); 4.06 (2H, t); 3.31 (3H, s); 2.80 (2H, q); 2.32 (2H, m); 1.29 (3H, t)

APCI-MS m/z: 446 [MH+]

Example 40

4-(2-Ethylaniline)-7-[2-(1H-imidazol-1-yl)ethoxy]-6-methoxy-3-chinoline boxlid

1H NMR (CD3OD): δ 8.78 (1H, s); 7.75 (1H, s); 7.36 (1H, m); 7.25 (1H, s); 7.17 (1H, s); 7.13 (2H, m); 6.93 (1H, s); 6.83 (1H, m); 6.78 (1H, s); 4.48 (2H, t); 4.36 (2H, t); 3.29 (3H, s); 2.78 (2H, q); 1.28 (3H, t)

APCI-MS m/z: 432 [MH+]

Example 41

7-(3-Aminopropoxy)-4-(2-ethylaniline)-6-methoxy-3-chinainternational

This compound was synthesized as described above using the BOC-amino-protected alcohol. After filtration of the resin and evaporation the residue was dissolved in CH2Cl2and TFA (50:50) and was stirred at room temperature for 30 minutes, the Solvent evaporated and the product was purified using preparative HPLC.

1H NMR (CD3OD): δ 8.79 (1H, s); 7.36 (1H, m); 7.20 (1H, s); 7.13 (2H, m); 6.83 (1H, m); 6.77 (1H, s); 4.21 (2H, t); 3.28 (3H, s); 2.88 (2H, t); 2.79 (2H, q); 2.03 (2H, m); 1.29 (3H, t)

APCI-MS m/z: 395 [MH+]

Example 42

7-Hydroxy-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 34(b).

1H NMR (DMSO-d6): δ 10.86 (1H, s); 8.81 (1H, s); 8.21 (1H, br s); 7.54 (1H, br s); 7.18 (1H, d); 7.12 (1H, s); 7.08 (1H, t); 6.69 (1H, d); 6.65 (1H, s); 5.14 (1H, br s); 4.56 (2H, s); 3.25 (3H, s); 2.25 (3H, s)

APCI-MS m/z: 354 [MH+]

Example 43

6-{[3-(1H-Imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinainternational

a) Ethyl-4-chloro-6-bromo-7-methoxy-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

b) Ethyl-6-bro what about the-7-methoxy-4-(2-toluidino)-3-chinainternational

Ethyl-6-bromo-4-chloro-7-methoxy-3-chinainternational (0,90 g, 2.6 mmol), ortho-toluidine (0,30 ml, 2.9 mmol) and Asón (1 ml) was dissolved in EtOH (50 ml) and boiled under reflux for 4 hours. After cooling, the mixture was neutralized aqueous ammonia, and the residue was filtered to obtain 870 mg (80%) of a green powder.

1H NMR (DMSO-d6): δ 9.84 (1H, s); 8.94 (1H, s); 7.89 (1H, s); 7.41 (1H, s); 7.36 (1H, brd); 7.16 (2H, m); 6.94 (1H, brd); 4.15 (2H, q); 3.99 (3H, s); 2.28 (3H, s); 1.26 (3H, t)

C) 6-{[3-(1H-Imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinainternational

A mixture of 6-bromoquinoline (0.25 mmol), Pd2(dba)3(for example, 0.005 mmol), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (0.015 mmol), Cs2CO3(0.33 mmol) and 1-(3-aminopropyl)-imidazole (0.29 mmol) was stirred at 90°during the night in an atmosphere of N2. After cooling, the mixture was purified column flash chromatography on silica gel. After elution with CH2Cl2and then with a mixture of CH2Cl2/MeOH (10:1) received 110 mg (100%) yellow oil, which contained minor phosphine impurities.

APCI-MS m/z: 460 [MH+]

The crude ethyl ester of hydrolyzed in a mixture of Meon/5M NaOH (1:1) at room temperature over night. After concentration in vacuo, the remaining aqueous phase was acidified using 2 M HCl and washed with CH2Cl2. The aqueous phase was neutralized with 5 M NaCCO3and was extracted with CHCl 3. After concentration in vacuo received 25 mg (25%) yellow oil.

APCI-MS m/z: 432 [MH+]

The crude acid (0.025 g, 0.06 mmol) and CDI (at 0.020 g, 0.1 mmol) was dissolved in DMF and stirred at 60°C for 1 hour. The mixture was cooled in a bath EtOH/dry ice and saturated NH3(gas.) and then was stirred at room temperature for 45 minutes. The mixture was diluted with CHCl3, washed with saturated aqueous NaHCO3and water and concentrated in vacuum. After purification using preparative HPLC was obtained after removal triperoxonane salt acetate 15 mg (60%) of a white solid.

1H NMR (CD3OD): δ 8.67 (1H, s); 7.56 (1H, s, Im); 7.27 (1H, brd); 7.13 (1H, s); 7.02 (1H, s, Im); 6.97 (1H, s, Im); 6.95 (2H, m); 6.68 (1H, brd); 6.28 (1H, s); 3.99 (3H, s); 3.90 (2H, t); 2.67 (2H, t); 2.36 (2H,, s); 1.68 (2H, m)

APCI-MS m/z: 431 [MN+]

The connections defined in the headers of examples 44-46, obtained by the method similar to that described in Example 43.

Example 44

7-Methoxy-6-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational

1H NMR (CD3OD): δ 8.66 (1H, s); 7.31 (1H, m); 7.11 (1H, s); 7.10 (2H, m); 6.81 (1H, m); 6.34 (1H, s); 4.00 (3H, s); 3.27 (3H, s); 3.24 (2H, t); 2.77 (2H, t); 2.35 (3H, s).

APCI-MS m/z: 381 [MN+].

Example 45

7-Methoxy-6-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational

1H NMR (DMSO-d6): δ 10.41 (1H, s); 8.74 (1H, s); 8.23 (1H, br s); 7.56 (1H, br s); 7.25 (1H, d); 7.17 (2H, s); 6.96 (2H, m); 6.50 (1H, s); 6.22 (1H, d); 5.43 (1H, t); 3.95 (3H, s); 3.42 (4H, brt); 2.71 (2H, q); 2.33 (3, s); 2.19 (6H, m).

APCI-MS m/z: 436 [MN+].

Example 46

7-Methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational

1H NMR (CD3OD): δ 8.65 (1H, s); 7.27 (1H, brd); 7.11 (1H, s); 7.03 (2H, m); 6.72 (1H, brd); 6.32 (1H, s); 3.99 (3H, s); 3.69 (4H, t); 2.68 (2H, t); 2.39 (4H, brm); 2.37 (3H, s); 2.27 (2H, t); 1.49 (2H, m).

APCI-MS m/z: 450 [MH+].

Example 47

6-Methoxy-7-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational

a) Ethyl-4-chloro-7-bromo-7-methoxy-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

b) Ethyl-7-bromo-6-methoxy-4-(2-toluidino)-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 43(b).

1H NMR (DMSO-d6): δ 9.83 (1H, s); 8.87 (1H, s); 8.15 (1H, s); 7.38 (1H, m); 7.17 (2H, m); 7.09 (1H, s); 6.98 (1H, m); 4.17 (2H, q); 3.45 (3H, s); 2.30 (3H, s); 1.28 (3H, t).

b) 6-Methoxy-7-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational

Specified in the title compound was obtained according to the method described in Example 43(b).

1H NMR (CD3OD): δ 8.68 (1H, s); 7.28 (1H, brd); 7.06 (2H, m); 6.81 (1H, brd); 6.73 (1H, s); 6.60 (1H, s); 3.67 (4H, brt); 3.34 (2H, t); 3.33 (3H, s); 2.65 (2H, t); 2.49 (4H, brt); 2.31 (3H, s).

APCI-MS m/z: 436 [MH+].

The connections defined in the headers of examples 48-51, obtained by the method similar to that described in Example 47.

Example 48

6-Methoxy-7-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational

1H NMR (CDCl3): δ 10.50 (1H, s); 8.73 (1H, s); 7.25 (1H, brd); 7.04 (2H, m); 6.88 (1H, s); 6.87 (1H, brd); 6.63 (1H, s); 5.06 (1H, brt); 3.66 (2H, t); 3.42 (2H, q); 3.39 (3H, s); 3.34 (3H, s); 2.37 (3H, s).

APCI-MS m/z: 381 [MH+].

Example 49

7-{[3-(1H-imidazol-1-yl)propyl]amino}-6-methoxy-4-(2-toluidino)-3-chinainternational

1H NMR (CDCl3): δ 10.93 (1H, br s); 8.93 (1H, s); 7.51 (1H, s); 7.27 (1H, brd); 7.09 (2H, m); 7.06 (1H, s); 6.93 (1H, brd); 6.91 (1H, s); 6.90 (1H, s); 6.62 (1H, s); 4.81 (1H, brt); 4.06 (2H, t); 3.32 (3H, s); 3.25 (2H, m); 2.35 (3H, s); 2.16 (2H, m).

APCI-MS m/z: 431 [MH+].

Example 50

7-[(1-Benzyl-4-piperidinyl)amino]-6-methoxy-4-(2-toluidino)-3-chinainternational

1H NMR (CD3OD): δ 8.68 (1H, s); 7.32 (6N, m); 7.09 (2H, m); 6.85 (1H, brd); 6.78 (1H, s); 6.65 (1H, s); 3.59 (2H, s); 3.49 (1H, m); 3.35 (3H, s); 2.93 (2H, brd); 2.34 (3H, s); 2.28 (2H, brt); 2.08 (2H, brd); 1.60 (2H, m).

APCI-MS m/z: 496 [MH+]

Example 51

6-Methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational

1H NMR (CD3OD): δ 8.67 (1H, s); 7.31 (1H, brd); 7.11 (2H, m); 6.89 (1H, s); 6.70 (1H, s); 6.61 (1H, s); 4.84 (3H, s); 3.33 (3H, s); 3.30 (2H, t); 2.49 (2H, t); 2.46 (4H, brt); 2.32 (3H, s); 1.87 (2H, m).

APCI-MS m/z: 450 [MH+]

Example 52

4-[3-(Hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

a) Ethyl-6,7-dimethoxy-4-chloro-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

b) 6,7-Dimethoxy-4-chloro-3-chinainternational

A mixture of ethyl-6,7-dimethoxy-4-chloro-3-chinainternational (3.0 g, 10.2 mmol) was dissolved in 40 ml of methanol and NaOH(aq.) (20 ml, 5 M). The mixture was heated to 100°C for four hours. After cooling, the methanol evaporated. The aqueous solution was acidified with 2 M HCl to pH 2-3. A white precipitate was centrifuged and then decantation. This procedure was repeated twice. The solid was dried in vacuum over night. The solid was dissolved in 50 ml of thionyl chloride and heated to boiling under reflux for three hours. After cooling, the excess thionyl chloride was removed by evaporation on a rotary evaporator and the residue is suspended in acetone, the resulting suspension was cooled in an ice bath. Was added ammonium hydroxide (7 ml), keeping the temperature below 0°C. the Suspension was stirred for 30 minutes and the resulting suspension was filtered, washed with water and dried in the air.

1H NMR (DMSO-d6): δ 8.66 (1H, s); 8.12 (1H, br s); 7.87 (1H, br s); 7.46 (2H, d); 3.98 (3H, s); 3.97 (3H, s).

C)4-[3-(Hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0.15 g, 0,56 mmol), 3-amino-2-methylbenzylamino alcohol (0.1 g, 0.73 mmol), acetic acid (0.2 ml) in EtOH (10 ml) was boiled under reflux for 4 hours. After cooling, the pH was brought to 9 water NH3. The resulting precipitate was filtered and washed with cold EtOH, and dried in vacuum at 40°to obtain 0.1 g of 49%yield) specified in the connection header.

1H NMR (DMSO-d6): δ 10.84 (1H, s); 8.83 (1H, s); 8.25 (1H, s); 7.56 (1H, s); 7.21 (1H, s); 7.17 (1H, d); 7.05 (1H, t); 6.17 (1H, d); 6.15 (1H, s); 5.12 (1H, br s); 4.52 (2H, s); 3.87 (3H, s); 3.21 (3H, s); 2.23 (3H, s).

APCI-MS m/z: 368.2 [MH+].

The connections defined in the headers of examples 53-56, obtained by the method similar to that described in Example 52.

Example 53

4-(2-Bromoaniline)-6,7-dimethoxy-3-chinainternational

1H NMR (CDCl3): δ 10.28 (1H, s); 8.80 (1H, s); 7.63 (1H, d); 7.34 (1H, s); 7.21 (1H, s); 7.10 (1H, t); 7.05 (1H, t); 6.90 (1H, t); 6.75 (1H, s); 6.72 (1H, s); 4.0 (3H, s); 3.48 (3H, s).

APCI-MS m/z: 402,1, 404,1 [MH+].

Example 54

4-(4-Hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 10.81 (1H, s); 9.30 (1H, s); 8.79 (1H, d); 8.18 (1H, br s); 7.45 (1H, br s); 7.19 (1H, s); 6.75-6.50 (4H, m); 3.84 (3H, s); 3.26 (3H, s); 2.32 (3H, s).

APCI-MS m/z: 354,1 [MH+].

Example 55

6,7-Dimethoxy-4-(2-methoxyaniline)-3-chinainternational

1H NMR (DMSO-d6): δ 10.41 (1H, s); 8.87 (1H, s); 8.13 (1H, s); 7.57 (1H, br s); 7.28 (1H, s); 7.09 (1H, dd); 7.03 (1H, dt); 6.83-6.78 (2H, m); 6.65 (1H, brd); 3.91 (3H, s); 3.83 (3H, s).

APCI-MS m/z: 354,1 [MH+].

Example 56

4-(4-Fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 10.91 (1H, br s); 8.83 (1H, s); 8.22 (1H, br s); 7.61 (1H, br s); 7.26 (1H, s); 7.23-6.93 (5H, m); 7.03 (1H, dt); 3.89 (3H, s); 3.37 (3H, s); 2.28 (3H, s).

