Condensed with heterocyclic ring derivatives of pyrimidine

 

(57) Abstract:

The compounds of formula I

< / BR>
and stereoisomers, pharmaceutically acceptable salts, where Y is-NR4-CR3= CR3- CH= CR3-N=CH-, CR3=N-CR3=CR3-, -CR3=CR3-NR4-,

-NR4-CR3= N-N=N-NR4-; Z IS - NR1R2, R1- H, R2is phenyl, substituted by a group (R5)mor Q, or R1R2N represents a group of the formula A

< / BR>
(other designations, see p. 1 f-ly), can be used in the treatment of hyperproliferative diseases such as cancer and psoriasis, astinos, kidney disease and pancreatitis. 11 C.p. f-crystals.

This invention relates to pyrimidine derivatives, condensed with the heterocyclic ring, and to methods of their use in the treatment of hyperproliferative diseases such as cancer and psoriasis; ESTENOZ; kidney disease and pancreatitis, and to prevent beastialy implantation, for example, contraception in mammals.

Many of the current modes of treatment of cancer using compounds that inhibit DNA synthesis. Such compounds are usually toxic to cells, but their toxicity against cancer cells have developed alternative approaches to the search for anticancer agents which act through other mechanisms than the inhibition of DNA synthesis.

It is known that cells can become malignant or cancerous due to the transformation of their DNA into an oncogene (i.e., a gene, which when activated leads to the formation of malignant tumor cells). Many oncogenes encode proteins that represent aberrant tyrosine kinase that can cause transformation of cells. Alternatively, overexpression of normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes leading to a malignant phenotype.

Receptor tyrosine kinase are large enzymes that spacerow the cell membrane and possess an extracellular binding domain of growth factors such as epidermal growth factor, a transmembrane domain and an intracellular part, which functions as a kinase, phosphorylase specific the tyrosine residues in proteins, and thus affecting cell proliferation. It is known that these kinases are often aberrant expressed in normal cancers, such as breast cancer, cancer of the gastrointestinal tract, such as colon cancer, direct receptor of epidermal growth factor (EGFR), which possesses tyrosine kinase activity, motirola (subject to mutation) and/or sverkhekspressiya in many cancerous human tumors, such as tumors of the brain, lung, squamous cell, bladder, gastric, breast, head and neck, esophagial, gynecological and thyroid (thyroid gland) tumors.

Respectively, was recognized that inhibitors of receptor tyrosinekinase are useful as selective inhibitors of the growth of malignant mammalian cells. For example, erbstein, a tyrosine kinase inhibitor that selectively attenuatum at animicheskih naked mice the growth of transplanted breast carcinoma person, which expresses the receptor tyrosinekinase epidermal growth factor (EGFR), but not affecting the growth of other carcinomas, which does not Express EGF receptor (the receptor for the epidermal growth factor).

It was also shown that a variety of other compounds, such as derivatives of styrene, possess the properties of tyrosine kinase inhibition. Recently, in three European patent publications, namely EP 0556226 A1, EP 0602851 A1 and EP 0520722 A1, it was noted that some condensed with heteroaryl pyrimidine derivative publication WO 92/20642 also disclosed bis mono-and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors. In European patent publication EP 0496617 A1 describes some pyrazolo[3,4-d] pyrimidines and pyrrolo[2,3-d]pyrimidines, which have the property to inhibit adenosines.

In European patent publication EP 0475413 A2 describes some of carbocyclic nucleoside analogues as useful immunosuppressive substances. In European patent publication EP 0414386 A1 describes some pyrido[2,3-d]pyrimidines as fungicides, insecticides and miticides. In publication II Farmco-Ed. Sc, volume 35, fasc. 4, pages 308-323 (1980) describes the synthesis and protivoallergichesky activity of derivatives of 9-aryl-8-asadena.

In pending patent applications U.S. (NN 08/200359 and 08/413300) and PCT application N PC8836A owned by the applicant of this application, describes optionally substituted indolyl and phenylamino hintline, respectively, which are useful in the treatment of hyperproliferative diseases involving receptor tyrosine kinase. In addition to the above U.S. patent 4012513 reveals some derivatives of 1-(heterocyclic)-indol-3-yl-acetic acids, which are anti-inflammatory, analgesic and antipyretic (anti-fever) activity.

Although described the search continues for improved anticancer pharmaceutical substances.

Brief disclosure of the invention.

This invention is directed to compounds of the formula

< / BR>
and stereoisomers, pharmaceutically acceptable salts, where Y is-NR4-CR3= CR3-, -CH= CR3-N= CH-, -CR3=N-CR3=CR3-, CR3=CR3-NR4-, -NR4-CR3= N - or-N=N-NR4-;

Z represents NR1R2where R1is H and R2represents phenyl substituted by a group (R5)mor Q, or R1R2N represents a group of the formula

< / BR>
in which the dotted line represents an optional double bond;

each R3attached to the carbon atom in Y, and independently selected from: hydroxy, (C1-C4)alkoxy, hydroxy(C1-C4)alkoxy, amino(C2-C4)alkyl, amino(C2-C4)alkoxy, (C1-C4)alkoxy(C2- C4)alkoxy, hydroxy(C1-C4)alkyl(C1- C4)alkylenedioxy, (C1-C4)alkoxy(C1- C4)alkyl(C1-C4)alkylenedioxy, mono-N - or di-N, N-(C1-C4)alkylamino(C2-C4)alkoxy, 3 - or 4-(C1-C4)alkoxy-(2-hydroxy)-(C3- C4)alkoxy, carboxy(C1-C4)alkoxy, morphol the-1 - yl-(C2-C4)alkoxy,

(C1-C4)alkoxy(C1- C4)alkanoyloxy, nitro, hydroxyamino, amino, phenyl, pyridyl, pyrrolo, imidazole, thiazole, benzimidazole, pyridinyl, mono-N - or di-N, N-(C1-C4)alkylamino, (C1-C4)alkanolamine, hydroxy(C2-C4)alkylamino,

(C1-C4)alkoxy (C2-C4)alkylamino, (C1-C4)alkylsulfonamides, morpholino, (C1-C4)alkyl-piperazine-1-yl, bis(C1-C4)alkane-sulfonamide, di-N, N-(C1- C4)alkylamino(C2-C4)alkylamino, (C1-C4)alkylamino(C2-C4)alkylamino,

piperidine-1-yl, imidazol-1-yl, pyrrolidin-1-yl, (C1-C4)alkoxy(C1-C4)alkylcarboxylic, carboxy, (C1-C4)alkoxycarbonyl,

(C1-C4)alkoxycarbonyl(C1-C4)alkoxy, amido, mono-N - or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N - or di-N,N-(hydroxy(C2-C4)alkylaminocarbonyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, mono-N - or di-N, N-((C1-C4)alkoxy(C1- C4)alkylamino(C1-C4)alkyl, mono-N - or di-N,N-(C1-C4)alkylamino(C1-C4)alkyl, (C1-CB>2- C4)alkylthio or hydroxy(C2-C4)alkylthio;

each R4attached to the N atom and Y is independently selected from: hydrogen, benzyl, phenyl, (C2-C4)alkyl, hydroxy(C2-C4)alkyl, or each of such groups as hydroxy(C2-C4)alkyl, amino(C2-C6)alkyl, (C2-C4)alkoxycarbonyl, substituted amino, halogen, hydroxy, (C2-C4)alkanoyloxy, (C1-C4)alkoxy, mono-N - or di-N,N-(C1-C4)alkylamino, mono-N - or di-N,N-(hydroxy(C2-C4)alkylamino, mono-N - or di-N,N-(C1-C4)alkoxy(C2-C4)alkyl)amino, sulfonylureas(C1-C4)alkylamino, (C1-C4)alkanolamine, imidazol-1-yl, piperidino, morpholino, piperazine-1 - yl, 4-(C1-C4)alkylpiperazine-1-yl, pyridyl, pyrrolo, imidazole, thiazole, pyridinyl, carboxy, (C1-C4)alkoxycarbonyl, carbarnoyl, mono-N - or di-N,N-(C1-C4)allylcarbamate, carboxamido, mono-N - or di-N,N-(C1-C4)alkylcarboxylic, or mono-N - or di-N,N-(C1-C4)alkyl)carboxamido;

each R5independently selected from mono-, di - or trifloromethyl, halogen, nitro, hydroxy, amino, azido, isothiocyante, (C1-C4-C6)quinil, (C1-C4)alkylenedioxy, cyano, benzoylamine, triftormetilfullerenov, (C1-C4)alkanolamine, (C1-C4)alkanoyl, mono-N - or di-N,N-(C1-C4)alkylamino,

(C1-C4)alkylsulfonyl, triftormetilfullerenov, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl or (C1-C4)alkylsulfonyl, pyrrol-1-yl, piperidine-1-yl or pyrrolidin-1-yl; these phenyl, benzyloxy, phenoxy and benzoylamine are optionally monosubstituted with halogen, nitro, trifluoromethyl, hydroxy or (C1-C4)alkyl; specified (C1-C4)alkylenedioxy connected at both ends to adjacent carbon atoms of the benzene fragment or two groups R5with the carbon atoms to which they are attached, form a group selected from imidazolyl, pyrrole and pyrazolyl;

each R6independently selected from hydroxy, amino, mono-N - or di-N,N-(C1-C4)alkylamino, sulfo or (C1-C4)alkoxy (provided that such groups are not attached to the carbon atom of the ring, which is directly adjacent to the nitrogen atom of the ring) or R6in each case independently represents carboxy, hydroxy(C1 is di-N, N-(C1-C4)alkylamino(C1-C4)alkyl, morpholino(C1-C4)alkyl, 4-(C1-C4)alkyl - piperazine-1-yl(C1-C4)alkyl, carboxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, sulfo(C1-C4)alkyl, pyridyl(C1-C4)alkyl or (C1-C4)alkyl;

m represents an integer from 1 to 3;

n represents 0, 1 or 2;

p represents 0 or an integer from 1 to 3;

provided that when Y in the direction shown by the arrow in the formula 1 represents-CR3=N-CR3=CR3-, p=0, m=1, and Z is substituted phenyl, then R5is not 4-ethoxy, 4-methoxy, 4 - triptoreline, 4-tert-bootrom or 4-isopropyl;

Q represents a 9 - or 10-membered bicyclic heteroaryl cyclic fragment or gidrirovannoe derivative containing one or two nitrogen heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen and sulphur, and can optionally carry one or two substituent selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, di-[(C1-C4)alkyl] amino, (C2-C4)alkanolamine, (C4-CR3=CR3-, R3is CH3and R4is H, then R5is not group 4-CH3, 3,5-(CH3)2, 2,6-(CH3)2, 2-C2H5, 4-n-C4H9, 2-Cl, 4-Cl, 3,4-Cl2, 2-F or 3-CF3.