APCI-MS m/z: 356,2 [MH+].

Example 57

4-[(1-Ethyl-1H-pyrazole-5-yl)amino]-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 1-ethyl-5-and is inoperable (0,030 g, 0.27 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 7.5 hours. DMF is evaporated under reduced pressure and the residue was dissolved in a mixture of MeCN and water (1:7)containing 0.1% triperoxonane acid. After preparative HPLC using a gradient containing 0.1% triperoxonane acid) 10→40% MeCN in water as eluent was obtained after evaporation specified in the title compound in the form of salts triperoxonane acid. The product is suspended in a saturated aqueous NaHCO3and to absorb short-SPE extraction solid phase) column [ISOLUTE™ C18 (EC)], pre-conditioned successively with methanol and water. The column is extensively washed with water until such time as eluent pH became neutral. The product was then suirable with methanol, the solvent evaporated and the residue was led from ethanol to obtain specified in the title compound (19 mg, 32%).

1H NMR (DMSO-d6): δ 11.09 (1H, bs); 8.88 (1H, s); 8.34 (1H, bs); 7.71 (1H, bs); 7.42 (1H, d, J 1.4 Hz); 7.27 (1H, s); 6.67 (1H, s); 5.87 (1H, bs); 4.02 (2H, q, J 7.2 Hz); 3.90 (3H, s); 3.46 (3H, s); 3.12 (3H, s), 1.29 (3H, t, J 7.2 Hz).

APCI-MS m/z: 342,1 [MH+]

Example 58

4-(3-Aminocarbonyl-2-methylaniline)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 3-amino-2-methylbenzamide (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated Ave is 100° C for 18 hours. After cooling, the reaction mixture was diluted with water (20 ml) and podslushivaet using 1 M NaOH. The precipitate was filtered, washed with water and dried to obtain specified in the title compound (41 mg, 61%).

1H NMR (DMSO-d6): δ 10.76 (1H, s); 8.90 (1H, s); 8.30 (1H, bs); 7.75 (1H, bs); 7.64 (1H, bs); 7.44 (1H, bs); 7.28 (1H, s); 7.13-7.06 (2H, m); 6.75-6.45 (1H, m); 6.67 (1H, s); 3.90 (3H, s); 3.33 (3H, s), 2.36 (3H, s).

APCI-MS m/z: 381,1 [MH+].

Example 59

6,7-Dimethoxy-4-(2,3-dimethylaniline)-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 2,3-dimethylaniline (20 μl, 0.22 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 3.5 hours. After cooling, the reaction mixture was diluted with water (15 ml) and podslushivaet using 1 M NaOH. The precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (48 mg, 79%).

1H NMR (DMSO-d6): δ 10.87 (1H, s); 8.87 (1H, s); 8.26 (1H, bs); 7.58 (1H, bs); 7.24 (1H, s); 7.02-6.96 (1H, m); 6.98 (1H, s); 6.68 (1H, s); 6.66-6.60 (1H, m); 3.88 (3H, s); 3.25 (3H, s); 2.31 (3H, s), 2.23 (3H, s).

Example 60

6,7-Dimethoxy-4-(5,6,7,8-tetrahydro-1-naphthaleneamine)-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,090 g, 0.34 mmol), 5,6,7,8-tetrahydronaphthalene (0,062 g, 0.42 mmol) and acetic acid (80 μl) in DMF (1.6 ml) was heated at 100°C for 3.5 hours. After cooling, the reaction mixture was diluted with water (20 is l) and podslushivaet using 1 M NaOH. The precipitate was filtered, washed with water and dried to obtain specified in the title compound (62 mg, 48%).

1H NMR (DMSO-d6): δ 10.66 (1H, s); 8.86 (1H, s); 8.26 (1H, bs); 7.59 (1H, bs); 7.25 (1H, s); 6.98 (1H, t, J 7.7 Hz); 6.86 (1H, d, J 7.4 Hz); 6.70 (1H, s); 6.53 (1H, d, J 7,6 Hz); 3.89 (3H, s); 3.29 (3H, s); 2.76 (1H, bt, J 6 Hz); 2.70 (1H, bt, J 6 Hz); 1.86-1.77 (1H, m), 1.77-1.69 (1H, m).

APCI-MS m/z: 378,1 [MH+].

Example 61

4-(4-Carboxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 3-amino-2-methylbenzoic acid (0.035 g, 0.23 mmol) and acetic acid (40 μl) in DMSO (0.8 ml) was stirred at 100°C for 5 hours. After cooling, the reaction mixture was washed several times with diethyl ether. The oil residue was dissolved in water and podslushivaet using 1 M NaOH, and then slightly acidified with acetic acid. The mixture was left at 5°C overnight and the resulting precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (35 mg, 50%).

1H NMR (DMSO-d6): δ 12.9 (1H, b); 10.74 (1H, s); 8.89 (1H, s); 8.28 (1H, bs); 7.63 (1H, bs); 7.45 (1H, d, J7.6 Hz); 7.28 (1H, s); 7.13 (1H, t, J7.8 Hz); 6.84 (1H, t, J 7.9 Hz); 3.90 (3H, s); 3.07 (3H, s), 2.50 (3H, s).

APCI-MS m/z: 382,1 [MH+].

Example 62

4-(1H-Indol-4-ylamino)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,90 g, 0.34 mmol), 4-aminoindole (0,039 g, 0.23 mmol), the acetate is sodium (0,020 g, 0.23 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 4.5 hours. After cooling, the reaction mixture was diluted with water (20 ml) and podslushivaet using 1 M NaOH. The precipitate was separated by centrifugation, resuspendable in water and centrifuged. This procedure was repeated twice, the solid was dried to obtain specified in the title compound (27 mg, 43%).

1H NMR (DMSO-d6): δ 11.20 (1H, s); 11.10 (1H, s); 8.91 (1H, s); 8.27 (1H, bs); 7.60 (1H, bs); 7.27 (1H, m); 7.24 (1H, s); 7.17 (1H, d, J 8.1 Hz); 6.99 (1H, t, J 7.8 Hz); 6.87 (1H, s); 6.50 (1H, d, J 7.5 Hz); 6.21 (1H, m,); 3.88 (3H, s), 3.08 (3H, s).

APCI-MS m/z: 363,1 [MH+].

Example 63

4-(3-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 3-chloro-2-methylaniline (25 μl, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 4.5 hours. After cooling, the reaction mixture was diluted with water (15 ml) and podslushivaet using 1 M NaOH. The precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (51 mg, 79%).

1H NMR (DMSO-d6): δ 10.65 (1H, s); 8.89 (1H, s); 8.29 (1H, bs); 7.65 (1H, bs); 7.30 (1H,8);7.17(1H, d, J 7.8 Hz); 7.01 (1H, t, J 8.0 Hz); 6.71 (1H, s); 6.63 (1H, d, J 7.9 Hz); 3.91 (3H, s); 3.38 (3H, s), 2.40 (3H, s,).

Example 64

4-[2-(Aminocarbonyl)aniline]-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational(0,046 g, 0,17 mmol), 2-aminobenzamide (0,029 g, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 6 hours. After cooling, the reaction mixture was evaporated. The residue was dissolved in a mixture of MeCN and water (1:3)containing 0.1% triperoxonane acid, and the cloudy solution was filtered through a bed of glass. After preparative HPLC using a gradient containing 0.1% triperoxonane acid) 10→40% MeCN in water as eluent was obtained after evaporation specified in the title compound in the form of salts triperoxonane acid. The product is suspended in a saturated aqueous NaHCO3and to absorb for a short SPE column [ISOLUTE™ C18 (EC)], pre-conditioned sequentially with methanol and then with water. The column is extensively washed with water up until the pH of the eluent was not neutral. The product was then suirable methanol. After evaporation the residue was recrystallized from ethanol to obtain specified in the title compound (26 mg, 41%).

1H NMR (DMSO-d6): δ 10.87 (1H, s); 8.79 (1H, s); 8.07 (1H, bd, J 7.5 Hz); 7.66 (1H, dd, J of 7.7 and 1.2 Hz); 7.47 (1H, bd, J 5.6 Hz); 7.34 (1H, s); 7.20 (1H, dt, J of 7.7 and 1.2 Hz); 6.95 (1H, s); 6.92 (1H, d, J 7.4 Hz); 6.52 (1H, d, J 8.1 Hz); 3.93 (3H, s), 3.50 (3H, s).

APCI-MS m/z: 367,0 [MN+]

Example 65

4-(3-Hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 3-the Ino-2-METHYLPHENOL (0,032 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 1.5 hours. After cooling, the mixture was diluted with water (15 ml) and podslushivaet saturated NaHCO3. Specified in the title compound, which slowly precipitated, was filtered and dried to obtain 34 mg (55%).

1H NMR (DMSO-d6): δ 10.77 (1H, s); 9.49 (1H, s); 8.86 (1H, s); 8.25 (1H, bs); 7.58 (1H, bs); 7.24 (1H, s); 6.88 (1H, t, J 8.0 Hz); 6.76 (1H, s); 6.61 (1H, d, J 8.0 Hz); 6.23 (1H, d, J 7.9 Hz); 3.89 (3H, s); 3.30 (3H, s,) and 2.11 (3H, s).

APCI-MS m/z: 354,1 [MN+]

Example 66

6,7-Dimethoxy-4-(3-methoxy-2-methylaniline)-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 3-methoxy-2-methylaniline (0.036 g, 0.26 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 2.5 hours. After cooling, the mixture was diluted with water (15 ml) and podslushivaet saturated NaHCO3. The resulting gummy precipitate was collected and was led from methanol-water to obtain specified in the title compound (45 mg, 70%).

1H NMR (DMSO-d6): δ 10.76 (1H, s); 8.87 (1H, s); 8.26 (1H, bs); 7.60 (1H, bs); 7.25 (1H, s); 7.05 (1H, t, J 8.2 Hz); 6.77 (1H, d, J 8.2 Hz); 6.72 (1H, s); 6.36 (1H,d,J 8.0 Hz); 3.89 (3H, s); 3.81 (3H, s); 3.29 (3H, s,) and 2.16 (3H, s).

APCI-MS m/z: 368,1 [MN+]

Example 67

6,7-Dimethoxy-4-[(1-methyl-1H-indol-4-yl)amino]-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,028 g, 0.10 mmol), 4-amino-1-methylindole Hydra is chloride (0,026 g, 0.14 mmol) and sodium acetate (0,013 g, 0.16 mmol)in DMF (0.6 ml) was heated at 100°C for 8 hours. After cooling, the mixture was diluted with water and podslushivaet saturated NaHCO3. The sticky precipitate was collected and was led from methanol-water to obtain specified in the title compound (24 mg, 60%).

1H NMR (DMSO-d6): δ 11.07 (1H, s); 8.91 (1H, s); 8.28 (1H, bs); 7.61 (1H, bs); 7.27 (1H, d, J 3.2 Hz); 7.26 (1H, s); 7.20 (1H, d, J 8.2 Hz); 7.05 (1H, t, J 7.9 Hz); 6.50 (1H, d, J 7.4 Hz); 6.23 (1H, d, J 3.1 Hz); 3.98 (3H, s); 3.79 (3H, s), 3.12 (3H, s).

APCl-MS m/z: 377,1 [MH+]

Example 68

6,7-Dimethoxy-4-[(1-oxo-2,3-dihydro-1H-inden-4-yl)amino]-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 4-amino-1-indanone (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.6 ml) was heated at 100°C for 1 hour and 45 minutes. After cooling, the mixture was diluted with water and podslushivaet saturated NaHCO3. The precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (59 mg, 90%).

1H NMR (DMSO-d6): δ 10.60 (1H, s); 8.92 (1H, s); 8.30 (1H, bs); 7.67 (1H, bs); 7.36 (1H, s); 7.32-7.25 (2H, m); 6.89 (1H, dd, J 6.6 and 2.0 Hz); 6.87 (1H, s); 3.94 (3H, s); 3.42 (3H, s); 3.06-2.95 (2H, m), 2.74-2.67 (2H, m,).

APCl-MS m/z: 378,1 [MH+]

Example 69

4-(1-Hydroxy-2,3-dihydro-1H-inden-4-yl)amino-6,7-dimethoxy-3-chinainternational

6,7-Dimethoxy-4-[(1-oxo-2,3-dihydro-1H-inden-4-yl)amino]-3-chinainternational (0,062 g, 16.4 mmol) was dissolved in the art of methanol (7 ml), tetrahydrofuran (4 ml) and water (3 ml). Sodium borohydride was added in portions (3×5 mg) for 5 minutes. After 20 minutes the reaction mixture was acidified with acetic acid and then podslushivaet saturated aqueous sodium bicarbonate and evaporated. The residue was separated between water and ethyl acetate. The organic phase is twice washed with water and evaporated. The residue was dissolved in methanol and added water. Specified in the title compound, which slowly precipitated, was filtered and dried to obtain 40 mg (64%).

1H NMR (DMSO-d6): δ 10.68 (1H, s); 8.82 (1H, s); 8.20 (1H, bs); 7.55 (1H, bs); 7.22 (1H, s); 7.07 (1H, t, J 7.5 Hz); 7.04 (1H, t, J 7.4 Hz); 6.75 (1H, s); 6.63 (1H, d, J 7.5 Hz); 5.20 (1H, d, J 5.7 Hz); 5.01 (1H, q, J 6,2 Hz); 3.85 (3H, s); 3.26 (s, overlapping signal from moisture); 2.72-2.63 (1H, m); 2.50-2.36 (m, overlapping the signal of solvent); 2.30-2.20 (1H, m), 1.76-1.65 (1H, m).

Example 70

4-(4-Carboxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0,17 mmol), 4-amino-2-methylbenzoic acid (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100°C for 12 hours. After cooling, the mixture was diluted with water (15 ml) and podslushivaet saturated NaHCO3and then slightly acidified with acetic acid. The precipitate was filtered and suspended in warm methanol. After cooling, the precipitate was filtered and dried to obtain the criminal code is related to the title compound (31 mg, 47%).

1H NMR (DMSO-d6): δ 12.59 (1H, bs); 10.52 (1H, s); 8.93 (1H, s); 8.34 (1H, bs); 7.58 (1H, d, J 1.4 Hz); 7.73 (1H, s); 7.60 (1H, dd, J 8.4 and 1.9 Hz); 7.36 (1H, s); 6.75 (1H, s); 6.53 (1H, d, J 8,4 Hz); 3.94 (3H, s); 3.42 (3H, s), 2.41 (3H, s).

APCI-MS m/z: 382,1 [MH+]

Example 71

6,7-Dimethoxy-4-(4-methoxycarbonyl-2-methylaniline)-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,046 g, 0.35 mmol), methyl-4-amino-2-methylbenzoic acid (0,076 g, 0.46 mmol) and acetic acid (100 μl) in DMF (0.8 ml) was heated at 100°C for 9 hours. After cooling, the mixture was combined with two similar reaction mixtures (since 92 and 46 mg of 4-chloro-6,7-dimethoxy-3-chinainternational respectively) and diluted with water. The mixture was podslushivaet saturated NaHCO3, sticky precipitate was collected, washed with water and recrystallized from methanol to obtain specified in the title compound (130 mg, 47%).

1H NMR (DMSO-d6): δ 10.49 (1H, s); 8.94 (1H, s); 8.35 (1H, bs); 7.88 (1H, d, J 1.4 Hz); 7.62 (1H, dd, J of 8.2 and 2.0 Hz); 7.37 (1H, s); 6.53 (1H, d, J=8,4 Hz); 3.94 (3H, s); 3.80 (3H, s); 3.43 (3H, s), 2.43 (3H, s).

APCI-MS m/z: 395,9 [MH+]

Example 72

4-(4-Hydroxymethyl-2-methylaniline)-6,7-dimethoxy-3-chinainternational

6,7-Dimethoxy-4-(4-methoxycarbonyl-2-methylaniline)-3-chinainternational (0,080 g, 0.20 mmol) was dissolved in tetrahydrofuran (25 ml), dried 4 a molecular sieves). Was added lithium borohydride (0.15 mg, 6.8 mmol). The mixture was stirred for 24 hours is added an additional amount of lithium borohydride (0,050 g, 2.2 mmol). The reaction mixture was stirred for 25 hours and then was poured into a cold mixture of water (20 ml) and acetic acid (0.5 ml). Was added acetic acid (2 ml) and the mixture is evaporated under reduced pressure. The residue is suspended in water, filtered, and the precipitate washed with water and recrystallized from aqueous methanol to obtain specified in the title compound (32 mg, 43%).

1H NMR (DMSO-d6): δ 11.54 (1H, s); 8.94 (1H, s); 8.46 (1H, bs); 7.86 (1H, s); 7.69 (1H, bs); 7.31 (1H, d, J 1.3 Hz); 7.16 (1H, dd, J 8.1 and 1.4 Hz); 7.04 (1H, d, J 8.0 Hz); 6.89 (1H, s); 5.20 (1H, t, J 5.6 Hz); 4.47 (2H, d, J 5.7 Hz); 3.91 (3H, s); 3.27 (3H, s), 2.23 (3H, s).

APCI-MS m/z: 368,1 [MH+]

Example 73

6,7-Dimethoxy-4-(2-propylaniline)-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (0,062 g, 0.23 mmol), 2-propylaniline (of 0.038 g, 0.28 mmol), 2-butanol (2 ml), DMF (2 ml) and acetic acid (8,2 ml) was heated overnight at 100°C. After cooling, the solution volume was reduced by evaporation. The residue was dissolved in water (3 ml) and was treated with aqueous ammonia. The solid product was filtered, washed with water, dried in air for 0.5 hours, again washed with heptane and dried in a vacuum dryer at 50°With a yellow-brown solid, 35 mg (41%) specified in the connection header.

APCI-LC/MS m/z: 366,1 [MN+].

1H NMR (DMSO-d6): δ 10.95 (1H, s); 8.88 (1H, s); 8.28 (1H, br s); 7.62 (1H, br s); 7.29 (M, m); 7.24 (1H, s); 7.05 (2H, m); 6.68 (1H, m); 6.63 (1H, s); 3.88 (3H, s); 3.21 (3H, s); 2.67 (2H, t); 1.65 (2H, m); 0.93 (3H, t).

The connections defined in the headers of examples 74-86, obtained by the method similar to that described in Example 73.

Example 74

4-(2-Isopropylaniline)-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 11.07 (1H, s); 8.87 (1H, s); 8.28 (1H, br s); 7.58 (1H, br s); 7.40 (1H, d); 7.23 (1H, s); 7.13 (1H, t); 7.07 (1H, t); 6.68 (1H, d); 6.59 (1H, s); 3.88 (3H, s); 3.35 (1H, m); 3.18 (3H, s); 1.27 (6H, d).

APCI-MS m/z: 366,1 [MN+]

Example 75

4-[2-(sec-Butyl)aniline]-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 11.08 (1H, s); 8.87 (1H, s); 8.28 (1H, br s); 7.59 (1H, br s); 7.34 (1H, d); 7.22 (1H, s); 7.13 (1H, t); 7.07 (1H, t); 6.68 (1H, d); 6.61 (1H, s); 3.86 (3H, s); 3.17 (3H, s); 3.13 (1H, m); 1.65 (2H, m); 1.21 (3H, d); 0.80 (3H, t).

APCI-MS m/z: 380.2 [MN+].

Example 76

6,7-Dimethoxy-4-[3-(methoxymethyl)-2-methylaniline]-3-chinainternational

1H NMR (DMSO-d6): δ at 10.82 (1H, s); 8.86 (1H, s); 8.25 (1H, br s); 7.58 (1H, br s); 7.22 (1H, s); 7.08 (2H, m); 6.71 (1H, d); 6.64 (1H, s); 4.45 (2H, s); 3.86 (3H, s); 3.22 (3H, s); 2.25 (3H, s).

APCI-MS m/z: 382,1 [MN+]

Example 77

4-[3-(ISO-Butoxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 10.83 (1H, s); 8.83 (1H, s); 8.23 (1H, br s); 7.58 (1H, br s); 7.22 (1H, s); 7.08 (2H, m); 6.72 (1H, d); 6.62 (1H, s); 4.48 (2H, s); 3.86 (3H, s); 3.22 (3H, s); 3.19 (2H, d); 2.25 (3H, s); 1.80 (1H, m); 0.84 (6H, d).

APCI-MS m/z: 424,1 [MN+]

Example 78

4-[3-(Cyanomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6): δ 10.76 (1 is, s); 8.86 (1H, s); 8.25 (1H, br s); 7.60 (1H, br s); 7.24 (1H, s); 7.12 (2H, m); 6.71 (1H, d); 6.61 (1H, s); 4.07 (2H, s); 3.87 (3H, s); 3.22 (3H, s); 2.30 (3H, s).

APCl-LC/MS m/z: 377,1 [MN+].

Example 79

4-{3-[(Ethylamino)methyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational

Specified in the title compound was obtained starting from tert-butyl 3-amino-2-methylbenzyl(ethyl)carbamate, after you remove the protection using TFA has been specified in the header of the connection.

1H NMR (CDCl3): δ 10.68 (1H, s); 8.75 (1H, s); 7.23 (1H, s); 7.13 (1H, d); 7.05 (1H, t); 6.83 (1H, d); 6.72 (1H, s); 6.25 (2H, br s); 3.95 (3H, s); 3.82 (2H, s); 3.31 (3H, s); 2.73 (2H, q); 2.35 (3H, s); 0.64 (3H, t).

APCI-MS m/z: 395,1 [MN+]

Example 80

4-{3-[2-(Ethylamino)-2-oxoethyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6) δ 10.86 (1H, s); 8.85 (1H, s); 8.23 (1H, br s); 7.94 (1H, m); 7.56 (1H, br s); 7.21 (1H, s): 7.01 (1H, d); 6.66 (1H, m); 6.62 (1H, s); 3.86 (3H, s); 3.49 (2H, s); 3.21 (3H, s); 3.05 (2H, m); 2.25 (3H, s); 1.00 (3H, t).

APCI-MS m/z: 423,3 [MN+]

Example 81

Ethyl-2-(3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-were)acetate

1H NMR (DMSO-d6) δ 10.87 (1H, s); 8.86 (1H, s); 8.26 (1H, br s); 7.56 (1H, br s); 7.22 (1H, s); 7.04 (2H, m): 6.72 (1H, m); 6.16 (1H, s); 4.06 (2H, q); 3.86 (3H, s); 3.76 (2H, s); 3.23 (3H, s); 2.20 (3H, s); 1.15 (3H, t).

APCI-MS m/z: 424,1 [MN+]

Example 82

4-[3-(2-Amino-2-oxoethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6) δ 10.83 (1H, s); 8.83 (1H, s); 8.24 (1H, br s); 7.56 (1H, br s); 7.38 (1H, br s); 7.21 (1H, s): 7.08 (2H, m); 6.89 (1H, br s); 6.66 (1H, m); 6.62 (1H, s); 3.86 (3H, s); 3.50 (2H, s); 3.22 (3H, s); 2.26 (3H, s).

APCI-MS m/z: 395,1 [MH+]

Example 83

4-[3-(2-Hydroxyethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6) δ at 10.82 (1H, s); 8.82 (1H, s); 8.24 (1H, br s); 7.56 (1H, br s); 7.22 (1H, s); 7.01 (2H, m); 6.62 (2H, m); 4.66 (1H, t); 3.86 (3H, s); 3.55 (2H, q); 3.21 (3H, s); 2.82 (2H, t); 2.26 (3H, s); 2.27 (3H, s).

APCI-MS m/z: 382,1 [MH+]

Example 84

4-(3-{2-[(2-Hydroxyethyl)amino]-2-oxoethyl}-2-methylaniline)-6,7-dimethoxy-3-chinainternational

1H NMR (DMSO-d6) δ 10.83 (1H, s); 8.82 (1H, s); 8.25 (1H, br s); 7.95 (1H, m); 7.58 (1H, br s); 7.21 (1H, s); 7.03 (2H, m): 6.68 (1H, m); 6.62 (1H, s); 4.65 (1H, t); 3.86 (3H, s); 3.54 (2H, s); 3.39 (2H, m); 3.23 (3H, s); 3.12 (2H, m); 2.26 (3H, s).

APCI-MS m/z: 439,1 [MH+]

Example 85

tert-Butyl 3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-methylbenzylamine

1H NMR (DMSO-d6) δ 10.83 (1H, s); 8.84 (1H, s); 8.22 (1H, br s); 7.55 (1H, br s); 7.32 (1H, m); 7.22 (1H, s); 7.08 (2H, m); 6.66 (1H, d); 6.60 (1H, s); 4.15 (2H, d); 3.85 (3H, s); 3.21 (3H, s); 2.25 (3H, s); 1.39 (9H, s).

APCI-MS m/z: 467,2 [MH+]

Example 86

4-[3-(Aminomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational

tert-Butyl 3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-methylbenzylamine (0,12 mg, 0.25 mmol) was dissolved in CH2Cl2(5 ml), cooled on ice and added TFA (3 ml). After 2 hours stirring at room temperature the mixture was evaporated to obtain an oil, which was dissolved in a mixture of CH2Cl2/water solution of Na2CO3. The aqueous phase was extracted with CH2Cl2(×6). Extracts about ivali brine, dried (Na2SO4) and was evaporated. The residue was purified by chromatography (CH2Cl2/MeOH/NH3) obtaining specified in the connection header, 54 mg (59%), in the form of a white powder.

1H NMR (CDCl3) δ 10.83 (1H, s); 8.82 (1H, s); 8.11 (1H, br s); 7.55 (1H, br s); 7.22 (1H, s); 7.16 (1H, d); 7.05 (1H, m); 6.65 (2H, m); 3.86 (3H, s); 3.75 (2H, s); 3.22 (3H, s); 2.27 (3H, s).

APCI-MS m/z: 353,1 [MH+]

Intermediate compounds used as starting materials in examples 87-179

Ethyl-7-methoxy-4-chloro-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

7-Methoxy-4-chloro-3-chinainternational

1H NMR (DMSO-d6) δ 8.80 (1H, s); 8.19 (1H, s); 8.15 (1H, br s); 7.90 (1H, br s); 7.50 (1H, d); 7.46 (1H, dd); 3.96 (3H, s).

Ethyl-4-chloro-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

4-Chloro-3-chinainternational

1H NMR (DMSO-d6) δ 8.8 (1H, s); 8.30 (1H, d); 8.19 (1H, br s); 8.13 (1H, d); 7.96 (1H, br s); 7.93 (1H, t); 7.83 (1H, t).

Ethyl-6,7-sodium dichloro-4-chloro-3-chinainternational

Specified in the title compound was obtained essentially as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

6,7-sodium dichloro-4-chloro-3-chinainternational

1H NMR (DMSO-d6) δ 8.94 (1H, s); 8.47 (2H, d); 8.27 (1H, br s); 8.06 (1H, br s).

Ethyl-6-methoxy-4-chloro-3-chinainternational

Specified in the title compound which was alocale essentially so, as described by Burke et al. J. Med. Chem, 36 (1993) 425-432.

6-Methoxy-4-chloro-Z-chinainternational

1H NMR (DMSO-d6) δ 8.70 (1H, s); 8.17 (1H, br s); 8.04 (1H, d); 7.92 (1H, br s); 7.56 (1H, dd); 7.52 (1H, d); 3.97 (3H, s).