Preferred compounds of formula 1 in which Y in the direction shown by the arrow in the formula 1 is selected from-NR4-CR3=CR3-, -CH=CR3-N=CH-, -CR3= CR3-NR4-;

Especially compounds 1, in which Y in the direction shown by the arrow in the formula 1 represents CR3=CR3-NR4-, a R4represents hydrogen;

Among the compounds of formula 1 should be allocated to the connection in which NR1R2is

< / BR>
and R5, R6, m and n have the meanings defined above;

in particular, in which each R5independently selected from 4-hydroxy, 4-amino, 5-fluorine, 5-hydroxy, 5-amino, 6-halogen-free, 6-methyl, 6-Attila, 6-ethinyl, 6-nitro-and 7-methyl and each R6independently selected from hydroxy, amino, mono-N - or di-N,N-(C1-C4)alkylamino, sulfo or (C1-C4)alkoxy (provided that such groups are not attached to the carbon atom of the ring, which directly adjoins the>alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino(C1-C4)alkyl, mono-N - or di-N, N-(C1-C4)alkylamino(C1-C4)alkyl, morpholino(C1-C4)alkyl, 4-(C1-C4)alkyl - piperazine-1-yl(C1-C4)alkyl, carboxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, sulfo(C1-C4)alkyl, pyridyl(C1-C4)alkyl and (C1-C4)alkyl;

Also preferred compounds of formula 1 in which R1is H, and R2is (R5)m-substituted phenyl, in which R5and m have the meanings defined above;

Especially the connection, in which each R5independently selected from 4-fluoro-3-chlorine, 3-trifloromethyl, 4-fluoro-3-trifloromethyl, 3-nitro-4-chloride, 3-nitro-4-fluorine, 4-fluoro-3-bromo, 3-iodine-5-amino, 3-methyl-4-fluorine, 4-amino, 3-fluorine, 3-hydroxy, 3-amino, 3-halogen, 3-methyl, 3-Attila, 3-ethinyl, 3-nitro and 4-methyl;

Among these compounds, one should highlight the connection in which R1is H, and R2is Q;

in particular, the compound in which Q is selected from 4-, 5-, 6-indolyl, 1H-benzimidazole-4-yl, 1H-benzimidazole-5-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-benzotri,3]thiadiazole-4-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-izochinolina, 4-, 5-, 6-, 7- or 8-indolinyl, 5-, 6-, 7 - or 8-hintline or 2-, 5 - or 6-khinoksalinona, which may optionally bear one or two substituent selected from fluorine, bromine, chlorine, methyl, ethyl, Attila, ethinyl and methoxy;

Especially, the compound in which Q is selected from 5-indolyl, 1H-indazol-5-yl, 1H-benzotriazol-5-yl, 6-benzothiazolyl, benzo[C] [2,1,3] thiadiazole-4-yl, 5-chinoline, 6-chinoline, 8-chinoline, 5-izochinolina or 5-khinoksalinona, which may optionally bear one or two substituent selected from fluorine, bromine, chlorine, methyl, ethyl, Attila, ethinyl and methoxy;

Among these compounds include compounds selected from the group consisting of the following compounds: (3-ethynylphenyl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine hydrochloride; (3-course)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydro-indol-1-yl)7H-pyrrolo[2,3-d] pyrimidine hydrochloride; (7H-pyrrolo[2,3-d]pyrimidine-4-yl)m-tolylamino hydrochloride; (1H-indol-5-yl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine hydrochloride; (6 methylindolin-1-yl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine hydrochloride; (benzo[b]Tien-5-yl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine; (6-chloro-5-floridain-1-yl)-(7H-pyrrolo[2,3-d]pyrimidine-4-hydrochlorid; (5-iodo-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-m-tolylamino; (3-chlorophenyl)-(1H-[1,2,3] triazole[4,5-d]pyrimidine-7-yl)-amine hydrochloride; (3-chlorophenyl)-pyrido[4,3-d] pyrimidine-4-yl-amine hydrochloride; (1H-indol-5-yl)-pyrido[4,3-d]pyrimidine-4-yl-amine hydrochloride; (3-ethynylphenyl)-(7 methylpyridin[4,3-d]pyrimidine-4-yl)-amine hydrochloride; (3-chlorophenyl)(7 methylpyridin[4,3-d]pyrimidine-4-yl)-amine hydrochloride; (3-ethynylphenyl)-(pyrido[4,3-d]pyrimidine-4-yl)-amine hydrochloride; (6-bromo-5-floridain-1-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (6-chloro-5-floridain-1-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (1H-indazol-5-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (benzo[b] Tien-5-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (3-methyl-4-hydroxyphenyl)(6 methylpyridin[4,3-d] pyrimidine-4-yl)-amine; (6-joindomain-1-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (benzo[b] Tien-5-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (3-ethinyl-phenyl)-(9H-purine-6-yl)-amine; (1H-indol-5-yl)-(9H-purine-6-yl)-amine hydrochloride; (3-chlorophenyl)-(9H-purine-6-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydroindol-1-yl)-pyrido[3,4-d]pyrimidine; (pyrido[3,4-d]pyrimidine-4-yl)-(m-tolyl)amine; (1H-indazol-5-yl)-(pyrido[3,4-d] pyrimidine-4-yl)-amine; (1H-indol-5-yl)-(pyrido[3,4-d] pyrimidine-4-yl)-amine; (phenyl)-(pyrido[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(pyrido[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amyl)-pyrido[3,4-d]pyrimidine; (pyrido[3,4-d] pyrimidine-4-yl)-(m-tolyl)-amine; (1H-indazol-5-yl)-pyrido[3,4-d] pyrimidine-4-yl-amine; (1H-indol-5-yl)-pyrido[3,4-d]pyrimidine-4-yl-amine; phenyl-pyrido[2,3-d]pyrimidine-4-yl-amine; 3-chlorophenyl-pyrido[2,3-d]pyrimidine-4-yl-amine; 3-chlorophenyl-pyrido[3,4-d] pyrimidine-4-yl-amine; 3-bromophenyl-pyrido[3,4-d] pyrimidine-4-yl-amine; phenyl-(pyrido[3,4-d]pyrimidine-4-yl)-amine; (7-endolsulfan-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethynylphenyl)-amine; 4-(6-chloro-2,3-dihydroindol-1-yl)-5H-pyrrolo[3,2-d] pyrimidine-6-ol; (3-ethynylphenyl)-[7-(2-morpholine-4-yl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine - 4-yl)] -amine; (3-ethynylphenyl)-[7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine - 4-yl)] -amine; (3-ethynylphenyl)-{7-[2-(2-methoxyethoxy)-ethyl]-7H - pyrrolo[2,3-d]pyrimidine-4-yl} -amine; (7-arylpyrrolo[2,3-d]pyrimidine - 4-yl)-(3-ethynylphenyl)-amine hydrochloride; (3-ethynylphenyl)-(7-methylpyrrole[2,3-d]pyrimidine-4-yl)-amine hydrochloride; (5-bromo-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(5-iodine-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d] pyrimidine-5-carboxylic acid; (3-ethynylphenyl)-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine hydrochloride; N-(5-iodine-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-N-m-tolylacetic; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester hydrochloride; (1H-indazol-5-yl)-(6 is drochloric; (3-ethinyl-4-forfinal)-(6 methylpyridin[3,4-d]pyrimidine-4-yl)-amine; 2-methyl-4-(6-methylpyridin[3,4-d] pyrimidine-4-ylamino)-phenol dihydrochloride; 4-(4-bromo-7-methyl-2,3 - dihydroindol-1-yl)-6-methylpyridin[3,4-d]pyrimidine hydrochloride; 4-(6-bromo-7-methyl-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine hydrochloride; 4-(6-bromo-5-fluoro-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine hydrochloride; (3-chloro-4-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; (6 methylpyridin[3,4-d] pyrimidine - 4-yl)-(3-trifluoromethyl-phenyl)-amine hydrochloride; (4-fluoro-3-were)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; 2-iodine-4-(6-methylpyridin[3,4-d] pyrimidine-4-ylamino)-phenol hydrochloride; (4-bromo-3-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; 4-(6,7-dimethyl-2,3-dihydroindol-1-yl)-pyrido[3,4-d] pyrimidine hydrochloride; (3-ethynylphenyl)-pyrido[3,4-d] pyrimidine-4-yl-amine hydrochloride; benzo[b]thiophene-5-yl-pyrido[3,4-d] pyrimidine-4-yl)-amine hydrochloride; (3-ethynylphenyl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine; (3-ethynylphenyl)-(5-methylsulfanyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d] pyrimidine-5-yl-carbonitrile; (1H-indol-5-yl)-(6 methylpyridin[3,4-d]pyrimidine-4-yl-amine metasul-5-yl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine - 5-carbonitrile; (1H-indol-5-yl)-pyrido[3,4-d] pyrimidine-4-yl-amine; (3-chloro-4-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; benzo[b]thiophene-5-yl(6-methylpyridin[3,4-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-pyrido[3,4-d]pyrimidine-4-yl-amine; (4-fluoro-3-were)-(6 methylpyridin[3,4-d]pyrimidine-4-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydroindol-1-yl)-pyrido[3,4-d]the pyrimidine (pyrido[3,4-d]pyrimidine-4-yl)-(m-tolyl)amine; (6-methylpyridin[3,4-d]pyrimidine - 4-yl)-(3-triptoreline)-amine hydrochloride; (1H-indazol-5-yl)-(6 methylpyridin[3,4-d]pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(5-methylsulfanyl - 7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (1H-indol-5-yl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (5-bromo-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3 - ethynylphenyl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d]pyrimidine - 5-yl-carbonitrile.

The invention also provides compounds of formula

< / BR>
in which W in the direction of the arrows, is selected from =CHC(CH3 According to another aspect of the invention provides the compound as described above, in which W represents-CH= C(CH3)-N=CH-.

Another aspect of the invention provides a compound as described above, in which W represents-CH2=N-C(CH3)=CH-.

Another aspect of the invention provides a compound as described above, in which W is =C(CH3)-NH-CH=.

This invention also provides a method of treating hyperproliferative disorders, which includes the purpose for admission to a mammal in need of such treatment of hyperproliferative disorders, the number of the compounds of formula 1 are effective for treatment.

According to another aspect of the invention is the method described above, in which the hyperproliferative disease is cancer.

Another aspect of the invention provides the method described above, wherein the disease is cancer of the brain, lung, squamous cell, bladder, gastric, pancreatic cancer, liver cancer, kidney, colon, breast, head, neck, oesophageal, gynecological cancer, or thyroid cancer.

Another aspect of the invention provides a method, described above, in which the hyperproliferative disorder or destroy what about, as described above, in which non-cancer proliferative infringement is psoriasis or benign prostatic hyperplasia.

The invention further provides a pharmaceutical composition for treating hyperproliferative disorders in mammals, which comprises the compound of formula 1 in an amount effective for the treatment of hyperproliferative disease, and a pharmaceutically acceptable carrier.

In this application some of the terms used are defined as follows:

The term halogen refers to chlorine, bromine, iodine or fluorine.

Alkyl means hydrocarbon group with a straight chain, or when the number of carbon atoms is 3 or higher, cyclic or branched hydrocarbon group, optionally unsaturated.

Used herein, the expression "reaction inert solvent" refers to a solvent which does not react with the starting materials, reagents, intermediate compounds or products in any way that adversely affects the yield of the desired product.

Other characteristics and advantages of the invention evident from the description and claims, which accounted for the almost acceptable salts and prodrugs can be obtained using any known method, which can be used to obtain chemically related compounds.

As shown in the diagram (see the end of the text), the compounds of formula 1 can usually be obtained from 4-chloro or hydroxy derivatives appropriately substituted condensed with heteroaryl pyrimidines 1, using the appropriate substituted amine ZH2.

In a typical case, the pyrimidine 1 condensed with an appropriately substituted 4-galinhatrololo (or pyrimidine, condensed with heteroaryl carrying a suitable substitutable leaving group at the 4-position, such as aryloxy, alkyl-sulfonyloxy, such as tripterocalyx, arylsulfonate, siloxy, cyano, pyrazolo, triazolo or tetrazole), preferably galinhatrololo, such as 4-chlorotriazine derived, is subjected to reaction with an appropriate amine 2 in a solvent such as (1-6)C-alcohol, dimethylformamide (DMF), N-methylpyrrolidine-2-he, chloroform, acetonitrile, tetrahydrofuran (THF), dimethylsulfoxide (DMSO) 1,4-dioxane, pyridine or other aprotic solvent. The reaction mix or joining can be carried out in the presence of a base, preferably a carbonate or hydroxide of shelo the one, N-methyl-morpholine, triethylamine, diethylethanolamine, 4-dimethylamino-pyridine or N,N-dimethylaniline. These grounds are called hereafter "proper grounds". The mixture is maintained at a temperature from ambient temperature to the temperature of reflux distilled, preferably from about 35oC to the temperature of reflux distilled, up until essentially will not be able to detect the remaining condensed with 4-galinhatrololo pyrimidine, typically from about 2 hours to 72 hours. The reaction is preferably conducted in an inert atmosphere such as nitrogen gas. In the case of pyrrolopyrimidine reaction preferably takes place in methanol at a temperature of about 90-140oC in a sealed tube in the absence of additional grounds.