Example 87

4-(4-Fluorescent-2-methylaniline)-6-methoxy-3-chinainternational

A mixture of 4-fluorescent-2-methylaniline (of 0.025 mmol), 6-methoxy-4-chloro-Z-chinainternational (of 0.025 mmol), 50 μl of a mixture of 20% acetic acid/ethanol and 250 μl of ethanol was boiled under reflux for four hours. After cooling to room temperature the solvent was removed in vacuum.

APCI-MS m/z: 326 [MN+]

The connections defined in the headers of examples 88-179, was obtained in a manner analogous to the one described in Example 87.

Example 88

4-(4-Bromo-2-methylaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 388 [MN+]

Example 89

4-(4-Chloro-2-methylaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 342 [MN+]

Example 90

4-(2,4-Dimethylaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 322 [MN+]

Example 91

6-Methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational

APCI-MS m/z: 338 [MN+]

Example 92

4-(4-Hydroxy-2-methylaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 324 [MN+]

Example 93

4-(2-Bromoaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 374 [MN+]

Example 94

4-(2,4-Dimethoxyaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 354 [MN+]

Example 95

6-Methoxy-4-(2-meth is xianlin)-3-chinainternational

APCI-MS m/z: 324 [MN+]

Example 96

4-(2-Ethoxyaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 338 [MN+]

Example 97

4-(2-Ethylaniline)-6-methoxy-3-chinainternational

APCI-MS m/z: 322 [MN+]

Example 98

6-Methoxy-4-(2-toluidino)-3-chinainternational

APCI-MS m/z: 308 [MN+]

Example 99

6-Methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 340 [MN+]

Example 100

4-(4-Bromo-2-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 417 [MH+]

Example 101

4-(4-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 372 [MN+]

Example 102

4-(2,4-Dimethylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 352 [MN+]

Example 103

6,7-Dimethoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational

APCI-MS m/z: 368 [MN+]

Example 104

4-(2-Bromo-4-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z:417[MH+]

Example 105

4-(2-Bromo-4-foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 421 [MN+]

Example 106

4-(2,4-Dimethoxyaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 384 [MN+]

Example 107

4-(4-Fluorescent-2-methylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 326 [MN+]

Example 108

4-(4-Bromo-2-methylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 388 [MN+]

Example 109

4-(4-Chloro-2-methylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 342 [MN+]

Example 110

4-(2,4-Dimethyl is iLine)-7-methoxy-3-chinainternational

APCI-MS m/z: 322 [MN+]

Example 111

7-Methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational

APCI-MS m/z: 338 [MN+]

Example 112

4-(4-Hydroxy-2-methylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 324 [MN+]

Example 113

4-(2-Bromoaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 374 [MN+]

Example 114

4-(2-Bromo-4-methylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 388 [MN+]

Example 115

4-(2-Bromo-4-foranyone)-7-methoxy-3-chinainternational

APCI-MS m/z: 390 [MH+]

Example 116

4-(2,4-Dimethoxyaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 354 [MN+]

Example 117

6,7-sodium dichloro-4-(4-methoxy-2-methylaniline)-3-chinainternational

APCI-MS m/z: 376 [MH+]

Example 118

6,7-sodium dichloro-4-(2,4-dimethoxyaniline)-3-chinainternational

APCI-MS m/z: 392 [MN+]

Example 119

4-(2-Ethylaniline)-3-chinainternational

APCI-MS m/z: 292 [MN+]

Example 120

4-(2-Toluidino)-3-chinainternational

APCI-MS m/z: 278 [MN+]

Example 121

4-[2-(Methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 310 [MN+]

Example 122

4-(2-Ethoxyaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 368 [MN+]

Example 123

4-[2-(Hydroxymethyl)aniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 354 [MN+]

Example 124

4-(2-Ethylaniline)-6,7-dimethoxy-3-chinainternational

APCI-LC/MS m/z: 352 [MN+]

Example 125

6,7-Dimethoxy-4-(2-toluidino)-3-chinainternational

<> APCI-MS m/z: 338 [MN+]

Example 126

6,7-Dimethoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 370 [MN+]

Example 127

4-(2,4-Dibromoanisole)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 481 [MN+]

Example 128

7-Methoxy-4-(2-methoxyaniline)-3-chinainternational

APCI-MS m/z: 324 [MN+]

Example 129

4-(2-Ethoxyaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 338 [MN+]

Example 130

4-[2-(aminocarbonyl)aniline]-7-methoxy-3-chinainternational

APCI-MS m/z: 337 [MN+]

Example 131

4-(2-Ethylaniline)-7-methoxy-3-chinainternational

APCI-MS m/z: 322 [MN+]

Example 132

7-Methoxy-4-(2-toluidino)-3-chinainternational

APCI-MS m/z: 308 [MN+]

Example 133

7-Methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 340 [MN+]

Example 134

6,7-sodium dichloro-4-(2-methoxyaniline)-3-chinainternational

APCI-MS m/z: 361 [MN+]

Example 135

6,7-sodium dichloro-4-(2-ethylaniline)-3-chinainternational

APCI-MS m/z: 360 [MN+]

Example 136

6,7-sodium dichloro-4-[2-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 378 [MN+]

Example 137

4-(2,5-Dimethylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 352 [MN+]

Example 138

4-(5-Fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 356 [MN+]

Example 139

4-(5-Chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 372 [MN+]

Example 140

4-(3-Fluorescent-2-methylaniline)-6,7-is metoxy-3-chinainternational

APCI-MS m/z: 356 [MN+]

Example 141

4-(4-Hydroxy-2,5-dimethylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 368 [MN+]

Example 142

4-(2-Hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 354 [MN+]

Example 143

4-Aniline-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 324 [MN+]

Example 144

4-(4-Chloro-2-foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 375 [MN+]

Example 145

4-(2-Foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 341 [MN+]

Example 146

4-(2,6-Diptiranjan)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 359 [MH+]

Example 147

4-(3-Bromoaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 401, 403 [MH+]

Example 148

4-(3-Foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 341 [MN+].

Example 149

6,7-Dimethoxy-4-(4-methoxyaniline)-3-chinainternational

APCI-MS m/z: 337 [MN+].

Example 150

4-(3-Chloroanilino)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 357 [MN+].

Example 151

4-(2-Chloroanilino)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 357 [MN+].

Example 152

4-[3-(Acetylamino)aniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 380 [MH+].

Example 153

4-(2,5-Diptiranjan)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 359 [MH+].

Example 154

4-(1H-Indol-5-ylamino)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 363 [MH+].

Example 155

4-(1H-Indazol-ylamino)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z 364 [MH+].

Example 156

4-(1H-Indazol-6-ylamino)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 364 [MH+].

Example 157

4-(2,4-Diptiranjan)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 359 [MH+].

Example 158

4-(2-Fluorescent-4-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 356 [MN+].

Example 159

4-(2,4-Dichloroaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 391, 393 [MH+].

Example 160

4-(2,5-Dichloroaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 391, 393 [MH+].

Example 161

4-[2-(2-Hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 368 [MN+].

Example 162

4-(3-Chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 375 [MN+].

Example 163

6,7-Dimethoxy-4-[3-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 370 [MN+].

Example 164

6,7-Dimethoxy-4-(2-methoxy-5-methylaniline)-3-chinainternational

APCI-MS m/z: 368 [MN+].

Example 165

4-[4-(Dimethylamino)aniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 367 [MN+].

Example 166

6,7-Dimethoxy-4-[4-(methylsulfonyl)aniline]-3-chinainternational

APCI-MS m/z: 370 [MN+].

Example 167

4-[4-(2-Hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 368 [MN+].

Example 168

4-(3-Hydroxy-4-methoxyaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 370 [MN+].

Example 169

4-(2,3-Dichloroaniline)-6,7-dimethoxy-chinainternational

APCI-MS m/z: 391 [MH+].

Example 170

6,7-Dimethoxy-4-(2,3,4-triptoreline)-3-chinainternational

APCI-MS m/z: 378 [MN+].

Example 171

6,7-Dimethoxy-4-(3-toluidino)-3-chinainternational

APCI-MS m/z: 338 [MN+].

Example 172

4-(2-Hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 354 [MN+].

Example 173

4-(2-Fluorescent-4-hydroxyanisole)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 358 [MN+].

Example 174

4-[2-(Hydroxymethyl)-4-methylaniline]-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 368 [MN+].

Example 175

4-(2-chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 375 [MN+].

Example 176

4-(2-fluorescent-5-methylaniline)-6,7-dimethoxy-3-chinainternational

APCI-MS m/z: 356 [MN+].

Example 177

4-[(2-Cyanophenyl)amino]-6,7-dimethoxyquinazolin-3-carboxamide

APCI-MS m/z: 349 [MN+].

Example 178

4-[(2,5-Defloriani)amino]-6,7-dimethoxyquinazolin-3-carboxamide

APCI-MS m/z 360[MH+]

Example 179

4-(1H-indol-5-ylamino)-6,7-dimethoxyindole-3-carboxamide

APCI-MS m/z: 363[MH+]

Example 180

6,7-sodium dichloro-4-(2-methylaniline)-3-chinainternational

A mixture of ethyl-6,7-sodium dichloro-4-(2-methylaniline)-3-chinainternational (0,050 g, mmol) and NH4Cl was heated in a pressure vessel with methanol, saturated NH3within five days. The mixture was evaporated and the residue recrystallized from EtOH.

1H NMR (DMSO-d6): δ 10.9 (1H, s); 9.0 (1H, s); 83 (1H, br s); 8.1 (1H, s); 7.7 (1H, br s); 7.6 (1H, s); 7.6 (1H, dd); 7.2 (2H, m); 6.6 (1H, dd); 2.27 (3H, s).

Example 181

4-(2,3-Dihydro-1H-inden-1-ylamino)-6,7-dimethoxy-3-chinainternational

A mixture of 4-chloro-6,7-dimethoxy-3-chinainternational (of 0.066 g, 0.25 mmol), 1-aminoindane (0,66 mg, 0.50 mmol), 2-butanol (2 ml), DMF (2 ml) was heated for 48 hours at 100°C. After cooling, the solution volume was reduced by evaporation. The residue was dissolved in water (3 ml) and was treated with aqueous ammonia. The solid product was filtered, washed with water, dried in air for 0.5 hours, again washed with heptane and dried.

The residue was purified by chromatography on silica (CH2Cl2/MeOH) to give 63 mg (70%) indicated in the title compound as a white solid.

1H NMR (DMSO-d6): δ 8.74 (1H, d); 8.63 (1H, s); 8.05 (1H, br s); 7.55 (1H, s); 7.35 (1H, br s); 7.30-7.14 (5H, m); 5.46 (1H, q); 3.89 (3H, s); 3.83 (3H, s); 2.99-2.91 (1H, m); 2.88-2.76 (1H, m); 2.62-2.52 (1H, m); 1.02-0.91 (1H, m).

APCI-MS m/z: 364,1 [MN+]

The connections defined in the headers of examples 182-183, obtained by the method similar to that described in Example 181.

Example 182

6,7-Dimethoxy-4-{[2-(trifloromethyl)benzyl]amino}-3-chinainternational

1H NMR (DMSO-d6): δ 8.91 (1H, t); 8.59 (1H, s); 7.98 (1H, br s); 7.75 (2H, m); 7.68 (1H,t); 7.51 (1H, t); 7.34 (1H,br s); 7.25 (1H,s); 7.21 (1H, s); 4.91 (2H, d); 3.88 (3H, s); 3.51 (3H, s).

APCI-MS m/z: 406,1 [MH+]

Example 183

6,7-Dimethoxy-4-[(1-phenylethyl)amino]-3-chinainternational

1H NMR DMSO-d 6): δ 9.40 (1H, d); 8.66 (1H, s); 8.06 (1H, br s); 7.43-7.35 (2H, m); 7.30 (2H, t); 7.18-7.22 (2H, m); 7.14 (1H, s); 5.18 (1H, m); 3.83 (3H, s); 3.45 (3H, s); 1.52 (3H, d).

APCI-MS m/z: 352,1 [MH+]

Example 184

4-(3-Hydroxymethyl-2-methylaniline)-3-chinainternational

a) Diethyl-2-[1,3-benzodioxol-5-ylamino)methylene]malonate

Diethyl-2-(ethoxymethylene)malonate (4,1 ml, 20.3 mmol), 3,4-methylenedioxyaniline (2,77 g, a 20.2 mmol) was stirred in nitrogen atmosphere at 120°C for 2.5 hours. The reaction mixture was cooled and was added ethanol. The precipitate was collected by filtration and recrystallized from ethanol to obtain specified in the connection header (3,52 g, 56%)

1H NMR (DMSO-d6): δ 10.67 (1H, d, J a 13.9 Hz); 8.28 (1H, d, J a 13.9 Hz); 7.12 (1H, d, J 2.2 Hz); 6.91 (1H, d, J 8,3 Hz); 6.81 (1H, dd, J 8.4 and 2.3 Hz); 6.04 (2H, s); 4.19 (2H, q, J 7,1 Hz); 4.10 (2H, q, J 7,1 Hz); 1.25 (3H, t, J 7,1 Hz); 1.23 (3H, t, J 7.2 Hz).

b) Ethyl-4-chloro-6,7-methylenedioxy-3-chinainternational

Diethyl-2-[1,3-benzodioxol-5-ylamino)methylene]malonate (3.25 g, 11.6 mmol) was dissolved in POCl3(60 ml) and heated under reflux for 4.5 hours, cooled and evaporated twice with toluene. The residue suspended in ice-cold saturated aqueous NaHCO3, the precipitate was collected by filtration, washed with water and dried to obtain specified in the connection header (3,01 g, 95%).

1H NMR (DMSO-d6): δ 8.92 (1H, s); 7.64 (1H, s); 7.49 (1H, s); 6.33 (2H, s); 4.40 (2H, q, J 7,1 Hz) and 1.36 (ZN, t, J 7,1 Hz).