Typically, the reactants are combined in stoichiometric amount, when used with a suitable amine base, though, for those compounds for which use salt (usually HCl salt) amine, it is preferable to use an excess of amine 2, typically an additional equivalent of amine 2. Alternatively, if the amine base is not used, can be used an excess of amine reactant.

For those compounds, if it is actiondisplay condensed with 4-galinhatrololo pyrimidine, preferably tert-butyl alcohol or a polar aprotic solvent, such as dimethylformamide or N-methylpyrrolidine-2-he, as a solvent.

Other compounds of formula 1 can be obtained using the following reactions after the above combinations.

The compounds of formula 1 in which R3or R5represents a primary amino or hydroxyamino can be obtained by restoring the compounds of formula 1 in which R3or R5is the nitro group.

Recovery may conveniently be carried out using any of the many procedures known for such a transformation. The recovery may, for example, be carried out by hydrogenation of a solution of the nitro compound in a reaction inert solvent in the presence of a suitable metal catalyst, such as palladium or platinum. Additional suitable regenerating agent is, for example, activated metal, such as activated iron (obtained by using iron powder diluted aqueous acid, such as hydrochloric acid). For example, the recovery may be carried out by heating a mixture of the nitro joint the temperature in the interval, for example, 50-150oC generally equal to or close to the 70oC temperature.

To obtain compounds of formula 1 in which R5or R6includes primary or secondary amino fragment (other than the amino group is intended for reaction with hinazolinam), the free amine is preferably protected prior to the above reaction with a subsequent removal of the protection after the above reaction with 4-galoidkyetonov.

As for descriptions of protective groups and their use, see the work of T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis" second edition, John Willy & sons, new York, 1991.

The protective group of nitrogen are well known in the art and include (1-6) C-alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxyalkyl, trityl, vinyloxycarbonyl, O-nitrophenyloctyl, diphenylphosphinyl, p-toluensulfonyl and benzyl. Adding a protective group of the nitrogen can be carried out in a chlorinated hydrocarbon solvent such as methylene chloride or 1,2-dichlo-chlorate, or in an ether solvent, such as diglyme, glyme or THF, in the presence or absence of a tertiary amine base, such as triethylamine, diisopropylethylamine IO at about ambient temperature. Alternatively, the protective group of the easy way join using the conditions of the Schotten's-Baumann.

After the reaction described above attach amine protective group may be removed using methods of release known to experts in the art, such as using triperoxonane acid in methylene chloride, to secure tert-butoxycarbonyl products.

The compounds of formula 1 in which R3is hydroxy, can preferably be obtained by splitting the compounds of formula 1 in which R3is (1-4)C-alkoxy.

The cleavage reaction may conveniently be carried out using any of the many procedures known for such a transformation. For reactions of O-dealkylation can be processed condensed with heteroaryl pyrimidine derivative of formula 1 with molten pyridine hydrochloride (20-30 EQ. ). Alternatively, the reaction may be carried out, for example, by processing condensed with heteroaryl pyrimidine derivative (1-4)C-alkylsulfides alkali metal, such as attentional sodium, or, for example, by processing diarylphosphino alkali metal, that is, by processing condensed with heteroaryl pyrimidine derivative with trihalogen boron or aluminum, such as trichromacy Bor. Such reactions are preferably carried out in the presence of a reaction inert solvent and at a suitable temperature.

To obtain compounds of formula 1 in which R3is (1-4)C-alkylsulfonyl or (1-4)C-alkylsulfonyl group, preferred oxidation of compounds of formula 1 in which R3is (1-4)C-alkylthio group.

Suitable oxidising agent is, for example, an agent that is known in the art for the oxidation of thio in sulfinil and/or sulfonyl, for example, hydrogen peroxide, nakilat (such as 3-chlorodeoxyadenosine acid or peroxidasa acid), peroxosulfates alkali metal (such as peroxymonosulfate potassium, chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is usually carried out in mild conditions and with the required stoichiometric amount of oxidizing agent in order to reduce the risk of over-oxidation and damage to other functional groups. Usually the reaction is carried out in a suitable solvent, such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature of, for example, -25 oC 50oC, convenient obsidiana, support sulfonyloxy group, can be used more mild oxidizing agent, for example, metaperiodate sodium or potassium hydroxide, conveniently in a polar solvent such as acetic acid or ethanol. Obviously it is clear that when you want the connection formula 1, containing (1-4)C-alkylsulfonyl) group, it can be obtained by oxidation of the corresponding (1-4)C-alkylsulfonyl compounds, as well as the corresponding (1-4)C-alkylthio connection.

To obtain those compounds of formula 1 in which R3- (2-4)C-alkanolamine, or substituted (2-4)C-alkanolamine, ureido, 3 phenylurea, benzamido or sulphonamido, is appropriate acylation or sulfonylamine the compounds of formula 1 in which R3represents amino.

Suitable allermuir agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example, allalone (for example, (2-4)C-alcoholclone or chloride, or benzoyl chloride or bromide), anhydride alanovoy acid or a mixed anhydride (for example, (2-4)C-alkalophilicity anhydride such as acetic anhydride or mixed anhydride formed by the reaction alanovoy acid and (1-4)C-alkoxycarbonylmethyl, n is 1, in which R1is ureido or 3-phenylurea suitable allermuir agent is, for example, cyanate, for example, alkali metal cyanate such as sodium cyanate, or for example, isocyanate, such as phenylisocyanate. Reaction of N-sulfonylurea can be carried out using suitable sulphonylchloride or sulfanilamide, in the presence of a tertiary amine base. Typically, the acylation or sulfonylurea is carried out in a reaction inert solvent at a temperature in the range of, for example, from -30 to 120oC, conveniently at a temperature close to or equal to the ambient temperature.

To obtain compounds of formula 1 in which R3is (1-4)alkoxy or substituted (1-4)alkoxy; or R1is (1-4)C-alkylamino or substituted mono-N - or di-N,N-(1-4)C-alkylamino, preferred alkylation, preferably in the presence of a suitable base, the compounds of formula 1 in which R1represents hydroxy or amino, as it corresponds.

A suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation hell or substituted (1-4)C-alkylchloride, bromide or iodide, in the presence of a suitable base in a reaction inert solvent at a temperature in the range of, for example, from 10 to 140oC, conveniently at a temperature close to or equal to the ambient temperature.

To obtain those compounds of formula 1 in which R3represents amino, hydroxy or cyano-substituted (1-4)C-alkyl substituent is the reaction of the corresponding compounds of formula 1 in which R3is (1-4)C-alkyl substituent bearing the substituted group with an appropriate amine, alcohol or cyanide, as it corresponds, preferably, in the presence of a suitable base.

The reaction preferably is carried out in a reaction inert solvent or diluent and at a temperature in the range of, for example 10-100oC, conveniently at a close or equal to the ambient temperature.

To obtain compounds of formula 1 in which R3, R5or R6represents carboxy Deputy or Deputy, which includes a carboxy group, the desired hydrolysis of the compounds of formula 1 in which R3, R5, R6is (1-4)C-alkoxycarbonyl replacement to be carried out, for example, in basic conditions, such as hydrolysis, carried out using a hydroxide of an alkali metal, as illustrated in the accompanying examples.

To obtain compounds of formula 1 in which R3represents amino, (1-4)C-alkylamino, di-((1-4)C-alkyl) amino, pyrrolidin-1-yl, piperidino, morpholino, piperazine-1-yl, 4-(1-4)C-alkylpiperazine-1-yl or (1-4)C-alkylthio, preferred reaction of compounds of formula 1 in which R3the substituted group with an appropriate amine or thiol, conveniently in the presence of a suitable base.

The reaction preferably is carried out in a reaction inert solvent or diluent and at a temperature in the range of, for example, 10-180oC, conveniently in the range of 100-150oC.

To obtain compounds of formula 1 in which R3is 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl, convenient is the cyclization in the presence of a suitable base, the compounds of formula 1 in which R3- halogen-(2-4)C-alkanolamine group.

The reaction preferably is carried out in a reaction inert solvent or diluent, at a temperature in the range of, for example, from 10 to 100oC, conveniently at equal - carbarnoyl, substituted carbarnoyl, alkanoyloxy or substituted, alkanoyloxy, comfortable is carbamylcholine or acylation of compounds of formula 1 in which R3represents hydroxy.

Suitable allerease agents are, for example, any agent known in the art for acylation hydroxyaryl fragments in alkanoyloxy. For example, can be used (2-4)C-alkanolamine, (2-4)C-alkanolamide or mixed anhydrides, and suitable substituted derivatives, typically in the presence of a suitable base. Alternatively, (2-4)C-alcamovia acid or an appropriately substituted derivative can be combined with compounds of formula 1 in which R3represents hydroxy, using a condensing agent such as carbodiimide. To obtain compounds of formula 1 in which R3-carbarnoyl or substituted carbarnoyl, suitable carbamoyloximes agents are, for example, cyanate or alkyl - or aryl-isocyanate, typically in the presence of a suitable base. Alternatively, a suitable intermediate connection, such as chloroformic or imidazoledicarbonitrile derivative condensed with heteroaryl pyrimidine forms izvorovo with phosgene (or the equivalent of phosgene or carbonyl diimidazol. The resulting intermediate compound can then be subjected to reaction with an appropriate amine or substituted amine to obtain the desired carbamoyl derivatives.

To obtain condensed with heteroaryl pyrimidine derivatives of formula 1 in which R3- aminocarbonyl or substituted aminocarbonyl is preferred aminals appropriate intermediate compounds produced from condensed with heteroaryl-condensed pyrimidine of formula 1 in which R3represents carboxy.

Activating or combination of compounds of formula 1 in which R3is carboxy, may be conducted using a variety of methods known to experts in this field. Suitable methods include activating carboxyl, such as galoyanized acid, acid azide, or a symmetrical or mixed anhydride or active ester of the appropriate reactivity, for combination with the desired amine. Examples of such types of intermediate compounds and their receipt and use of the addition reactions of with amines, can be found widely in the literature; for example, in the work of M. Bodansky and A. Bodansky, "The Practice of Peptide is sterile and purified using standard methods, such as the removal of solvent and recrystallization or chromatography, if necessary.

Optionally substituted indoles and indoline, useful for carrying out the invention, and methods for their preparation are described in conjunction pending application U.S. N 08/200359 provided here for information. In addition to the methods described there, getting different indolines, indoles, oxindoles and satinov, useful as intermediate compounds are additionally described in the publication "Heterocyclic Compounds with Indole and Carbazole Systems. W. C. Sumpter and F. M Miller, in volume 8 of the series "the Chemistry of Heterocyclic Compounds", Interscience Publishers Inc., New York, 1954, and the references given there.

Substituted anilines, useful in a practical embodiment of the invention and methods for their preparation are described in conjunction pending application U.S. 08413300 and international application N PCT/IB95/00436 here for details.

The compounds of formula ZH, where ZH is the QNH2used in a practical embodiment of the invention, and methods for their preparation are described in European patent application N EP 0496617 A1, is shown here for information.

Some compounds of formula 1 can exist in solvated that the e invention encompasses all such solvated, and nonsolvated forms, which have activity against hyperproliferative diseases.

Suitable pharmaceutically acceptable salts of condensed with heteroaryl pyrimidine derivatives of this invention are, for example, an acid additive salt condensed with heteroaryl pyrimidine derivatives of the invention which is sufficiently basic (alkaline), for example, an acid additive salt, for example, with inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, methanesulfonic, benzosulfimide, triperoxonane, citric, lactic or maleic acid. In addition a suitable pharmaceutically acceptable additive salts of the base of the pyrimidine derivatives of the invention, condensed with heteroaryl that are sufficiently acid are alkali metal salts, e.g. lithium, sodium or potassium salt; salts of alkaline-earth metals, e.g. calcium or magnesium salt; ammonium salts; or salts with organic bases, which give a pharmaceutically acceptable cation, for example, a salt with methylamine, dimethylamine, trim the th of the invention, and they can be obtained using conventional methods. For example, they can be obtained simply by bringing into contact of the acid and base fragments, usually in a stoichiometric ratio, or in aqueous, non-aqueous or partially aqueous medium, as appropriate. Salt allocated or using filtration, or precipitation with aristotelem, preferably ether or hydrocarbon solvent, followed by filtration or by evaporation of the solvent, or in the case of aqueous solutions, by lyophilization.

Some of the compounds of formula 1 have asymmetric carbon atoms. Such diastereomer mixture can be separated into the individual diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture through the reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure inationary. All such isomers, including diastereomers and enantiomerically oncogenic and protooncogene the protein tyrosinekinase family erb, such as the receptor for the epidermal growth factor (EGFR), erbB2, HER3or HER4and thus all may find therapeutic use as protivoprolezhnevyh agents (e.g., anticancer) for mammals, in particular humans. In particular, the compounds of this invention are therapeutic or prophylactic agents for the treatment of various human cancers (renal, liver, kidneys, bladder, breast, stomach, ovarian, colon, prostate, pancreatic tumors (pancreatic cancer), lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, various head and neck tumors), and other hyperplastic conditions such as benign hyperplasia of the skin (e.g. psoriasis) or prostate (e.g., BPH). In addition, it is expected that heteroarylboronic pyrimidines of the present invention may have activity against a number of leukemias and lymphoid malignancies.

You can also expect that the compounds of formula 1 may be useful in the treatment of additional disorders in which involved aberrant expression of ligand-receptor interactions, activating or Torah inhibited by the compounds of formula 1.

Such violations can include violations of neuronal, glial, astrocytic, hypothalamic nature and other glandulars, makropoulou, epithelial, stromal and blastoconidia nature, which may be involved aberrant function, expression, activation or signaling tyrosine kinase. In addition to the above compounds of formula 1 may have therapeutic utility in inflammatory, angiogenic and immunologic disorders, which involved, as identified, and yet unidentified tyrosine kinase that is inhibited by compounds of formula 1.

Activity in vitro of these compounds in the inhibition of the receptor tyrosinekinase (and thus subsequent proliferative response, such as cancer) can be determined using the procedure described in detail below. The activity of the compounds of formula 1 in vitro can be determined by the degree of inhibition of the phosphorylation of exogenous substrate (e.g., Lys3- Gastrin or poly GluTyr (4:1) random copolymer (1. Posner and others, J. Biol. Chem. 267 (29), 20638-47 (1992)), at tyrosine under the influence receptor kinase of epidermal growth factor with the test compound relative to EOI, described in G. N. Gill, W. Weber, Methods in Enzymology 146, 82-88 (1987) from A431 cells (American culture collections, Roxie, MD) and was pre-incubated in microcentrifuge with EGF (2 μg/ml) in a mixture of buffer phosphorylation + Vanadate (PBV : 50 mm HEPES, pH 7.4; 125 mm NaCl; 24 mm MgCl2; 100 μm orthovanadate sodium), in a total volume of 10 ál, for 20-30 minutes at room temperature. The test compound dissolved in dimethyl sulfoxide (DMSO), diluted in PBV, and 10 μl mixed with a mixture of EGF receptor/EGF and incubated for 10-30 minutes at 30oC. the phosphorylation Reaction is initiated by adding 20 ál of a mixture of33P-ATP/substrate (120 μm Lys3-Gastrin (the amino acid sequence indicated by a letter code, KKKGPWLEEEEEAYGWLDF), and 50 mm Hepes pH 7.5, 40 μm ATP, 2 MK Ci V-[33P]-ATP) to a mixture of EGFr/EGF and incubated for 20 minutes at room temperature. The reaction is stopped by adding 10 μl of stop solution (0.5 M EDTA, pH 8; 2 mm ATP) and 6 ál 2 standards. HCl. Tube centrifugeuse at 1400 turnover. in minutes 4oC, for 10 minutes. 35 μl of the supernatant in each tube is withdrawn by pipette 2.5 cm circle paper Whatman P81, washed four times with 5% acetic acid, 1 liter of wash, and then dried in air. This results in liquid scintillation counting. Introduction in the absence of substrate (for example, lyys3-gastrin) is subtracted from all values as the basis, and the percentage of inhibition is calculated compared to the control, in which case the test compound is not present.

Such analyses carried out in the range of doses of the test compounds, allow to determine the approximate IC50the magnitude of inhibition in vitro activity of EGFR kinase. Although inhibiting properties of the compounds of formula 1 vary with structural change as expected, in General, the activity shown by these agents determined in the manner described above, is in the interval IC50=0.0001-30 ám.

The activity of the compounds of formula 1 in vitro can be determined by the degree of inhibition of tumor growth with the test compound relative to the control. Inhibitory effect of various compounds on tumor growth is measured in accordance with the methods of the authors T. H. Corbett and other "Tumor Induction Relationship in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure, Cancer Res. , 35, 2434-2439 (1975) and T. H. Corbett and others, "A Mouse Colon-tumor Model for Experimental Therapy", Cancer Chemother. Pep. (Part 2)" 5, 169-186 (1975), with minor modifications. Tumors are induced in lady man MOA-MB-468 or head and neck of a person HN5), suspended in 0.10 ml of RPM1 1640. After passage of a sufficient period of time to tumor became palpable (2-3 mm in diameter), the test animals (atipicheskie mouse) were subjected to treatment with the compound (prepared in the preparative form by dissolving in DMSO typically at a concentration of 50-100 mg/ml and then 1:9 dilution in 0.1% Pluronic P105 in 0.9% saline) intraperitoneally (IP) or oral (po) methods by introducing twice daily (i.e., every 12 hours) for 5 to 20 consecutive days. In order to determine the anti-tumor effect, the tumor is measured in mm using Vernier calipers in two diameters, and the tumor size (mg) (i.e., the weight of the tumor TuW) is calculated using the formula: tumor Weight = (length [width]2)/2, in accordance with the methods Geran, R. I., and other Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and other Biological Systems. The third edition of Cancer Chemother. The results are expressed as percent inhibition using the formula: Inhibition (%) = (TuWcontrol- TuWispytav.)/TuWcontrol100%. The site of implantation of the tumor in the side gives reproducible effects dose/response to various chemotherapeutic agents, and the method of measurement (Diamanti of the present invention can be made to accept by any method, which enables delivery of the compounds to the site of action (e.g., cancer cells). These methods include oral route, intraduodenal routes of administration, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical or local purpose and so on.

Assigned number heteroaryl-condensed pyrimidine derivative will, of course depend on the subject being treated, on the severity of the disease, method of appointment and the experience and knowledge of the prescribing physician. However, an effective dosage is in the range of approximately 0.1-100 mg/kg, preferably from 1 to 35 mg/kg in single or divided doses. For a person of average weight of 70 kg, this number will amount to 0.05 to 7 g/day, preferably from 0.2 to 2.5 g/day.

The composition may be, for example, in the form suitable for oral assignments in the form of tablets, capsules, pills, powders, preparative forms with delayed release of active agent, in the form of solutions, suspensions, parenterally injection is a sterile solution, suspension or emulsion, for topical purposes in the form of ointment or cream, or on the ü in the form of a unit dose, suitable for a single reception in the prescribed dosages. The pharmaceutical compositions will include a conventional pharmaceutical carrier or excipient and the connection according to the invention as an active ingredient. In addition, they may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

The pharmaceutical composition according to the invention may contain 0.1 to 95% of the compound, preferably 1-70%. In any event, the composition or formulation form, intended for the introduction, contains a compound according to the invention in an amount effective to alleviate or reduce the symptoms of the subject being treated, i.e., proliferative diseases, in the course of treatment.

Examples of parenteral products include solutions or suspensions of the compounds according to the invention of formula 1 in sterile aqueous solutions, for example, used aqueous solutions of propylene glycol or dextrose. Such dosage forms can be suitably buffered, if necessary.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. These are the pharmacist who desirous supplements binders, excipients and similar. Thus for oral administration, tablets containing various excipients such as citric acid, can be used together with various dezinfeciruyuhimi agents such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and gum acacia. Additionally, for the purposes of tabletting often are useful lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be applied in the form of a filled soft or hard gelatin capsules. Preferred materials therefore include lactose or milk sugar and glycols of high molecular weight. When oral administration is desirable aqueous suspensions or elixirs, essential active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspendresume agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Methods of obtaining various pharmaceutical composition is. the for example, see the publication Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, PA., 15th edition (1975).

Anticancer treatment, described above, can be applied as a sole therapy or may involve, in addition to heteroaryl-condensed pyrimidine derivative of this invention with one or more other anti-cancer substances. Such joint treatment can be achieved by simultaneous, sequential, cyclic or separate dosing of the individual components of treatment.

It should be clear that the invention is not limited to the specific embodiments shown and described herein, and may employ various changes and modifications without deviating from the essence and scope of this new concept of the invention defined in the following claims.

Example 1. Hydrochloride (3-ethinyl-phenyl)-(7H-pyrrolo[2,3-d]pyrimidine - 4-yl)-amine.

To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0,065 mol) in dry pyridine (90 ml) was added m-aminophenylacetylene (9.2 g, 0,078 mol) and the mixture was heated on an oil bath with a temperature of 85oC for 2 days. The reaction mixture was cooled to ambient temperature and contains) using 5% methanol/methylene chloride, giving the target compound in the form of a pink-orange solid (1.9 g, 12%). HRMS (mass range, high resolution). Calculated 235.0984 found 235.1000; anal. RP18-HPLC retention time: (RT) 3.48 min

The above compound was dissolved in minimum quantity of methanol, was added dropwise a solution of HCl in ethyl ether (HCl, barbotirovany in 2 ml of ethyl ether until then, until the mixture became turbid. Precipitated precipitated HCl salt was dried in vacuum were washed once with ethyl ether, and dried in vacuum to constant weight. So pl.: 196-198oC.

Example 2. (3-Chloro-phenyl)-(7-pyrrolo[2,3-d]pyrimidine-4-yl)-amine.

Following the procedure described in example 1 was obtained target compound from 4-chloro-7H-pyrrolo[2,3-d] pyrimidine and 3-Chloroaniline (3.4 %). LS-MS : 245 (MH+); the analysis. RP-18 HPLC RT: 3.74 min; HCl salt so pl.: 227-228oC.

Example 3. The hydrochloride of 4-(6-chloro-2,3-dihydro-indol-1-yl)-7H - pyrrolo[2,3-d]pyrimidine.

In accordance with the procedure described in example 1, a target compound was obtained from 4-chloro-7H-pyrrolo[2,3-d] pyrimidine and 6-chloro-2,3-dihydroindol-1-yl (4.3%). HRMS: Calculated 271.0750 found: 271.0729; Anil. RP18-HPLC RT: 4.88 min, HCl salt so pl. 266oC (decomp.).

Example 4. Hydrochloride (7H-pyrrolo[2,3 tion was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and t-toluidine (34%). HRMS: Calculated: 225.1140 Found: 225.1131; anal. RP18-HPLC RT: 3,45 minutes; HCl salt so pl.: 219oC.

Example 5. Hydrochloride (1H-indol-5-yl)-(7H-pyrrolo[2,3-d]pyrimidine - 4-yl)-amine.