APCI-MS m/z: 279,9 [MH+]

Ethyl-4-chloro-6,7-methylenedioxy-3-chinainternational (1.54 g, 5.5 mmol) suspended in ethanol (25 ml), THF (5 ml) and aqueous 2 M NaOH (25 ml) and stirred at ambient temperature for 2 hours. The reaction mixture was neutralized 1 M aqueous HCl and the organic solvents evaporated under reduced pressure. After acidification to pH 2-3 with 1 M HCl the precipitate was separated by centrifugation. Sediment resuspendable in water and centrifuged again. The procedure was repeated twice to obtain after drying specified in the title compound (1.25 g, 90%)

1H NMR (DMSO-d6): δ 13.71 (1H, bs); 8.93 (1H, s); 7.63 (1H, s); 7.47 (1H, s), 6.32 (2H, s).

g) 3-Chloro-6,7-methylenedioxy-3-chinainternational

4-Chloro-6,7-methylenedioxy-3-quinoline-carboxylic acid (0.68 g, 2.7 mmol) suspended in thionyl chloride (30 ml) and the mixture was heated to boiling under reflux for 1 hour and then evaporated with toluene. The residue suspended in ice-cold acetone (25 ml) and treated portions chilled on ice, saturated aqueous ammonia (28%, 2 ml) at 0°C. the Reaction mixture was stirred at 0°C for 2 minutes and then filtered. The solid is washed with water and dried to obtain specified in the title compound (501 mg, 74%).

1H NMR (DMSO-d6): δ 8.63 (1H, s); 8,10 (1H, bs); 7.84 (1H, s); 7.56 (1H, s); 7.46 (1H, s), 6.30 (2H, s).

The) 4-(3-Hydroxymethyl-2-methylaniline)-3-chinainternational

A mixture of 3-chloro-6,7-methylenedioxy-3-chinainternational (106 mg, 0.42 mmol); 3-amino-2-methylbenzylamino alcohol (72 mg, 0.52 mmol) and acetic acid (100 μl) in DMF (2 ml) was heated at 100°C for 6 hours. After cooling, the mixture was diluted with water (20 ml) and washed twice with ethyl acetate. The aqueous phase was podslushivaet using 1 M NaOH and the precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (113 mg, 75%).

1H NMR (DMSO-d6): δ 10.47 (1H, s); 8.86 (1H, s); 8.30 (1H, s); 7.64 (1H, s); 7.26 (1H, s); 7.13 (1H, d, J7,3 Hz); 7.00 (1H, t, J7,7 Hz); 6.66 (1H, s); 6.49 (1H, d, J 7.8 Hz); 6.11 (2H, s); 5.14 (1H, bs); 4.56 (2H,s) and 2.28 (3H, s).

APCI-MSm/z: 352,1 [MH+]

Example 185

9-(3-Hydroxymethyl-2-methylaniline)-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxamide

a) Ethyl-9-chloro-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxylate

Diethyl-2-(ethoxymethylene)malonate (4,1 ml, 20.3 mmol) and 2,3-dihydro-1,4-benzodioxin-6-amine (2,48 ml, at 20.2 mmol)) was stirred in nitrogen atmosphere at 120°C for 4 hours, the reaction mixture was then evaporated under reduced pressure. The crude diethyl-2-[2,3-dihydro-1,4-benzodioxin-6-ylamino)methylene]malonate was dissolved in POCl3and heated under reflux for 5 hours, the mixture is then evaporated with toluene. The residue was dissolved in methylene chloride and washed with saturated aqueous NaHCO3and water, dried (Na2SO4), Phi is trevali and evaporated. The residue was led from methanol-water to obtain 3.5 g of the crude product. After recrystallization from methanol-water and finally from methanol has been specified in the header connection (1,14 g, 19%).

1H NMR (DMSO-d6): δ 8.93 (1H, s); 7.65 (1H, s); 7.51 (1H, s); 4.49-4.42 (4H, m); 4.40 (2H, q, J 7,1 Hz); 1.36 (3H, t, J 7,1 Hz).

APCI-MS m/z: 293,9 [MH+]

b) 9-Chloro-2,3-dihydro[1,4]like[1,3g]quinoline-8-carboxylic acid

Ethyl-9-chloro-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxylate (1.1 g, 3.7 mmol) was dissolved in ethanol (20 ml) and THF (5 ml). Was added aqueous NaOH (2 M, 20 ml). After stirring at ambient temperature for 1 hour and 45 minutes the reaction mixture was acidified with 1 M HCl. Organic solvents were evaporated under reduced pressure and the crude product was separated by centrifugation. After decanting, the precipitate resuspendable in water, centrifuged again. This procedure was repeated twice and the residue was finally dried to obtain specified in the title compound (0.65 g, 65%).

1H NMR (DMSO-d6): δ 13.78 (1H, bs); 8.94 (1H, s); 7.66 (1H,s); 7.51 (1H, s), 4.45 (4H, s).

in) 9-Chloro-2,3-dihydro[1,4]like[1,3g]quinoline-8-carboxamide

9-Chloro-2,3-dihydro[1,4]like[1,3g]quinoline-8-carboxylic acid (0,61 g) in thionyl chloride (30 ml) was heated under reflux for 3 hours and the reaction mixture then was evaporated together with Tolu is scrap. The residue is suspended in chilled on ice acetone (25 ml) and was treated with chilled on ice, saturated aqueous ammonia (28%, 1.5 ml) in portions at 0°C. the Reaction mixture was stirred at 0°C for 2 minutes and then filtered. The solid is washed with water and dried to obtain slightly contaminated specified in the title compound (435 mg, 71%). From the aqueous filtrate additionally besieged specified in the title compound (91 mg), which was sufficiently pure to use without further purification.

1H NMR (DMSO-d6): δ 8.64 (1H, s); 8.10 (1H, bs); 7.85 (1H, bs); 7.58 (1H, s); 7.50 (1H, s), 4.40 (4H, s).

APCI-MS m/z: 265,0 [MH+]

g) 9-(3-Hydroxymethyl-2-methylaniline)-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxamide

A mixture of 9-chloro-2,3-dihydro[1,4]like[1,3g]quinoline-8-carboxamide (0,090 g, 0.34 mmol), 3-amino-2-methylbenzylamino alcohol (0,058 g, 0.45 mmol) and acetic acid (80 μl) in DMF (1.6 ml) was heated at 100°C for 3 hours. After cooling, the mixture was diluted with water and podslushivaet using 1 M NaOH. Was added methanol and the mixture was heated to partial dissolution sticky sludge. After cooling, the precipitate was collected by filtration, washed with water and dried to obtain specified in the title compound (98 mg, 75%).

1H NMR (DMSO-d6): δ 10.78 (1H, s); 8.85 (1H, s); 8.27 (1H, bs); 7.61 (1H, bs); 7.26 (1H, s); 7.17(1H,q, J 7.4 Hz); 7.03 (1H,t, J 7,6 Hz); 6.79 (1H, s), 6.59 (1H, d, J 7.9 Hz); 5.17 (1H, t, J 5.2 Hz); 4.57 (2H, d, J 5.2 Hz); 4.31 (2H, s); 4.21 (2H, s), 2.27 (3H, s).

APCI-MS m/z: 366,1 [MH+]

The connections defined in the headers of examples 186-195, obtained by the method similar to that described in Example 3.

Example 186

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[2-(propylamino)ATOC-C]quinoline-3-carboxamide

APCI-MS m/z: 423 [MH+]

Example 187

6-[2-(Ethylamino)ethoxy]-4-[(2-ethylphenyl)amino]-methoxyquinoline-3-carboxamide

APCI-MS m/z: 409 [MH+]

Example 188

6-[2-(Isopropylamino)ethoxy]-7-methoxy-4-[(3-methoxy-2-were)amino]quinoline-3-carboxamide

APCI-MS m/z: 439 [MH+]

Example 189

6-[2-(Dimethylamino)ethoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 667 [MH+]

Example 190

6-[3-(Diethylamino)propoxy]-4-{[3-(hydroxymethyl)-2-were]amino}-7-methoxyquinoline-3-carboxamide

APCI-MS m/z: 467 [MH+]

Example 191

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxy-6-[2-(methylamino)ethoxy]quinoline-3-carboxamide

APCI-MS m/z: 425 [MH+]

Example 192

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-4-ylamino)propoxy]quinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 700 [MN+]

Example 193

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-[(2-amino-2-oxoethyl)amino]propoxy]-quinoline-3-carboxamide

APCI-MS m/z: 680 [MN+]

Example 194

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-(1H-pyrazole-3-ylamino)propoxy]quinoline-3-carboxamide triptorelin

APCI-MS m/z: 575 [MN+]

Example 195

4-[(2-Ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-2-ylamino)propoxy]quinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 700 [MN+]

The connection specified in the header of example 196, obtained by the method similar to that described in Example 12.

Example 196

Ethyl-4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-7-yl)oxy]butanoate triptorelin

APCI-MS m/z: 597 [MN+]

The connections defined in the headers of examples 197-218, obtained by the method similar to that described in Example 23.

Example 197

7-[3-(Diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)amino]quinoline-3-carboxamide

APCI-MS m/z: 453 [MN+]

Example 198

7-[3-(Ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino}quinoline-3-carboxamide

APCI-MS m/z: 463 [MH+]

Example 199

7-[3-(Ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 423 [MN+]

Example 200

4-[(2-Ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 437 [MN+]

Example 201

7-[3-(Ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 453 [MN+]

Example 202

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide

APCI-MS m/z: 467 [MH+]

Example 203

7-[3-(Dimethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-metoxy the Olin-3-carboxamide bis(triptorelin)

APCI-MS m/z: 651 [MN+]

Example 204

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 677 [MN+]

Example 205

7-[3-(Diethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 679 [MN+]

Example 206

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 691 [MN+]

Example 207

7-[3-(Dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 681 [MN+]

Example 208

7-[3-(Diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 709 [MN+]

Example 209

7-{3-[(2-Ethoxyethyl)amino]propoxy}-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 467 [MH+]

Example 210

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-piperidine-ipropose)quinoline-3-carboxamide

APCI-MS m/z: 463 [MH+]

Example 211

4-[(2-Ethylphenyl)amino]-6-methoxy-7-(3-thiomorpholine-4-ylpropionic)quinoline-3-carboxamide

APCI-MS m/z: 481 [MN+]

Example 212

4-{[3-(Hydroxymethyl)-2-were]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide

APCI-MS m/z: 465 [MH+]

Example 213

7-[3-(1,1-Diocletianopolis-4-yl)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide

API-MS m/z: 513 [MN+]

Example 214

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide

APCI-MS m/z: 479 [MH+]

Example 215

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide

APCI-MS m/z: 493 [MN+]

Example 216

4-{[3-(Hydroxymethyl)-2-were]amino}-7-[3-(3-hydroxypiperidine-1-yl)propoxy]-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 495 [MN+]

Example 217

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]quinoline-3-carboxamide bis(triptorelin)

APCI-MS m/z: 705 [MN+]

Example 218

7-(3-Azepin-1 ipropose)-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide

APCI-MS m/z: 477 [MH+]

The connections defined in the headers of examples 219-222, obtained by the method similar to that described in Example 87.

Example 219

6,7-Dimethoxy-4-{[2-(methylthio)phenyl]amino}quinoline-3-carboxamide triptorelin

APCI-MS m/z: 484 [MN+]

Example 220

6,7-Dimethoxy-4-[(4-methoxy-2-were)amino]quinoline-3-carboxamide triptorelin

APCI-MS m/z: 482 [MH+]

Example 221

4-{[2-Bromo-3-(hydroxymethyl)phenyl]amino}-6,7-dimethoxyindole-3-carboxamide

APCI-MS m/z: 433 [MN+]

Example 222

4-{[2-Ethyl-3-(hydroxymethyl)phenyl]amino}-6,7-dimethoxyindole-3-carboxamide

APCI-MS m/z: 382 [MN+]

Synthesis of anilines used above

Methyl-2-methyl-3-nitrobenzyloxy ether

To dissolve is the sodium (0.10 g, 4.3 mmol) in methanol (40 ml) was added 2-methyl-3-nitrobenzanthrone (0.50 g, 2.7 mmol) and catalytic amounts Lil in nitrogen atmosphere. After the reaction proceeded at 40°overnight, the solvent evaporated and the residue was purified using chromatography (heptane/EtOAc) to obtain specified in the connection header, 450 mg (92%), as yellow oil.

1H NMR (CDCl3): δ 7.70 (1H, d); 7.58 (1H, d); 7.29 (1H, t); 4.49 (2H, s); 3.43 (3H, s); 2.42 (3H, s).

Isobutyl-2-methyl-3-nitrobenzyloxy ether

Used the same procedure as for methyl 2-methyl-3-nitrobenzyl ether, obtaining specified in the connection header, 486 mg (81%), as yellow oil.

1H NMR (CDCl3): δ 7.71 (1H, d); 7.58 (1H, d); 7.29 (1H, t); 4.52 (2H, s); 3.27 (2H, d); 2.42 (3H, s); 1.91 (1H, m); 0.93 (6H, d).

3-(Methoxymethyl)-2-methylaniline

A mixture of methyl 2-methyl-3-nitrobenzyl ether (0,19 g, 1.05 mmol) and 5% Pd/C (70 mg) in a mixture of EtOAc/EtOH 1:1 (14 ml) was first made at a pressure of 1 ATM (1,01×105PA) during the night. The mixture was filtered through celite and the filtrate was concentrated to obtain specified in the connection header, 125 mg (78%), as yellow oil.

1H NMR (CDCl3): δ 6.99 (1H, t); 6.75 (1H, d); 6.66 (1H, d); 4.42 (2H, s); 3.60 (2H, br s); 3.37 (3H, s); 2.12 (3H, s).

3-(Isobutoxy)-2-methylaniline

Specified in the title compound was obtained using the same procedure as 3-(methoxymethyl)-2-methylaniline.