The target compound was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5-aminoindole (7%) according to the procedure described in example 1. HRMC: Calculated: 250.1093 Found: 250.1081; anal. RP18-HPLC RT: 2,58 minutes; HCl salt so pl.: 218 to 221oC.

Example 6. (Phenyl)-(7-pyrrolo[2,3-d]pyrimidine-4-yl)-amine.

Using a procedure analogous to the procedure described in example 1, this product was obtained with a yield of 16% from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 EQ. ) and aniline (5.0 equiv.) in the pyrimidine. (So pl. 234-236oC; GC-MS 211 (MH+); anal. RP18-HPLC RT: 3.11 min).

Compounds of examples 7-10 were obtained in accordance with the method of example 1 from the appropriate starting materials (see end of text).

Example 11. Hydrochloride of 1-(4-m-Tolylamino)-1-(pyrrolo[2,3-d] pyrimidine - 7-yl)-ethanone.

To (3-methyl-phenyl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine (example 4) (0.168 g, 0.75 mmole), dissolved in hot acetonitrile (7 ml), was added sodium hydride (36 mg, of 0.90 mmole, 60% dispersion in mineral oil). After stirring at ambient temperature in the course who were enterovirus in vacuum, were pulverized in hot ethyl acetate and filtered. The filtrate was concentrated in vacuo, giving an orange solid residue. The solid substance was pulverized in methylene chloride and filtered, giving the target compound as a pale yellow solid (0.11 g, 55%). LC-MS: 267 (MH+); anal. RP18-HPLC RT: 3.53 min

Example 12. 5 - Iodine-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(m-tolyl)-amine.

To 1-(4-tolylamino-pyrrolo[2,3-d] pyrimidine-7-yl)-ethanone (113 mg, 0.42 mmole) in dry methanol (4 ml) and methylene chloride (1 ml) was added sodium carbonate (45 mg, 0.42 mmole). After stirring at ambient temperature for 0.75 hour was added N-iodosuccinimide (190 mg, 0.85 mmole) and stirring continued for 48 hours. The mixture was concentrated in vacuo and was distributed between methylene chloride and water. The organic phase was washed twice with water, dried over sodium sulfate and concentrated in vacuum. The resulting residue was purified using flash chromatography on silica gel (7 g, 40 µm mesh) using 2% methanol/methylene chloride, giving the target compound in the form of olive needles (6 mg, 4%. LC-MS: 351 (MH+); anal. RP18-HPLC RT: min).

Example 13. Hydrochloride (3-chloro-phenyl)-(1H-[1,2,3]triazolo[4,5-d] pyrimidine-7-yl)-amine.

Example 14. Hydrochloride (3-chloro-phenyl)-(pyrido[4,3-d]pyrimidine-4-yl)-amine.

To 4-hydroxy-pyrido[4,3-d] pyrimidine (0.13 g, 0.90 mmole) in phosphorus oxychloride (2 ml) was added dry pyridine (0.15 ml, 1.8 mmole). Adding the condenser and CaCl2drying tube, and the suspension was heated under reflux (under conditions of reflux distilled) for 3 hours. The final clear solution was concentrated in vacuum (CaCl2drying tube) with the subsequent transmission of toluene. The resulting 4-chloro-pyrido[4,3-d]pyrimidine was dissolved in dry pyridine (1.5 ml). Was added 3-Chloroaniline (0,096 ml, 0.90 mmole), and see what s environmental and concentrated in vacuum. The oily residue was distributed between methylene chloride and water, filtered, and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated in vacuum. The resulting residue was purified using flash chromatography on silica gel (5 g, 40 µm mesh) using a mixture of 5% methanol/methylene chloride, giving the target compound in the form of not-quite-white solid (3 mg, 1.3%). LC-MS 257 (MH+); anal. RP18-HPLC RT: 3.85 min

Example 15. Hydrochloride (1H-indol-5-yl)-(pyrido[4,3-d]pyrimidine - 4-yl)-amine.

To a suspension of 4-hydroxy-pyrido[4,3-d]pyrimidine (0.103 g, 0,70 mmole) in dry pyridine (2 ml), cooled in an ice-water bath was added dropwise triperoxonane anhydride (0.20 ml, 1.4 mmole). After stirring for 0.5 hours was added dropwise a solution of 5-aminoindole (0,204 g, 1.5 mmole) in dry dimethylformamide (DMF) (1.5 ml). The cold bath was left to be heated up to ambient temperature and stirring continued for 24 hours. The mixture was concentrated in vacuo and was distributed between methylene chloride and water. The aqueous phase was extracted with methylene chloride, and the combined organic phases were washed with water, dried over Sul is likehere (11 g, 40 µm mesh) using a mixture of 5% methanol/methylene chloride giving the target compound as an orange solid (37 mg, 20%) LC-MS: 262 (MH+); anal. RP18-HPLC RT: 2.02 min

Example 16. Hydrochloride (3-Ethynylphenyl)-(7-methyl-pyrido[4,3-d]pyrimidine - 4-yl)-amine.

Using a procedure analogous to the procedure described in example 15, the product was obtained with a yield of 28% of 4-hydroxy-7-methyl-pyrido[4,3-d]pyrimidine (1.0 EQ.) and m-aminophenylacetylene (40.0 equiv.) in pyridine. HCl salt was obtained from purified free base according to the procedure described in example 1. (So pl. 240-241oC; GC-MS: 261 (MH+); anal. RP18-HPLC RT: 3.73 min).

Example 17. Hydrochloride (3-chloro-phenyl)-(7-methyl-pyrido[4,3-d]pyrimidine - 4-yl)-amine.

Using a procedure analogous to the procedure described in example 16, the product was obtained with a yield of 34% of 4-hydroxy-7-methyl-pyrido[4,3-d] pyrimidine (1.0 EQ.) and m-Chloroaniline (40.0 equiv.) in pyridine. HCl salt was obtained from purified free base in accordance with the procedure given in example 1. (So pl. 255-256oC; GC-MS: 270 (MH+); anal. RP18-HPLC RT: 4.05 minutes).

Example 18. Hydrochloride (3-ethinyl-phenyl)-(pyrido[4,3-d]pyrimidine - 4-yl)-amine.

In sootvetstvenno.lechenie (5%) LC-MS: 247 (MH+); anal RP18-HPLC RT: 3.41 min

The compounds of examples 19 to 24 were obtained according to the method of example 15 from the corresponding starting materials (see end of text).

Example 25. (3-Ethinyl-phenyl)-(9H-purine-6-yl)-amine.

For the 6-chloropurine (1.0 g, 6.5 mmol) in dry pyridine (10 ml) was added m-aminophenylacetylene (0.91 g, 7.8 mmole). The mixture was heated on an oil bath with a temperature of 85oC for 23 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The oily residue was distributed between methylene chloride and water, then filtered, giving the target compound as a pale orange solid (50 mg, 3.3%). LC-MS: 236 (MH1); anal. RP18-HPLC RT: 3.25 min

Example 26. Hydrochloride (1H-indol-5-yl)(9H-purine-6-yl)-amine.

In accordance with the procedure described in example 9, the target compound was obtained from 6-chloropurine and 5-aminoindole (70%). TS-MS: 251 (MH+); anal. RP18-HPLC RT: 2.44 min

Example 27. Hydrochloride (3-chloro-phenyl)-(9H-purine-6-yl)-amine.

Following the procedure described in example 1, a target compound was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 3-Chloroaniline (3.4%). LC-MS:BP: 245 (MH+); anal. RP18-HPLC RT: 3.74 min; HCl salt so pl.: 227-228oC.

the à La carte), 6-chloroindole (0.10 g, 0.66 mmole) and pyridine (0.14 g, is 1.81 mmole) were combined in DMF (1 ml) and was heated at 70oC for 3 hours. The reaction mixture was cooled to room temperature, and then was added to methylene chloride (150 ml). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified using chromatography on a column (silica gel, 9:2:1 methylene chloride: hexane: methanol) to give a pale yellow residue (0.048 g, 28%). So pl. 194-6oC; LCMS 283 (MH+).

The products of examples 29-31 were obtained in accordance with the method of example 1 from 4-chloropyrid[3,4-d]pyrimidine (1 EQ.) and the specified amine.

Example 29. (Pyrido[3,4-d]pyrimidine-4-yl)-(m-tolyl)-amine.

This product was obtained with a yield of 44% of m-anisidine (1.1 EQ.). So pl. 172oC; LC-MS 237 (MH+).

Example 30. (1H-Indazol-5-yl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 96% of 5-aminoindazole (1.1 EQ.). So pl. 258oC; LC-MS: 263 (MH+).

Example 31. (1H-Indol-5-yl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 15% from 5-aminoindole (1.1 EQ.) and 4 chloropyrid[3,4-d]Piri is ASS="ptx2">

4 Chloropyrid[2,3-d]pyrimidine (0.15 g, 0.91 mmole) was added carefully to a solution of aniline (0.15 g, of 1.61 mmole) in water (1.5 ml). This solution was heated for 0.5 hour on the steam bath, cooled, and then podslushivaet concentrated ammonium hydroxide. The crude precipitate was collected by filtration and was precrystallization of 95% ethanol, giving the desired product as yellow crystals (0,054 g, 27%). So pl. 258oC; LC-MS: 223 (MH+).

The products of examples 33-36 obtained in accordance with the procedure of example 5 from 4-chloropyrid[2,3-d] pyrimidine (1 EQ.) and the appropriate substituted aniline.

Example 33. (3-Chloro-phenyl)-(pyrido[2,3-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 61% of m-Chloroaniline (1.8 EQ.). So pl. 228oC; LC-MS: 257 (MH+).

Example 34. (3-Chloro-phenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 37% of m-Chloroaniline (1.8 EQ.). So pl. 228oC; MCBP: 257 (MH+).

Example 35. (3-Bromo-phenyl)-(pyrido[3,4-d]pyrimidine-4-yl)amine.

This product was obtained with a yield of 26% of m-bromoaniline (1.8 EQ.). So pl. 206oC; LC-MS: 301 (MH+).

Example 36. (Phenyl)(pyrido[3,4-d]pyrimidine-4-yl)amine.

This product was obtained with vyhodilo[3,4-d]pyrimidine.

4 Chloropyrid[3,4-d] pyrimidine (0.10 g, 0.60 mmole), 6-chloroindole (0.10 g, of 0.66 mmole) and pyridine (0.14 g, is 1.81 mmole) were combined in DMF (1 ml) and was heated at 70oC for 3 hours. The reaction mixture was cooled to room temperature, and then was added to methylene chloride (150 ml). The organic layer was washed with saturated sodium carbonate and water and then dried over sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified using chromatography on a column (silica gel, 9:2: 1 methylene chloride: hexane: methanol) to give the target product as a pale yellow residue (0,048 g, 28%). So pl. 194-196oC; LCMS: 283 (MH+).

Example 38. (Pyrido[3,4-d]pyrimidine-4-yl)(m-tolyl)amine.

This product was obtained with a yield of 44% of m-anisidine (1.1 EQ.). So pl. 172oC; LC-MS: 237 (MH+).

The products of examples 39-40 obtained in accordance with the procedure of example 1 from 4-chloropyrid[3,4-d]pyrimidine (1 EQ.) and the appropriate amine.

Example 39. (1H-Indazol-5-yl)(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 96% of 5-aminoindazole (1.1 EQ.) and 4 chloropyrid[3,4-d]pyrimidine (1 EQ.). So pl. 258oC. LC-MS: 263 (MH+).

Example 40. (1H-Indol-5-yl)(pyrido[3,4-d]p is]pyrimidine (1 EQ.). So pl. 265oC; LC-MS: 262 (MH+).

Example 41. (Phenyl)-pyrido[2,3-d]pyrimidine-4-yl-amine.