1/sup> H NMR (CDCl3): δ 6.99 (1H, t); 6.76 (1H, d); 6.65 (1H, d); 4.46 (2H, s); 3.60 (2H, br s); 3.21 (2H, d); 2.13 (3H, s); 1.89 (1H, m); 0.91 (6H, d).

2-(3-Amino-2-were)acetonitrile

2-(2-Methyl-3-nitrophenyl)acetonitrile (Askam, V. et al. J. Chem. Soc. (1969) 1935-1936) was first made over 5% palladium on charcoal, 50 mg in a mixture EUAs/EUN 1:1 (14 ml) for three hours. The mixture was filtered through celite and the filtrate was concentrated to obtain specified in the connection header, 77 mg (77%) as a white powder.

1H NMR (CDCl3): δ 7.03 (1H, t); 6.78 (1H, d); 6.68 (1H, d); 3.66 (2H, br s); 3.63 (2H, s); 2.22 (3H, s).

N-(2-methyl-3-nitrobenzyl)-1-ethanamine

A mixture of 2-methyl-C-nitrobenzylamine (0.50 g, 2.7 mmol) and ethylamine (2.76 g, to 61.2 mmol) in a mixture of THF (10 ml)/Meon (5 ml) was stirred at ambient temperature for 48 hours. The amount of solvent was reduced and the residue was dissolved in a mixture of EtOAc/water To2CO3solution. The aqueous phase was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to obtain specified in the connection header and 0.46 g (86%) as a yellow oil.

1H NMR (CDCl3): δ 7.65 (1H, d); 7.55 (1H, d); 7.27 (1H, d); 3.83 (2H, s); 2.72 (2H, q); 2.45 (3H, s); 1.15 (3H, t).

3-[(Ethylamino)methyl]-2-methylaniline

N-(2-methyl-3-nitrobenzyl)-1-ethanamine (0,46 g, 2.3 mmol) was first made over 5% palladium on coal, 80 mg in a mixture of EtOAc/EtOH 1:1 (14 ml) for four hours. The mixture of filter is Ali through celite, and the filtrate was concentrated to obtain specified in the connection header, 0,373 g (97%), as pale yellow oil.

1H NMR (CDCl3): δ 6.98 (1H, t); 6.74 (1H, d); 6,62 (1H, d); 3.74 (2H, s); 3.60 (2H, br s); 2.71 (2H, q); 2.14 (3H, s); 1.13 (3H, t).

tert-Butyl 3-amino-2-methylbenzyl(ethyl)carbamate

To a solution of 3-[(ethylamino)methyl]-2-methylaniline (0.32 g, of 1.95 mmol) in THF (20 ml) was added di-tert-BUTYLCARBAMATE, 0,43 g (1.97 mmol). After 16 hours stirring at ambient temperature the solvent is evaporated and the residue was purified using chromatography to obtain specified in the connection header, 0.51 g (99%), as colourless oil.

1H NMR (CDCl3): δ 6.97 (1H, s); 6.61 (2H, m); 4.42 (2H, br s); 3.60 (2H, br s); 3.12 (2H, br d); 2.08 (3H, s); 1.45 (9H, br s); 0.98 (3H, br s).

tert-Butyl-2-aminobenzylidene

To a cooled on ice to a solution of 2-amino-benzylamine (1.2 g, 10 mmol) in THF (70 ml) was added di-tert-BUTYLCARBAMATE (2.15 g, 9.9 mmol). After 18 hours stirring at ambient temperature the solvent was reduced, and the precipitate was collected by filtration, washed with cold diethyl ether (×2), heptane (x2) and dried to obtain specified in the connection header, and 1.9 g (85%), as pale yellow powder.

1H NMR (CDCl3): δ 7.09 (1H, t); 7.02 (1H, t); 6.66 (1H, t); 4.76 (1H, br s); 4.25 (2H, d); 4.21 (2H, br s); 1.43 (9H, s).

2-(3-Amino-2-were)-N-ethylacetamide

A mixture of 2-(3-Amin is-2-were)acetic acid (0.32 g, 1.78 mmol) and thionyl chloride (2 ml) was boiled under reflux for 1.5 hours. After cooling, the excess thionyl chloride was removed by evaporation. The last traces of thionyl chloride was removed by azeotropic distillation with toluene.

The residue was dissolved in dry EtOAc (2 ml) and cooled in a bath of ice. Added ethylamine (2 ml), the reaction proceeded overnight at ambient temperature. The organic layer was washed with water, brine, dried over Na2SO4and evaporated to obtain a white powder, which was first made on 5% palladium on coal (70 mg) in a mixture of EtOAc/EtOH 1:1 (25 ml) for three hours. The mixture was filtered through celite, and the filtrate was concentrated to obtain oil, which was then purified using chromatography on silica, (CH2Cl2/MeOH), with 0,266 g (78%) indicated in the title compound as a white solid.

1H NMR (CDCl3): δ 6.99 (1H, t); 6.65 (1H, d); 6.61 (1H, d); 5.32 (1H, br s); 3.66 (2H, br s); 3.55 (2H, s); 3.20 (2H, m); 2.41 (3H, s); 1.05 (3H, t).

2-(3-Amino-2-were)-N-(2-hydroxyethyl)ndimethylacetamide

A mixture of 2-(3-amino-2-were)acetic acid (0.33 g, of 1.84 mmol) and thionyl chloride (2 ml) was boiled under reflux for 1.5 hours. After cooling, the excess thionyl chloride was removed by evaporation. The last traces of thionyl chloride was removed by azeotropic distillation with toluene.

The remainder R which was storyli in dry EtOAc (2 ml) and cooled in a bath of ice. Was added 2-aminoethanol (2 ml), the reaction proceeded overnight at ambient temperature. The organic layer was diluted with EtOAc (15 ml), washed with water, brine, dried over Na3SO4and evaporated to obtain a white powder, which was first made on 5% palladium on coal (70 mg) in ethanol (20 ml) over night. The mixture was filtered through celite, and the filtrate was concentrated to obtain 0.28 g (73%) indicated in the title compound as a white solid.

1H NMR (DMSO-d6): δ 7.69 (1H, m); 6.77 (1H, t); 6.49 (1H, d); 6.39 (1H, d); 4.70 (2H, br s); 4.62 (1H, t); 3.36 (2H, q); 3.34 (3H, s); 3.09 (2H, q); 1.93 (3H, s).

APCI-MS m/z: 209,2 [MH+]

3-(Aminomethyl)-2-methylaniline

A mixture of 2-methyl-3-nitrobenzylamine (0,70 g of 3.77 mmol), sodium azide (1 g, to 15.4 mmol), ethanol (10 ml) and water (2 ml) was heated at 45°With during the night. The mixture was filtered, the filtrate was concentrated and the residue was purified using chromatography on silica (heptane/EtOAc) to give the compounds 2-methyl-3-nitrobenzamide, 0.35 g, which was first made over 5% palladium on coal, 80 mg, in a mixture of EtOAc/EtOH 1:1 (14 ml) over night. The mixture was filtered through celite, the filtrate was concentrated to obtain 0,23 g (45%) indicated in the title compound as a white solid.

1H NMR (DMSO-d6): δ 6.79 (1H, t); 6.52 (2H, t); 4.67 (2H, br s); 3.59 (2H, s); 1.96 (3H, s).

tert-Butyl 3-amino-2-methylbenzylamine

To a solution of the 3-[(ethylamino)methyl]-2-methylaniline (0.21 g, 1.54 mmol) in THF (20 ml) was added di-tert-BUTYLCARBAMATE (0.35 g, 1.97 mmol). After 18 hours stirring at ambient temperature the solvent is evaporated and the residue was purified using chromatography on silica (CH2Cl2/MeOH) to give 0.51 g (99%) indicated in the title compounds as colorless oils.

1H NMR (CDCl3): δ 6.99 (1H, t); 6.69 (1H, d); 6.64 (1H, d); 4.63 (1H, br s); 4.29 (2H, d); 3.63 (2H, br s); 2.10 (3H, s); 1.45 (9H, s).

3-(2-Nitrophenyl)propanoic acid

Specified in the title compound was obtained using the modified method described Grob et al. Helv. Chim. Acta 206 (1961) 1736-1747.

Sodium hydride (60% in paraffin oil, 1.0 g, 25 mmol) was added to a solution of diethylmalonate (3.2 g, 20 mmol) in DMF (20 ml), the mixture was stirred for 3 minutes. Then portions were added 1-bromomethyl-2-nitrobenzene (4.3 g, 20 mmol) for 5 minutes. The reaction mixture was stirred for 3 hours, diluted with water and was extracted twice with ethyl acetate. The combined organic phases are washed with water and evaporated. The residue is suspended in acetic acid (40 ml) and was added 7.5 M HCl (10 ml). The mixture was boiled under reflux for 19 hours, cooled and divided between diethyl ether and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3and then acidified with 2 M HCl. The precipitate was collected, filtratio and dried to obtain specified in the connection header (2,22 g, 77%).

1H NMR (CDCl3): δ 7.97 (1H, dd, J 8.1 and 1.3 Hz); 7.57 (1H, dt, J 7.5 and 1.3 Hz); 7.47-7.37 (2H, m); 3.24 (2H, t, J 7,6 Hz); 2.81 (2H, t, J 7,6 Hz).

4-Nitro-1-indanone

Specified in the title compound was obtained essentially as described in Grob et al. Helv. Chim. Acta 206 (1961) 1736-1747.

3-(2-Nitrophenyl)propanoic acid (2.17 g, 11.1 mmol) in thionyl chloride (30 ml) was heated at the temperature of reflux distilled for 1.5 hours and the reaction mixture is then evaporated. The residue was dissolved in carbon disulfide (15 ml, distilled over AlCl3) and with stirring was added AlCl3(3.2 g, 24 mmol). The mixture was heated at the temperature of reflux distilled for 4 hours and the solvent then evaporated using a stream of nitrogen at ambient temperature. To the residue under stirring was added a mixture of concentrated H2SO4(5,3 ml) and ice (33 g), then toluene (25 ml). The mixture was stirred until then, until all the solid did not dissolve, and then separating the organic phase. The aqueous phase was extracted twice with diethyl ether and the combined organic phases were washed sequentially with saturated NaHCO3, water and brine and finally dried over MgSO4, filtered and evaporated. The residue was chromatographically on a column of silica (2×18 cm)using a mixture of ethyl zitat-heptane (1:3) as eluent, to obtain specified in the header with the unity (0.8 g, 40%).

1H NMR (CDCl3): δ 8.49 (1H, dd, J 8.0 and 1.1 Hz); 8.10 (1H, d, J 7.5 Hz, optional dual); 7.63 (1H, t, J 7.8 Hz, optional dual); 3.67 (2H, m), 2.82 (2H, m).

4-Amino-1-indanone

4-Nitro-1-indanone (0.84 g, of 4.75 mmol) suspended in aqueous hydrochloric acid (9 M, 40 ml) was added chloride divalent tin (3 g, 15.8 mmol). The mixture was stirred at ambient temperature. After 2 hours got clear solution. Stirring was continued for 23 hours, after which formed a yellow precipitate. The reaction mixture was diluted with water and washed twice with methylene chloride. The aqueous phase was podslushivaet 2 M aqueous NaOH and was extracted four times with methylene chloride. The combined organic phases are washed with water, dried (Na2SO4), filtered, evaporated and finally dried to obtain specified in the title compound (630 mg, 90%).

1H NMR (CDCl3): δ 7.28-7.18 (2H, m); 6.93 (1H, d, J 7.0 Hz); 2.92 (2H, t, J 5.6 Hz, optional dual) and 2.71 (2H, t, J 5.5 Hz, optional dual).

2-Bromo-3-aminobenzoyl alcohol

The compound described in (Cladingboel, David E. et al. J. Chem. Soc. Chem. Commun.; EN; 21; 1990; 1543-1544.)

Methyl-3-nitro-2-vinylbenzoate

The compound described in (Söderberg, Björn S. et al. J. Org. Chem. 1997; 62; 5838-5845).

Methyl-3-amino-2-ethylbenzoic

A mixture of methyl-Z-nitro-2-vinylbenzoate (1.1 g, 5,31 mmol)and 5% Pd/C (100 mg) in a mixture of EtOAc/EtOH 1:1 (50 ml) gidron the Wali at a pressure of 3 atmospheres (3,03× 105PA) during the night. The mixture was filtered through celite and the filtrate was concentrated to obtain specified in the connection header, 0,93 g ( 97%). in the form of a colorless oil.

1H NMR (CDCl3): δ 7.20 (1H, q); 7.05 (1H, t); 6.82 (1H, q); 3.88 (3H, s); 3.75 (2H, br s); 2.78 (2H, q); 1.24 (3H, t).

(3-Amino-2-ethylphenyl)methanol

To a solution of methyl 3-amino-2-ethylbenzoic (0,83 g, 4,63 mmol) in THF (40 ml) was added alumoweld lithium (0.9 g, with 23.7 mmol). The mixture was heated at 50°C for 5 hours, cooled to 0°and carefully hydrolyzed with water. The suspension was extracted with EtOAc (×5). The extracts were washed with brine, dried Na2SO4and was evaporated. The residue was purified by chromatography (CH2Cl2/Meon) obtaining specified in the connection header, 0,63 g (89%). in the form of a white powder.

1H NMR (CDCl3): δ 7.05 (1H, t); 6.82 (1H, d); 6.70 (1H, d); 4.68 (2H, d); 3.71 (2H, br s); 2.68 (2H, q); 1.47 (1H, t); 1.23 (3H, t).