4 Chloropyrid[2,3-d]pyrimidine (0.15 g, 0.91 mmole) was carefully added to a solution of aniline (0.15 g, of 1.61 mmole) in water (1.5 ml). The solution was heated for 0.5 hour on the steam bath, cooled, and then podslushivaet concentrated ammonium hydroxide. The crude precipitate was collected by filtration and was precrystallization of 95% ethanol, yielding yellow crystals (0,054 g, 27%). So pl. 258oC; LC-MS: 223 (MH+).

Example 42. (3-Chloro-phenyl)-(pyrido[2,3-d]pyrimidine-4-yl)-amine.

Using a procedure analogous to the procedure described in example 5, the product was obtained with a yield of 61% of m-Chloroaniline (1.8 EQ.) and 4 chloropyrid[2,3-d]pyrimidine (1 EQ.). So pl. 228oC; LC-MS: 257 (MH+).

Example 43. (3-Chloro-phenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

Using the procedure analogous to the procedure described in example 5, the product was obtained with a yield of 37% of m-Chloroaniline (1.8 EQ.) and 4 chloropyrid[3,4-d]pyrimidine (1 EQ.). So pl. 228oC LC-MS: 257 (MH+).

Example 44. (3-Bromo-phenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 26% of m-bromoaniline (1.8 EQ.) and 4-chloropyridin+).

Example 45. (Phenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine.

This product was obtained with a yield of 22% of the aniline (1.8 EQ.) and 4 chloropyrid[3,4-d]pyrimidine (1 EQ.) using a procedure analogous to the procedure described in example 5. So pl. 161oC; LCMS: 223 (MH+).

Example 46. (7-Benzazolyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3 - ethinyl-phenyl)-amine.

To 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (1.0 g, 0.0065 mol) in dry THF (10 ml) in a nitrogen atmosphere at -78oC was added dropwise via syringe over 15 minutes n-utility (2.5 M in hexane; 2.88 ml, 0.0072 mol). The cooling bath was removed, and the solution was mixed for 1 hour. The resulting salt pyrrole anion to precipitate in the form of finely dispersed solids in turbid colorless solution. After the suspension was re-cooled to -78oC, was added benzosulphochloride (1.26 g, 0.0072 mol) via syringe. The resulting yellow reaction mixture was left to slowly heated to room temperature over night. Gray-white suspension was poured into 2% aqueous sodium bicarbonate (50 ml) and was extracted twice with diethyl ether (20 ml). The combined extracts were washed the ether, the product was collected by filtration, yielding 1.4 g (74%) of white solids. LC-MS = 294 (MH+) RP18-HPLC RT: 4:40 minutes

The above compound was dissolved in methanol and was added m-aminophenylacetylene (strength of 0.159 g, 0.0013 mol) and the reaction mixture was heated in an oil bath with a temperature of 85oC for 2 days. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was pulverized with diethyl ether, giving the desired product as a white solid (0,234 g, 92%). LC-MS = 375 (MH+), RP18-HPLC RT: 3.48 min

Example 47. 4-(6-Chloro-2,3-dihydro-indol-1-yl)-5H-pyrrolo[3,2-d] pyrimidine-6-ol.

To a solution of 4-(6-chloro-2,3-dihydro-indol-1-yl)-5-amino-6 - methylacetanilide (541 mg, 1.55 mmole) in 40 ml of ethanol was added to 25 mol.% 10% palladium on coal (125 mg) and 0.11 ml of 1 norms. HCl (1.55 mmole). The reaction mixture was gerasoulis for 3 hours at 50 lb./square inch (3.515 kg/sq. cm). The reaction mixture was filtered through celite and concentrated in vacuum. The brown residue was suspenderbelt in methanol, and a white solid target product was filtered off (279 mg, 63%) LC-MS: 287 (M+), RP18-HPLC RT: 5.61 min So square: 250oC (decomp.).

Example 48. (3-Ethinyl-phenyl)-[7-(2-morpholine-4-yl-ethyl)-7H - paralelos 276 mg (2.0 mmole) of anhydrous potassium carbonate, and then 32 mg (1.3 mmole) of 97% sodium hydride. After 30 minutes, was added 343 mg (1.0 mmol) sulfonylamino 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, and the reaction mixture was heated at 100oC for 2 hours. The reaction mixture is then distributed between ethyl acetate and water, and the aqueous layer was extracted with two additional portions of ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuum. The residue was chromatographically on silica gel using 10% methanol/methylene chloride; giving amber oil (140 mg, 55%). LC-MS: 267 (M+).

The above product was dissolved in methanol and was added m-aminophenylacetylene (0.123 g, 0.001 mol) and the reaction mixture was heated in a sealed tube in an oil bath with a temperature of 120oC for 12 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was pulverized with diethyl ether, giving the desired product as a white solid (0.135 g, 74%). LC-MS = 348 (MH+), RP18-HPLC RT: 3.33 min

Example 49. (3-Ethinyl-phenyl)-[7-(2-methoxy-ethyl)-7H-pyrrolo[2,3-d] pyrimidine-4-yl]-amine.

This product was obtained with a yield of 81% of 4-chloro-7-(2-metocean described in example 47. So pl. 240-241oC; LC-MS: 292 (MH+); RP18-HPLC RT: 4.16 min

Example 50. (3-Ethinyl-phenyl)-{ 7-[2-(2-methoxy-ethoxy)-ethyl]-7H - pyrrolo[2,3-d]pyrimidine-4-yl}-amine.

Using a procedure analogous to the procedure described in example 47, the product was obtained with a yield of 81% of 4-chloro-7-[2-(2-methoxy-ethoxy)-ethyl] -7H-pyrrolo[2,3-d] pyrimidine (1.0 EQ.) and m-aminophenylacetylene (1.2 EQ.) in methanol. So pl. 240-241oC; LC-MS: 336 (M+); RP18-HPLC RT: 4.29 min

Example 51. Hydrochloride (7-allyl-pyrrolo[2,3-d]pyrimidine-4-yl)-(3 - ethinyl-phenyl)-amine.

To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.3 g, 8.5 mmol) in dry THF (30 ml) was added sodium hydride (1.0 g, 0.25 mmole, 60% dispersion in mineral oil). After stirring at ambient temperature for 1 hour, was added allride (0.93 ml, 10 mmol), and stirring continued for 48 hours. The reaction mixture was concentrated in vacuum, were pulverized in hot ethyl acetate and filtered. The filtrate was concentrated in vacuo, giving an orange solid residue. The solid substance was pulverized in methylene chloride and filtered, yielding 4-chloro-7-allyl-pyrrolopyrimidine in the form of a light yellow powder (0.58 g, 36%). TS-MS: 194 (MH+). To 4-chloro-7-allyl-pyrrolo[2,3-d] pyrimidine (0.5 g who authorized the tube under pressure at 125oC for 20 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified using flash chromatography on silica gel (50 g, 40 mm mesh) using 3% methanol/methylene chloride, giving the desired product as a yellow powder (0.29 g, 41%). So pl. 150-150oC; TS-MS: 275 (MH+).

Example 52. Hydrochloride (3-ethinyl-phenyl)-(7-methyl-pyrrolo[2,3-d] pyrimidine-4-yl)-amine.

In accordance with the procedure described in example 51, the target compound was obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and under the conditions, and m-aminophenylacetylene (75%), TS-MS: 249 (MH+); so pl. 204-205oC.

Example 53. (5-Bromo-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethinyl - phenyl)-amine.

To 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (0.21 g, 1.4 mmole) in dry methylene chloride (10 ml) was added N-bromosuccinimide (0.26 g, 1.5 mmole) at ambient temperature. The reaction mixture is stirred for 18 hours and the resulting solid substance was filtered with methylenchloride leaching water and dried in vacuo, yielding 5-bromo-4-chloro-7H-pyrrolo[2,3-d] pyrimidine in the form of a reddish-brown powder (0.28 g, 88%). GC-MS: 233 (MH+), RT: 4.42 min

To 5-bromo-4-chloro-7H-pyrrole was heated in a sealed tube under pressure at 125oC for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified using flash chromatography on silica gel (10 g, 40 mm mesh) using a mixture of 3% methanol/methylene chloride, giving the target compound as a yellow powder (71 mg, 39%). TS-MS: 314 (MH+); So pl. 208oC (decomp.).

Example 54. (3-Ethinyl-phenyl)-(5-iodine-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine.

To (3-methyl-phenyl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine (17 mg, 0,076 mmole) in dry methylene chloride (1 ml) was added N-iodosuccinimide (19 mg, 0,083 mmole). The reaction mixture was stirred at ambient temperature for 2 hours, then filtered with methylenchloride leaching water and dried in vacuum, yielding the target compound in the form of gray-reddish-brown powder (12 mg, 46%). TS-MS: 351 (MH+).

Example 55. 4-(3-Ethinyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidine - 5-carboxylic acid.

To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.87 g, 3.7 mmole) in dry THF (29 ml), cooled in a bath of dry ice and acetone, was added dropwise n-utility (3.4 ml, 8.4 mmole, 2.5 M in hexano). The reaction mixture is stirred for 1 hour, then abruptly cooled barb who was evals for 5 minutes at ambient temperature. The reaction mixture was concentrated in vacuum, were pulverized with ethyl acetate and dried in vacuo, yielding 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid in the form of powder color avocado (0.80 g, 74%). TS-MS: 198 (MH+).

To 4-chloro-7H-pyrrolo[2,3-d] pyrimidine-5-carboxylic acid (0.38 g, 1.9 mmole) in dry methanol (4 ml) was added m-aminophenylacetylene (0.47 g, 4.0 mmole). The suspension was heated in a sealed tube under pressure at 125oC for 18 hours. The reaction mixture was cooled to ambient temperature, filtered with methylenchloride the products and dried in vacuum, yielding the target compound in the form of reddish-brown powder (0.30 g, 54%). TS-MS: 278 (MH+). So pl. 190oC (decomp.).

Example 56. Hydrochloride (3-ethinyl-phenyl)-(5-methyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine.

To 5-bromo-4-chloro-7H-pyrrolopyrimidine (0.28 g, 1.2 mmole) in dry THF (9 ml), cooled in a bath of dry ice and acetone, was added dropwise n-utility (1.1 ml, 2.7 mmole, 2.M hexano). The reaction mixture is stirred for 1 hour, then added methyliodide (0.12 ml, 1.9 mmole). The solution was mixed for 1 hour at ambient temperature, and water was added (1 ml). The reaction mixture was concentrated in acountry and concentrated in vacuum, giving 4-chloro-5-methyl-7H-pyrrolo[2,3-d] pyrimidine (0.17 g, 85%). GC-MS: 167 (M+), RT: 3.15 min

To 4-chloro-5-methyl-7H-pyrrolopyrimidine (0.17 g, 1.0 mmol) in dry methanol (3 ml) was added m-aminophenylacetylene (0.14 g, 1.2 mmole). The suspension was heated in a sealed tube under pressure at 125oC for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was purified using flash chromatography on silica gel (15 g, 40 mm mesh) using 5% methanol in methylene chloride, yielding the target compound as a yellow solid (0.11 g, 43%). TS-MS: 249 (M+).

Example 57. N-(5-Iodine-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-N-m-tolyl-ndimethylacetamide.

To (3-methyl-phenyl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine (0.75 g, 3.4 mmole), dissolved in hot acetonitrile (30 ml), was added sodium hydride (0.16 g, 4.0 mmole, 60% dispersion in mineral oil). After stirring at ambient temperature for 0.75 hours, was added acetylchloride (0.48 ml, 6.7 mmole) and stirring continued for 48 hours. The reaction mixture was concentrated in vacuum, were pulverized in hot ethyl acetate and filtered. The filtrate was concentrated in vacuo, giving orangeways using a 1:3 mixture of ethyl acetate/hexane, giving 1-(4-m-tolylamino-pyrrolo[2,3-d]pyrimidine-7-yl)-Etalon in the form of a yellow solid (0.21 g). TS-MS: 309 (MH+).

To 1-(4-m-tolylamino-pyrrolo[2,3-d]pyrimidine-7-yl)-ethanone (0.21 g, 0.79 mmole) in dry methylene chloride (5 ml) and dry methanol (2 ml) was added sodium carbonate (0.17 g, 1.6 mmole). After stirring at ambient temperature for 0.75 hour was added N-iodosuccinimide (0.35 g, 1.6 mmole). The reaction mixture was stirred at ambient temperature for 48 hours, and then concentrated in vacuum. The residue was diluted with methylene chloride and water. The aqueous phase was extracted once with methylene chloride. The organic phase was washed twice with water, dried over sodium sulfate and concentrated in vacuum. The resulting residue was purified using flash chromatography on silica gel (11 g, 40 mm mesh) using a mixture of 2% methanol/methylene chloride, giving the target compound as a yellow solid (30 mg). TS-MS: 393 (MH+). So pl. 178-179oC.

Example 58. Hydrochloride methyl ester 4-(3-ethinyl-phenylamino)-7H - pyrrolo[2,3-d]pyrimidine-5-carboxylic acid.

To 4-(3-ethinyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (0.108 g, 0.39 mmole) in dry methylene chloride m-1 drop of dry DMF. The suspension was mixed at ambient temperature for 1 hour, then concentrated in vacuo. To the resulting solid substance was added dry acetone (2 ml) and dry methanol (1 ml). The solution was mixed at ambient temperature for 15 hours, then concentrated in vacuo. The residue was diluted with ethyl acetate and water, and the solid is filtered and dried in vacuum, yielding the target compound in the form of reddish-brown powder (40 mg, 35%). TS-MS: 293 (MH+). So pl. 256oC (decomp.).

Example 59. (3-Ethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-yl - carbonitrile.

To 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.31 g, 1.3 mmole) in dry THF (4 ml), cooled in a bath of dry ice and acetone, was added dropwise n-utility (1.3 ml, 3.3 mmole, 2.5 M in hexano). The reaction mixture is stirred for 1 hour, then was added p-toluensulfonate (0.44 g, 2.5 mmole) suspended in dry THF (7 ml). The solution was mixed for 18 hours at ambient temperature, then was diluted aqueous ammonium chloride. The phases were separated and the organic phase was washed with water and aqueous sodium chloride. The organic phase was dried over sodium sulfate and koncentrira mm mesh) using a mixture of 3% methanol/methylene chloride, giving 4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (52 mg).

To 4-Chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.29 mmole) in dry methanol (3 ml) was added m-aminophenylacetylene (41 mg, 0.35 mmole). The suspension was heated in a sealed tube under pressure at 125oC for 18 hours. The reaction mixture was cooled to ambient temperature, filtered with a small amount of methanol, and dried in vacuum, yielding the target compound as a white solid (27 mg, 36%). TS-MS: 260 (MH+); anal. RP18-HPLC RT: 3.70 min

Example 60. Hydrochloride (1H-indazol-5-yl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)amine.

6-Methyl-pyrido[3,4-d] pyrimid-4-one (200 mg, 1.24 mmole), precipitated polymer triphenylphosphine (2.06 g, about 3.0 mmol. R/g resin, 6,20 mmole) and anhydrous carbon tetrachloride (1.20 ml, 12.40 mmol) were combined in 1,2-dichloroethane (6 ml). The reaction mixture was heated to 60oC in dry nitrogen atmosphere for 18 hours. Was added 5-Aminoindazole (221 mg, 1.66 mmole), and heating was continued at 60oC for 18 hours. Polymer coated with triphenylphosphine were filtered off and were washed several times with chloroform. The filtrate and wash water were concentrated is, giving 207 mg of the free base of the desired product (LC-MS: 277 (MH+). This material was dissolved in a minimal volume of chloroform and added dropwise with stirring was added 1 mole equivalent of HCl in ether. The reaction mixture was diluted with ether (4 volume), and precipitated precipitated HCl salt of the desired product was filtered and dried in vacuum (188 mg; so pl. 208oC; LC-MS: 277 (MH+); anal. RP18-HPLC: 2.71 min).

Example 61. (3-Ethinyl-4-fluoro-phenyl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This substance was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. ) and 5-amino-benzo[b]thiophene (1.5 equiv.) as described in example 60. The polymer was filtered off and were washed several times with a mixture of 30 % methanol/ 70% chloroform. To the filtrate, and proryvnym water was added triethylamine (3.0 EQ.) before they were concentrated in vacuum. The residue was subjected to flash chromatography on silica gel using a mixture of 10% methanol/methylene chloride, yielding 135 mg of the product as the free base (LC-MS: 293 (MH+)). This material was dissolved in a minimal volume of chloroform and added dropwise with stirring was added 1 equivalent of HCl in ether. The reaction mixture was diluted with ether (4 volume), and precipitated in the sediment target product Hotfile the EP 62. (3-Ethinyl-4-fluoro-phenyl)-(6-methyl-pyrido[3,4-d]pyrimidine - 4-yl)-amine.

6-Methyl-pyrido[3,4-d] pyrimid-4-one (44 mg, 0.27 mmole), polymer coated with triphenylphosphine (0.452 g to about 3.0 mmol. R/g resin, of 1.55 mmole) and anhydrous carbon tetrachloride (0.261 ml, 2.71 mmole) were combined in 1,2-dichloroethane (1.25 ml). The reaction mixture was heated to 60oC in dry nitrogen atmosphere for 2 hours. Was added 3-ethinyl-4-fluoro-aniline (55 mg, 0.407 mmole), and heating was continued at 60oC for 6 hours. The polymer was filtered off and were washed several times with a mixture of 50% methanol/chloroform. The filtrate and the washing water was concentrated in vacuo and subjected to flash chromatography on silica gel using a gradient from 0 to 10% methanol/methylene chloride, giving the desired product (10 mg, so pl. 225oC, LC-MS: 279 (MH+), anal. RP-HPLC: 3.94 min).

Example 63. Dichlorhydrate 2-methyl-4-(6-methyl-pyrido[3,4-d]pyrimidine - 4-ylamino)-phenol.

This substance was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. 4-amino-o-cresol (1.5 equiv.) as described in example 61. Polymer coated with triphenylphosphine were filtered off and were washed several times with 50% methanol/chloroform. The triethylamine (3.0 GCV.) was added to the filtrate before the 0 to 15 methanol and methylene chloride, giving 314 mg of the desired product as free base (LC-MS: 267 (MH+)). This substance is turned into diclorhidrato salt by dissolving in chloroform and titration with 2 equivalents of 1M HCl in ether. Dropped into the sediment target product was filtered off and dried in a vacuum (so pl. 298-305oC, LC-MS: 267 (MH+); anal. RP-HPLC: 2.88 min).

Example 64. The hydrochloride of 4-(4-Bromo-7-methyl-2,3-dihydro-indol-1-yl)-6 - methylpyridin[3,4-d]pyrimidine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. ) and 4-bromo-7-methyl-indoline (1.5 EQ.) in accordance with the procedure described for example 61. Raw or crude product from the filtrate was subjected to flash chromatography on silica gel using a mixture of ethyl acetate:hexane: methanol (9: 2: 1), giving the free base of the desired product, which was turned into a target product, as described for example 60 (33%, so pl. 232-244oC, LC-MS: 355 (MH+), anal. RP-HPLC: 5.20 min).

Example 65. The hydrochloride of 4-(6-bromo-7-methyl-2,3-dihydro-indol-1-yl)-6 - methylpyridin[3,4-d]pyrimidine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. ) and 6-bromo-7-methyl-indoline (1.5 EQ.) in accordance with the procedure described for example 61. The crude product of filitra free base of the desired product, which turned into a target product as a salt, as described for example 60, (34%, so pl. 212-229oC, LC-MS: 355 (MH+) anal. RP-HPLC: 4.90 min).

Example 66. The hydrochloride of 4-(6-bromo-5-fluoro-2,3-dihydro-indol-1-yl)-6 - methylpyridin[3,4-d]pyrimidine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. ) and 6-bromo-5-fluoro-indoline (1.5 EQ.) according to the procedure described for example 61. The crude product from the filtrate was subjected to flash chromatography on silica gel using a mixture of 2% methanol/98% methylene chloride, giving the free base of the desired product, which was turned into a target product, as described for example 60 (36%, so pl. 262 to 264oC; LC-MS: 361 (MH+), anal. RP-HPLC: a 4.83 min).

Example 67. Hydrochloride (3-chloro-4-fluoro-phenyl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This product was obtained from 6-methyl-pyrido-[3,4-d]pyrimid-4-it (1.0 EQ. ) and 3-chloro-4-fluoro-aniline (1.5 EQ.) in accordance with the procedure described for example 61. The crude product from the filtrate was subjected to chromatography on silica gel using a gradient of 0% -10% methanol/methylene chloride, giving the free base of the desired product, which was turned into a target product, as described for example 60 (47%, so pl. 251-258otrifluoromethyl-phenyl)-amine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1,0 EQ. ) and 3-triptorelin (1.5 EQ.) in accordance with the procedure described for example 61. The crude product from the filtrate was chromatographically on silica gel using a gradient of 0%-5% methanol/methylene chloride, giving the free base of the desired product, which was turned into a target product, as described for example 60 (33%, so pl. 269-270oC; LC-MS: 305 (MH+), anal. RP-HPLC: 4.30 min).

Example 69. Hydrochloride (4-fluoro-3-methyl-phenyl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1.0 EQ. 4-fluoro-3-methyl-aniline (1.5 EQ.) in accordance with the procedure described for example 61. The crude product from the filtrate was chromatographically on silica using a mixture of 4% methanol/96% methylene chloride, giving the free base of the desired product, which was turned into a target product, as described for example 60 (41%, so pl. 246-250oC, LC-MS: 269 (MH+), anal, RP-HPLC: 3.79 min).

Example 70. Hydrochloride 2-iodine-4-(6-methyl-pyrido[3,4-d]pyrimidine-4 - ylamino)-phenol.

6-Methyl-pyrido[3,4-d]pyrimid-4-one (161 mg, 1.00 mol) was added to the polymer coated with triphenylphosphine (1 is I and the mixture was heated to 60oC for 2 hours and then the resin was filtered off and were washed 1,2-dichloroethane. The filtrate was collected in a flask containing 4-hydroxy-3-iodine-aniline (0,235 g, 1.00 mmol) and concentrated to 5 ml by evaporation. After 12 hours of heating under reflux in a nitrogen atmosphere and then cooled to 20oC target product was going with. by filtration (347 mg, 83%; so pl. 261-265oC; LC-MS: 379 (MH+); anal. RP-HPLC: 3.20 min).

Example 71. Hydrochloride (4-bromo-3-fluoro-phenyl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This product was obtained from 6-methyl-pyrido[3,4-d]pyrimid-4-it (1 EQ.) and 3-bromo-4-fluoro-aniline (1.0 EQ.) and allocated in accordance with the method for example 70 (53%, so pl. 251-254oC LC-MS: 333, 335 (MH+); anal. RP-HPLC: 4.07 min).

Example 72. The hydrochloride of 4-(6,7-dimethyl-2,3-dihydro-indol-1-yl)- pyrido[3,4-d]pyrimidine.

To 4-chloro-pyrido[3,4-d]pyrimidine (200 mg, 1.21 mmole) in isopropanol (3 ml) were added 6,7-dimethylindoline (211 mg, 1.44 mmole) and pyridine (190 mg, 2,41 mmole). The reaction mixture was heated to the temperature of reflux distilled in an atmosphere of dry nitrogen for 6 hours. The solvent was removed in vacuo, and the residue was dissolved in chloroform and washed with saturated aqueous who stayed flash chromatography on silica in a mixture of 45% acetone/hexane, giving 60 mg of the free base of the desired product (LC-MS: 278 (MH+)). This material was dissolved in a minimum volume of 10% methanol in methylene chloride, dropwise and with stirring was added 1 mole equivalent of HCl in ether. The reaction mixture was diluted with four volumes of ether, and precipitated in the sediment target product was filtered off and dried in vacuum (58 mg; so pl. 248oC; GC-MS: 277 (M+); anal. RP-HPLC: 4.06 min).