Pharmacological data

JAK3 HTRF (homogenous time released fluorescence, homogeneous fluorescence with time resolution) analysis

In the analysis of JAK3 kinases used protein (JAK3 kinase domain fused with glutathione-3-transferase, GST), co-expressed in E. coli with Chaperonin/S, and purified by affinity chromatography on glutathione-sepharose. The enzyme was dissolved in a mixture of 10 mm Tris-HCl, 150 mm NaCl, 5% mannitol, 2 mm 2-mercaptoethanol, and 30% glycerol. Substrate in kinase reaction is biotinyl is consistent peptide site autophosphorylation JAK3 (Biotin-LPDKDYYWREPG), used at 2 μm. Conditions of the analysis are the following: JAK3, bonding and substrate are incubated in a mixture of 25 mm Tris-base, 5 mm MgCl2, 5 mm MnCl2, 0.05% Tritonx-100 and 2 μm ATP (adenosine triphosphate) for 45 min at room temperature. The reaction volume was 20 μm. Stop solution was added to a final concentration of EDTA (ethylenediaminetetraacetic acid) 100 µm. Finally add 0,065 mg/ml RT and 10,42 μm SA-XL665 in 50 mm HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 0.5 M KF and 0.1% BSA (bovine serum albumin). The tablet reads in Discovery device after 60 minutes of incubation.

Compounds of the examples have values IC50less than 25 microns.

Compounds according to the invention can be represented, for example, in the form of the following drugs.

1. The solutions for intravenous injection

Active connection (connection according to the invention)4 g
The polyethylene glycol 400 for injection400 g
Disodium hydrogen phosphateSC. required.
Water for injectionTo 1000 ml

The active compound is dissolved in polyethylene glycol 400 and add 550 ml of water. the pH of the solution was adjusted to about 7 by adding an aqueous solution of disodium hydrocarbon is the and then add water to final volume of 1000 ml, the Solution is filtered through a filter 22 μm and immediately poured into sterile ampoules of 10 ml, which is hermetically sealed.

2. Tablets for oral administration, g:

Active connection (connection according to the invention)150
The sodium aluminosilicate20
Paraffin120
Microcrystalline cellulose20
Hydroxypropylcellulose5
The sodium fumarate3

The active compound, sodium aluminosilicate, paraffin and microcrystalline cellulose are mixed and added an aqueous solution of hydroxypropylcellulose. The resulting mixture is dried and milled to obtain granules, which are then mixed with sodium fumarate. The mixture is pressed into tablets in a tablet machine to obtain 1000 tablets each containing 150 mg of active connections.

1. Aromatic derivatives of 6,7-disubstituted 3-chinainternational formula (I) and their pharmaceutically acceptable salts for use in the manufacture of drugs for the treatment of diseases mediated JAK3:

where n is 0 or 1;

p num="1390"> X represents NR3or;

Ar is selected from phenyl, tetrahydronaphthyl, indolyl, pyrazolyl, dihydroindole, 1-oxo-2,3-dihydroindole or indazole, each of which can be substituted one or more than one group selected from halogen, hydroxy, cyano, C1-C8alkoxy, CO2R8, CONR9R10C1-C8alkyl-O-C1-C8of alkyl, C1-C8alkyl-NR8-C1-C8of alkyl, C1-C8alkyl-CONR9R10, NR8COC1-C8of alkyl, C1-C8alkylthio or C1-C8the alkyl (possibly substituted by one or more than one hydroxy or cyano or fluorine atoms);

R groups are independently hydrogen or C1-C8by alkyl;

R1and R2independently selected from hydrogen, halogen, nitro, cyano, C1-C8of alkyl, C1-C8alkoxy, hydroxy, phenyl, Y(CR112)pNR4R5, Y(CR112)pCONR4R5, Y(CR112)pCO2R6, Y(CR112)pOR6, Y(CR112)pR6;

or R1and R2joined together as co2O -, or-och2CH2O-;

R11groups represent independently hydrogen, C -C8alkyl, hydroxy or halogen;

p is 0, 1, 2, 3, 4 or 5;

Y represents oxygen, CH2or NR7;

R3represents hydrogen or C1-C8alkyl;

R4and R5each independently represent hydrogen, C1-C8alkyl, or R4and R5together with the nitrogen atom to which they are attached, form a 4-7-membered saturated or aromatic heterocyclic ring system may contain an additional oxygen, sulphur or the group NR6or one of R4and R5is hydrogen or C1-C8the alkyl and the other represents a 5 - or 6-membered heterocyclic ring system may contain additional atom of oxygen, sulfur or nitrogen;

R6represents hydrogen, C1-C8alkyl, phenyl or benzyl;

R7represents hydrogen or C1-C8alkyl;

R8represents hydrogen or C1-C8alkyl;

R9and R10each independently represent hydrogen or C1-C8alkyl, provided that this compound is not 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-hyalinobatrachium, 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-hyalinobatrachium, 4-(2-bromoaniline)-6,7-dimethoxy-3-quinoline what carboxamide and 4-(1,5-dichloroaniline)-6,7-dimethoxy-3-chinainternational.

2. The compound according to claim 1 in which both R groups are hydrogen.

3. The compound according to claim 1, in which X represents NR3.

4. The compound according to claim 1, in which Ar represents a phenyl, possibly substituted by one or more than one group selected from halogen, hydroxy, cyano, C1-C8alkoxy, CO2R8, CONR9R10C1-C8alkyl-O-C1-C8of alkyl, C1-C8alkyl-NR8-C1-C8of alkyl, C1-C8alkyl-CONR9R10, NR8COC1-C8of alkyl, C1-C8alkylthio or C1-C8the alkyl (possibly substituted by one or more than one hydroxy or cyano or fluorine atoms).

5. The compound according to claim 1, in which R1represents methoxy, ethoxy, OCH2CONH2, O(CH2)2OMe, O(CH2)2NR4R5or O(CH2)3NR4R5where R4and R5both are hydrogen or stands, or together with the nitrogen to which they are attached, form piperidino or morpholino ring, or R1represents NH(CH2)3NR4R5where R4and R5together with the nitrogen to which they are attached, form an imidazole ring.

6. The compound according to claim 1, in which R2represents methoxy, ethoxy, O(CH2)2OMe, O(CH2) 3HE, O(CH2)3CO2IU, O(CH2)2NR4R5, O(CH2)3NR4R5or O(CH2)4NR4R5where one of R4or R5is stands, and the other is pyridium, or R4or R5selected from hydrogen or methyl, or together with the nitrogen to which they are attached, they form thiomorpholine, piperidine, morpholino, imidazole, triazole or 2,6-dimethylmorpholine group.

7. The compound according to claim 1, which is a

6-benzyloxy-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

6-hydroxy-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-(2-methoxyethoxy)-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-octyloxy-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(4-morpholinyl)ethoxy]-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-piperidinyl)ethoxy]-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-6-[2-(1-pyrrolidinyl)ethoxy]-3-chinainternational;

6-[2-(dimethylamino)ethoxy]-4-(3-(hydroxymethyl-2-m is telemilano)-7-methoxy-3-chinainternational;

6-[2-(dimethylamino)-2-oksidoksi]-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

6-(2-amino-2-oksidoksi)-4-(3-hydroxymethyl-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

6-methoxy-4-[2-(methylsulfonyl)aniline]-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

4-(1H-indol-4-ylamino)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational;

methyl-4-{[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-chinoline]oxy}of butanoate;

4-(2-ethylaniline)-7-(3-hydroxypropoxy)-6-methoxy-3-chinainternational;

6-methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(2-toluidino)-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-(2-methoxyethoxy)-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-[4-(4-morpholinyl)butoxy]-3-chinainternational;

7-(3-chloropropoxy)-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

7-{3-[(CIS)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

7-{3-[(TRANS)-2,6-dimethylmorpholine]Ministers who si}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(1-piperidinyl)propoxy]-3-chinainternational;

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-thiomorpholine)propoxy]-3-chinainternational;

6-[3-(dimethylamino)propoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

4-(2-ethylaniline)-6-[3-(1H-imidazol-1-yl)propoxy]-7-methoxy-3-chinainternational;

4-(2-ethylaniline)-7-methoxy-6-(3-teenrotica)-3-chinainternational;

6-[2-(dimethylamino)ethoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

6-(3-aminopropoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

4-(2-ethylaniline)-7-methoxy-6-[2-(methylamino)ethoxy]-3-chinainternational;

6-(2-aminoethoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational;

7-[3-(dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-[2-(methylamino)ethoxy]-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-7-[2-(1-piperazinil)ethoxy]-3-chinainternational;

4-(2-ethylaniline)-7-[3-(1H-imidazol-1-yl)propoxy]-6-methoxy-3-chinainternational;

4-(2-ethylaniline)-7-[2-(niridazole-1-yl)ethoxy]-6-methoxy-3-chinainternational;

7-(3-aminopropoxy)-4-(2-ethylaniline)-6-methoxy-3-chinainternational;

7-hydroxy-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational;

6-{[3-(1H-imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinainternational;

7-methoxy-6-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational;

7-methoxy-6-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational;

7-methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational;

6-methoxy-7-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational;

6-methoxy-7-[(2-methoxyethyl)amino]-4-(2-toluidino)-3-chinainternational;

7-{[3-(1H-imidazol-1-yl)propyl]amino}-6-methoxy-4-(2-toluidino)-3-chinainternational;

7-[(1-benzyl-4-piperidinyl)amino}-6-methoxy-4-(2-toluidino)-3-chinainternational;

6-methoxy-6-{[3-(4-morpholinyl)propyl]amino}-4-(2-toluidino)-3-chinainternational;

4-[3-(hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(4-hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(4-fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[(1-ethyl-1H-pyrazole-5-yl)amino]-6,7-dimethoxy-3-chinainternational;

4-(3-aminocarbonyl-2 metranil is about)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2,3-dimethylaniline)-3-chinainternational;

6,7-dimethoxy-4-(5,6,7,8-tetrahydro-1-naphthaleneamine)-3-chinainternational;

4-(4-carboxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(1H-indol-4-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(3-chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(aminocarbonyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-hydroxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(3-methoxy-2-methylaniline)-3-chinainternational;

6,7-dimethoxy-4-[(1-methyl-1H-indol-4-yl)amino]-3-chinainternational;

6,7-dimethoxy-4-[(1-oxo-2,3-dihydro-1H-inden-4-yl)amino]-3-chinainternational;

4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)amino-6,7-dimethoxy-3-chinainternational;

4-(4-carboxy-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(4-methoxycarbonyl-2-methylaniline)-3-chinainternational;

4-(4-hydroxymethyl-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2-propylaniline)-3-chinainternational;

4-(2-isopropylaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(sec-butyl)aniline]-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-[3-(methoxymethyl)-2-methylaniline]-3-chinainternational;

4-[3-(ISO-butoxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-[3-(cyanomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-{3-[(ethylamino)methyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational;

4-{3-[2-(ethylamino)-2-oxoethyl]-2-methylaniline}-6,7-dimethoxy-3-chinainternational;

ethyl-2-(3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-were)acetate;

4-[3-(2-amino-2-oxoethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-[3-(2-hydroxyethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(3-{2-[(2-hydroxyethyl)amino]-2-oxoethyl}-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

tert-butyl 3-{[3-(aminocarbonyl)-6,7-dimethoxy-4-chinoline]amino}-2-methylbenzylamine;

4-[3-(aminomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(4-fluorescent-2-methylaniline)-6-methoxy-3-chinainternational;

4-(4-bromo-2-methylaniline)-6-methoxy-3-chinainternational;

4-(4-chloro-2-methylaniline)-6-methoxy-3-chinainternational;

4-(2,4-dimethylaniline)-6-methoxy-3-chinainternational;

6-methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(4-hydroxy-2-methylaniline)-6-methoxy-3-chinainternational;

4-(2-bromoaniline)-6-methoxy-3-chinainternational;

4-(2,4-dimethoxyaniline is about)-6-methoxy-3-chinainternational;

6-methoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(2-ethoxyaniline)-6-methoxy-3-chinainternational;

4-(2-ethylaniline)-6-methoxy-3-chinainternational;

6-methoxy-4-(2-toluidino)-3-chinainternational;

6-methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(4-bromo-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,4-dimethylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(2-bromo-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-bromo-4-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2,4-dimethoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-fluorescent-2-methylaniline)-7-methoxy-3-chinainternational;

4-(4-bromo-2-methylaniline)-7-methoxy-3-chinainternational;

4-(4-chloro-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2,4-dimethylaniline)-7-methoxy-3-chinainternational;

7-methoxy-4-(4-methoxy-2-methylaniline)-3-chinainternational;

4-(4-hydroxy-2-methylaniline)-7-methoxy-3-chinainternational;

4-(2-bromoaniline)-7-methoxy-3-chinainternational;

4-(2-bromo-4-methylaniline)-7-methoxy-3-chinainternational;

4(2-bromo-4-foranyone)-7-methoxy-3-chinainternational;

4-(2,4-dimethoxyaniline)-7-methoxy-3-chinainternational;

6,7-sodium dichloro-4-(4-methoxy-2-methylaniline)-3-chinainternational;

6,7-sodium dichloro-4-(2,4-dimethoxyaniline)-3-chinainternational;

4-(2-ethylaniline)-3-chinainternational;

4-(2-toluidino)-3-chinainternational;

4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(2-ethoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(hydroxymethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(2-ethylaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2-toluidino)-3-chinainternational;

6,7-dimethoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(2,4-dibromoanisole)-6,7-dimethoxy-3-chinainternational;

7-methoxy-4-(2-methoxyaniline)-3-chinainternational;

4-(2-ethoxyaniline)-7-methoxy-3-chinainternational;

4-[2-(aminocarbonyl)aniline]-7-methoxy-3-chinainternational;

4-(2-ethylaniline)-7-methoxy-3-chinainternational;

7-methoxy-4-(2-toluidino)-3-chinainternational;

7-methoxy-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

6,7-sodium dichloro-4-(2-methoxyaniline)-3-chinainternational;

6,7-sodium dichloro-4-(2-ethylaniline)-3-chinainternational;

6,7-sodium dichloro-4-[2-(methylsulfonyl)aniline]-3-chinainternational;

4-(2,5-dimethylaniline)-6,7-dimethoxy-3-chinainternational;

4-(5-fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(5-chloro-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(3-fluorescent-2-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(4-hydroxy-2,5-dimethylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-aniline-6,7-dimethoxy-3-chinainternational;

4-(4-chloro-2-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2,6-diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(3-foranyone)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(4-methoxyaniline)-3-chinainternational;

4-(3-chloroanilino)-6,7-dimethoxy-3-chinainternational;

4-(2-chloroanilino)-6,7-dimethoxy-3-chinainternational;

4-[3-(acetylamino)aniline]-6,7-dimethoxy-3-chinainternational;

4-(2,5-diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(1H-indol-5-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(1H-indazol-5-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(1H-indazol-6-ylamino)-6,7-dimethoxy-3-chinainternational;

4-(2,4-diptiranjan)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,5-dichloroaniline)-6,7-dimethoxy-3-chinainternational;

4-[2-(2-hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-[3-(methylsulfonyl)aniline]-3-chinainternational;

6,7-dimethoxy-4-(2-methoxy-5-methylaniline)-3-chinainternational;

4-[4-(dimethylamino)aniline]-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-[4-(methylsulfonyl)aniline]-3-chinainternational;

4-[4-(2-hydroxyethyl)aniline]-6,7-dimethoxy-3-chinainternational;

4-(3-hydroxy-4-methoxyaniline)-6,7-dimethoxy-3-chinainternational;

4-(2,3-dichloroaniline)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-(2,3,4-triptoreline)-3-chinainternational;

6,7-dimethoxy-4-(3-toluidino)-3-chinainternational;

4-(2-hydroxy-4-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-4-hydroxyanisole)-6,7-dimethoxy-3-chinainternational;

4-[2-(hydroxymethyl)-4-methylaniline]-6,7-dimethoxy-3-chinainternational;

4-(2-chloro-4-foranyone)-6,7-dimethoxy-3-chinainternational;

4-(2-fluorescent-5-methylaniline)-6,7-dimethoxy-3-chinainternational;

4-[(2-cyanophenyl)amino]-6,7-dimethoxyquinazolin-3-carboxym is d;

4-[(2,5-defloriani)amino]-6,7-dimethoxyquinazolin-3-carboxamide;

4-(1H-indol-5-ylamino)-6,7-dimethoxyindole-3-carboxamide;

6,7-sodium dichloro-4-(2-methylaniline)-3-chinainternational;

4-(2,3-dihydro-1H-inden-1-ylamino)-6,7-dimethoxy-3-chinainternational;

6,7-dimethoxy-4-{[2-(trifloromethyl)benzyl]amino}-3-chinainternational;

6,7-dimethoxy-4-[(1-phenylethyl)amino]-3-chinainternational;

4-(3-hydroxymethyl-2-methylaniline)-3-chinainternational;

9-(3-hydroxymethyl-2-methylaniline)-2,3-dihydro[1,4]like[2,3g]quinoline-8-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[2-(propylamino)ethoxy]quinoline-3-carboxamide;

6-[2-(ethylamino)ethoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide;

6-[2-(isopropylamino)ethoxy]-7-methoxy-4-[(3-methoxy-2-were)amino]quinoline-3-carboxamide;

6-[2-(dimethylamino)ethoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide;

6-[3-(diethylamino)propoxy]-4-{[3-(hydroxymethyl)-2-were]amino}-7-methoxyquinoline-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxy-6-[2-(methylamino)ethoxy]quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-4-ylamino)propoxy]quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-[(2-amino-2-oxoethyl)amino]propoxy]quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(1H-pyrazole-3-ylamino)propoxy]quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-2-ylamino)propoxy]quinoline-3-carboxamide;

ethyl-4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-7-yl)oxy]butanoate;

7-[3-(diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)amino]quinoline-3-carboxamide;

7-[3-(ethylamino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino}quinoline-3-carboxamide;

7-[3-(ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide;

7-[3-(ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide;

7-[3-(dimethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

7-[3-(diethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

7-[3-(dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-CT is the oksamid;

7-[3-(diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-thiomorpholine-4-ylpropionic)quinoline-3-carboxamide;

4-{[3-(hydroxymethyl)-2-were]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

7-[3-(1,1-diocletianopolis-4-yl)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide;

4-{[3-(hydroxymethyl)-2-were]amino}-7-[3-(3-hydroxypiperidine-1-yl)propoxy]-6-methoxyquinoline-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]quinoline-3-carboxamide;

7-(3-azepin-1 ipropose)-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide;

6,7-dimethoxy-4-{[2-(methylthio)phenyl]amino}quinoline-3-carboxamidotryptamine;

6,7-dimethoxy-4-[(4-methoxy-2-were)amino]quinoline-3-carboxamide;

4-{[2-bromo-3-(hydroxymethyl)phenyl]amino}-6,7-dimethoxyindole-3-carboxamide;

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6,7-dim is tochinoshin-3-carboxamide;

or its pharmaceutically acceptable salt.

8. The compound of formula (I)as defined in any one of claims 1 to 7, for inhibition of JAK3.

9. 4-anilinophenol-3-carboxamide formula (IA)

where Ar represents a phenyl, substituted ethyl, propylene, hydroxymethyl or CO2N or disubstituted by stands and hydroxymethyl;

R1represents methoxy, ethoxy or group OCH2CONH2The co2CH2Och3or O(CH2)pNR4R5where p is 2 or 3, and R4and R5represent hydrogen, methyl, ethyl or propyl, or R4and R5together form a pyrolidine, imidazole or morpholine ring;

R2represents methoxy, ethoxy or O(CH2)pNR4R5where p is 2, 3 or 4, and R4and R5represent hydrogen, methyl or ethyl, or one of R4or R5is stands, and the other is pyridium or pyrazole, or R4and R5form piperidino, hydroxypiperidine, thiomorpholine, morpholine, pyrolidine, 2,6-dimethylmorpholine, imidazole or triazole ring;

or their pharmaceutically acceptable salt or MES,

provided that when a represents a phenyl, substituted e the sludge or propylene or disubstituted by stands, then R1and R2are not both methoxy, R1and R2are not both ethoxy, or one of R1/R2is not methoxy when another is ethoxy.

10. The compound of formula (IA) according to claim 9, selected from

4-(2-ethylaniline)-6-methoxy-7-{2-[methyl(4-pyridinyl)amino]ethoxy}-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-thiomorpholine)propoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(1-piperidinyl)propoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational,

7-[3-(dimethylamino)propoxy]-4-(2-ethylaniline)-6-methoxy-3-chinainternational,

7-{3-[(2R,6S)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[4-(4-morpholinyl)butoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-{3-[methyl(4-pyridinyl)amino]propoxy}-3-chinainternational,

4-(2-ethylaniline)-7-methoxy-6-[2-(methylamino)ethoxy]-3-chinainternational,

7-{3-[(2S,6S)-2,6-dimethylmorpholine]propoxy}-4-[3-(hydroxymethyl)-2-methylaniline]-6-methoxy-3-chinainternational,

4-(2-ethylaniline)7-[3-(1H-imidazol-1-yl)propoxy]-6-methoxy-3-chinainternational,

6-(2-aminoethoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-[2-(methylamino)ethoxy]-3-chinainternational,

4-(2-ethylaniline)-6-methoxy-7-(2-methoxyethoxy)-3-chinainternational,

4-(2-ethylaniline)-7-(3-hydroxypropoxy)-6-methoxy-3-chinainternational,

6-methoxy-7-[2-(4-morpholinyl)ethoxy]-4-(2-toluidino)-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[2-(1-pyrrolidinyl)ethoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

4-(2-ethylaniline)-7-[2-(1H-imidazol-1-yl)ethoxy]-6-methoxy-3-chinainternational,

4-[3-(2-hydroxyethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

7-methoxy-6-{[2-(4-morpholinyl)ethyl]amino}-4-(2-toluidino)-3-chinainternational,

4-(2-ethylaniline)-6-[3-(1H-imidazol-1-yl)propoxy]-7-methoxy-3-chinainternational,

7-(3-aminopropoxy)-4-(2-ethylaniline)-6-methoxy-3-chinainternational,

methyl-4-{[3-(aminocarbonyl)-6-methoxy-4-(2-toluidino)-7-chinoline]oxy}butanoate,

4-[3-(aminomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

6-{[3-(1H-imidazol-1-yl)propyl]amino}-7-methoxy-4-(2-toluidino)-3-chinoline the oksamida,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-(2-methoxyethoxy)-3-chinainternational,

6-[2-(dimethylamino)ethoxy]-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-[3-(cyanomethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

4-[3-(2-amino-2-oxoethyl)-2-methylaniline]-6,7-dimethoxy-3-chinainternational,

6-(3-aminopropoxy)-4-(2-ethylaniline)-7-methoxy-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[3-(4-morpholinyl)propoxy]-3-chinainternational,

4-[3-(hydroxymethyl)-2-methylaniline]-7-methoxy-6-[2-(4-morpholinyl)ethoxy]-3-chinainternational,

and its pharmaceutically acceptable salts.

11. The compound of formula (IA) according to claim 9, selected from

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-4-ylamino)propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-[(2-amino-2-oxoethyl)amino]propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(1H-pyrazole-3-ylamino)propoxy]quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-methoxy-6-[3-(pyridine-2-ylamino)propoxy]quinoline-3-carboxamide,

ethyl-4-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-7-yl)oxy]butanoate,

7-[3-(diethylamino)propoxy]-6-methoxy-4-[(2-methoxyphenyl)amino]quinoline-3-carboxamide,

7-[3-(these is amino)propoxy]-6-methoxy-4-{[2-(trifluoromethyl)phenyl]amino}quinoline-3-carboxamide,

7-[3-(ethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-7-[3-(isopropylamino)propoxy]-6-methoxyquinoline-3-carboxamide,

7-[3-(ethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(propylamino)propoxy]quinoline-3-carboxamide,

7-[3-(dimethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide,

7-[3-(diethylamino)propoxy]-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide,

7-[3-(dimethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

7-[3-(diethylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide,

7-{3-[(2-ethoxyethyl)amino]propoxy}-4-[(2-ethylphenyl)amino]-6-methoxyquinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-piperidine-ipropose)quinoline-3-carboxamide,

4-[(2-ethylphenyl)amino]-6-methoxy-7-(3-thiomorpholine-4-ylpropionic)quinoline-3-carboxamide,

4-{[3-(hydroxymethyl)-2-were]amino}-6-methoxy-7-(3-pyrrolidin-1 improper and)quinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-pyrrolidin-1 ipropose)quinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(3-piperidine-1-ylpropionic)quinoline-3-carboxamide,

4-{[3-(hydroxymethyl)-2-were]amino}-7-[3-(3-hydroxypiperidine-1-yl)propoxy]-6-methoxyquinoline-3-carboxamide,

4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(1H-1,2,4-triazole-1-yl)propoxy]quinoline-3-carboxamide,

and its pharmaceutically acceptable salts.

12. The compound of formula (IA) according to claim 9 for use as an inhibitor of JAK3 kinase.

13. The pharmaceutical composition inhibiting JAK3 kinase containing a compound of formula (IA) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

14. The use of the compounds of formula (I)as defined in claim 1, or its pharmaceutically acceptable salt for the manufacture of drugs for the treatment of a disease or condition mediated JAK3.

15. The application 14, where the disease or condition is a asthma, rejection/transplantation graft-versus-host or rheumatoid arthritis.

16. The method of obtaining the compounds of formula (I)in which:

the compound of formula (II)

where R1and R2such as defined in fo the mule (I), or are protected derivatives, and R20represents a leaving group, is subjected to the interaction with the compound of the formula (III)

where Ar and R such as defined in formula (I)or are protected derivatives,

and maybe then

remove any protective groups,

turn the compound of formula (I) into another compound of formula (I),

carry out the formation of pharmaceutically acceptable salts.

17. The method of obtaining the compounds of formula (I)in which:

for compounds of formula (I), where R1and/or R2are the groups Y(CH2)pNR4R5, Y(CH2)pCONR4R5, Y(CH2)pCO2R6, Y(CH2)pOR6or Y(CH2)pR6where Y is oxygen, the compound of formula (IV)

where R1'or R2'subject to transformation in group Y(CH2)pNR4R5, Y(CH2)pCONR4R5, Y(CH2)pCO2R6, Y(CH2)pOR6or Y(CH2)pR6represents hydroxy and the other R1'or R2'and Ar are as defined in article 16, is subjected to the interaction with the compound of the formula (V)

where R21represents NR4R5, CONR4R5, CO2R6, OR6or R6, a R4, R5and R6such as defined in formula (I)or are protected derivatives,

and maybe then

remove any protective groups,

turn the compound of formula (I) into another compound of formula (I),

carry out the formation of pharmaceutically acceptable salts.



 

Same patents:

The invention relates to new proizvodnim quinoline of formula (I), where R is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and allyl; R4is hydrogen and pharmaceutically acceptable inorganic or organic anion; R5is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, chlorine, bromine, CF3and coxFywhere x=0-2, y=1-3, provided that x+y=3; R6is hydrogen; R5and R6taken together, constitute methylendioxy

The invention relates to new substituted benzo/a/acridinium formula (II), where R1and R2are independently IT, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R1and R2together represent-OCH2O-; R3represents H; R5and R6are independently H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy, or R5and R6together represent-co2O-; R7represents H or (C1-C8)alkyl, or R1, R2, R3, R5, R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R1and R2together represent-OCH2O-; R2and R3together represent-co2O-; R5and R6together represent-OCH2O-; R7represents H or (C1-C8)alkyl, provided that one of R1and R2is (C1-C8)alkoxy, or R1and R2together represent-co2O-, or R1, R5and R6independently represent H, HE, NO2, NH2, halogen, NHCO(C1-C8)alkyl or (C1-C8)alkoxy; R2

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

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The invention relates to 3-substituted derivatives of 3H-2,3-benzodiazepine, method of production thereof and to pharmaceutical compositions based on them

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The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

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