Example 73. Hydrochloride (3-ethinyl-phenyl)-(pyrido[3,4-d]pyrimidine - 4-yl)-amine.

To 4-chloro-pyrido[3,4-d] pyrimidine (250 mg, 1.50 mmole) in N-methylpyrrolidine-2-one (0.5 ml) was added 3-itinerary (212 mg, 1.81 mmole) and pyridine (237 mg, 3.0 mmole). The reaction mixture was heated up to 80oC in dry nitrogen atmosphere for 3 hours. The reaction mixture was dissolved in chloroform and washed with saturated aqueous sodium carbonate and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography on silica using a gradient of 40% - 70% acetone/hexane, giving 120 mg of product. This product was dissolved in minimum amount of chloroform, titrated 1 EQ. HCl in ether, and diluted with ether. The resulting precipitate Otti. P-HPLC: 3.45 min).

Example 74. Hydrochloride (benzo[b] thiophene-5-yl)-(pyrido[3,4-d]pyrimidine - 4-yl)-amine.

To 4-chloro-pyrido[3,4-d] pyrimidine (250 mg, 1.50 mmole) in N-methylpyrrolidine-2-one (0.5 ml) was added benzo[b] thiophene-5-yl-amine (270 mg, 1.81 mmole) and pyridine (237 mg, 3.0 mmole). The reaction mixture was heated up to 80oC in dry nitrogen atmosphere for 3 hours. The reaction mixture was dissolved in chloroform and washed with saturated aqueous sodium carbonate and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and subjected to flash chromatography on silica in a mixture of 40% acetone-hexane, giving 180 mg of product. This product was dissolved in minimum amount of chloroform, was titrated with 1 EQ. HCl in ether, and diluted with ether. The resulting precipitate was filtered off and dried in vacuo, giving a yellow target product (188 mg; so pl. 280-282oC; LC-MS: 279 (MH+); anal. RP-HPLC: 3,63 minutes).

Example 75. Hydrochloride (3-ethinyl-phenyl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This substance was obtained from 4-chloro-6-methyl-pyrido[3,4-d]pyrimidine (1.0 EQ. ) and 3-itineraria (1.1 equiv.) as described for example 74. After extraction, chromatography of the residue on TLD is AutoRAE turned into a target product (so pl. 250-252oC; LC-MS: 261 (MH+); anal. RP-HPLC: 3.69 min).

Example 76. (4-(6-Chloro-2,3-dihydro-indol-1-yl)-6-methyl - pyrido[3,4-d]pyrimidine.

This material was obtained from 4-chloro-6-methyl-pyrido[3,4-d]pyrimidine (1.0 EQ. ) and 6-floridain (1.1 EQ.) as described in example 74. Preparative chromatography with reversed phase (C18) using a gradient of 15%-70% acetonitrile/pH 4.5, 50 mm ammonium acetate, followed by lyophilization of the appropriate fractions gave the desired product (30%) (so pl. 232-234oC; LC-MS: 297 (MH+), anal. RP-HPLC: 4.33 min).

Example 77. Methanesulfonate (1H-indol-5-yl)-(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine.

This substance was obtained from 4-chloro-6-methyl-pyrido[3,4-d]pyrimidine (1.0 EQ. ) and 5-aminoindole (1.1 equiv.) as described for example 74. Preparative chromatography with reversed phase (C18) using a gradient of 15%-70% acetonitrile/pH 4.5, 50 mm ammonium acetate, followed by lyophilization of the appropriate fractions gave the free base (30%) of the target product (i.e pl. 262-263oC; LC-MS: 276 (MH+); anal. RP-HPLC: 2.98 min). This substance is turned into a target product by dissolving in a minimum amount of chloroform with subsequent relax and dried in a vacuum (so pl. 317-318oC).

Example 78. (3-Ethinyl-phenyl)-(5-methylsulfanyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine.

To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 0.77 mmole) in dry THF (2 ml), cooled in a bath of dry ice and acetone was added dropwise n-utility (0.77 ml, 1.9 mmole, 2.5 M in hexano). The mixture was mixed for 1 hour, then was added dimethyl disulfide (0.077 ml, 0.77 mmole) suspended in dry THF (1 ml). The solution is stirred for 2.5 hours at - 78oC, and then diluted aqueous ammonium chloride. The phases were separated and the aqueous phase was extracted 2 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo, yielding 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine as an orange solid (150 mg).

To 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.75 mmole) in dry methanol (2 ml) was added m-aminophenylacetylene (110 mg, 0.90 mmole). The solution was heated in a sealed tube under pressure at 125oC for 5.5 hours. The reaction mixture was cooled to ambient temperature, filtered with a small amount of methanol and dried in vacuum, yielding the target compound in the form of reddish-brown nikodinovic acids.

6-Methyl-4-aminonicotinic acid (420 mg, is 2.74 mmole) and dry formamide was heated to 165oC for 6 hours in nitrogen atmosphere. The reaction mixture was cooled to room temperature, and formamide was removed in vacuum. The remaining residue was purified by HPLC with reversed-phase (linear gradient 5-100% acetonitrile at pH 4.50, 50 mm ammonium acetate for 1 hour with a flow rate of 23.0 ml/min), giving the desired product (50%, GCMS RT = 1.48 min, M+= 195).

Getting 2. 6-Methyl-pyrido[3,4-d]pyrimid-4-one.

5-Amino-2-methyl-4-piridinkarbonovaya acid was obtained by the method of Palt. K. ; Celadnik, M; Dvorackova, D.; Kubalda, B., Cesk. Farm., 32(8). 275-278 (1983). This carboxylic acid was transformed into the target product by heating in formamide at 165oC in accordance with the methodology Robins, R.; Hitchings, G.; J. Am. Chem. Soc. 77, 2256 (1955).

1. The connection formulas

< / BR>
and stereoisomers, pharmaceutically acceptable salts, where Y is-NR4-CR3= CR3-, -CH= CR3-N= CH-, -CR3=N-CR3=CR3-, -CR3=CR3-NR4-, -NR4-CR3= N - or-N=N-NR4-;

Z represents NR1R2where R1is H and R2represents phenyl substituted by a group (R5)mor Q, ILU double bond; each R3attached to the carbon atom in Y, and independently selected from: hydroxy, (C1-C4)alkoxy, hydroxy(C2-C4)alkoxy, amino(C2-C4)alkyl, amino(C2-C4)alkoxy, (C1-C4)alkoxy(C2-C4)alkoxy,

hydroxy(C1-C4)alkyl(C1-C4)alkylenedioxy, (C1-C4)alkoxy(C1-C4) alkyl(C1-C4)alkylenedioxy, mono-N - or di-N,N-(C1-C4)alkylamino(C2-C4)alkoxy, 3 - or 4-(C1-C4)alkoxy-(2-hydroxy)-(C3-C4)alkoxy, carboxy(C1-C4)alkoxy, morpholino (C2-C4)alkoxy, imidazol-1-yl(C2-C4)alkoxy, 4(C1-C4)alkylpiperazine-1-yl-(C2-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkanoyloxy, nitro, hydroxyamino, amino, phenyl, pyridyl, pyrrolo, imidazole, thiazole, benzimidazole, pyridinyl, mono-N - or di-N, N-(C1-C4)alkylamino, (C1-C4)alkanolamine, hydroxy(C2-C4)alkylamino,

(C1-C4)alkoxy(C2-C4)alkylamino, (C1-C4)alkylsulfonamides, morpholino, (C1-C4)alkyl-piperazine-1-yl, bis(C1- 2
-C4)alkylamino,

piperidine-1-yl, imidazol-1-yl, pyrrolidin-1-yl, (C1-C4)alkoxy(C1-C4)alkylcarboxylic, carboxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycarbonyl (C1-C4)alkoxy, amido, mono-N - or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N - or di-N, N-(hydroxy(C2-C4)alkyl)-aminocarbonyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, mono-N - or di-N,N-((C1-C4)alkoxy(C1-C4)alkyl)amino(C1-C4)alkyl, mono-N - or di-N, N-(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanolamine (C1-C4)alkyl,

(C1-C4)alkylthio, (C1-C4)alkoxy(C2-C4)alkylthio or hydroxy(C2-C4)alkylthio; each R4attached to the N atom and Y is independently selected from: hydrogen, benzyl, phenyl, (C2-C4)alkyl, hydroxy(C2-C4)alkyl, or each of such groups as hydroxy(C2-C4)alkyl, amino (C2-C6)alkyl, (C2-C4)alkoxycarbonyl, substituted amino, halogen, hydroxy, (C2-C4)alkanoyloxy, (C1-C4)alkoxy, mono-N - or di-N,N-(C1)alkoxy(C2-C4)alkyl)amino, sulfonylureas(C1-C4), (C1-C4)alkanolamine, imidazol-1-yl, piperidino, morpholino, piperazine-1-yl, 4-(C1-C4)alkylpiperazine-1-yl, pyridyl, pyrrolo, imidazole, thiazole, pyridinyl, carboxy, (C1-C4)alkoxycarbonyl, carbarnoyl, mono-N - or di-N,N-(C1-C4)allylcarbamate, carboxamido, mono-N - or di-N,N-(C1-C4)alkylcarboxylic, or mono-N - or di-N,N-(C1-C4)alkyl)carboxamido; each R5independently selected from mono-, di - or trifloromethyl, halogen, nitro, hydroxy, amino, azido, isothiocyante, (C1-C4)alkyl, phenyl, teinila, (C1-C4)alkoxy, benzyloxy, phenoxy, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C4)alkylenedioxy, cyano, benzoylamine, triftormetilfullerenov, (C1-C4)alkanolamine, (C1-C4)alkanoyl, mono-N - or di-N,N-(C1-C4)alkylamino, (C1-C4)alkylsulfonyl, triftormetilfullerenov, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl or (C1-C4)alkylsulfonyl, pyrrol-1-yl, piperidine-1-yl or pyrrolidin-1-yl; these phenyl, benzyloxy, phenoxy
-C4)alkyl; specified (C1-C4)alkylenedioxy connected at both ends to adjacent carbon atoms of the benzene fragment or two groups R5with the carbon atoms to which they are attached, form a group selected from imidazolyl, pyrrole and pyrazolyl; each R6independently selected from hydroxy, amino, mono-N - or di-N, N-(C1-C4)alkylamino, sulfo or (C1-C4)alkoxy (provided that such groups are not attached to the carbon atom of the ring, which is directly adjacent to the nitrogen atom of the ring) or R6in each case independently represents carboxy, hydroxy (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino(C1-C4)alkyl, mono-N - or di-N, N-(C1-C4)alkylamino(C1-C4)alkyl, morpholino(C1-C4)alkyl, 4-(C1-C4)alkyl-piperazine-1-yl(C1-C4)alkyl, carboxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl,

sulfo(C1-C4)alkyl, pyridyl(C1-C4)alkyl or (C1-C4)alkyl; m represents an integer from 1 to 3; n represents 0, 1 or 2; p represents 0 or an integer from 1 to 3; provided that when Y in the direction PIR>5is not 4-ethoxy, 4-methoxy, 4-triptoreline, 4-tert-bootrom or 4-isopropyl; Q represents a 9 - or 10-membered bicyclic heteroaryl cyclic fragment or gidrirovannoe derivative containing one or two nitrogen heteroatom and optionally containing an additional heteroatom selected from nitrogen, oxygen and sulphur, and can optionally carry one or two substituent selected from halogen, hydroxy, oxo, amino, nitro, carbamoyl, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylamino, di-[(C1-C4)alkyl]amino, (C2-C4)alkanolamine, (C2-C4)alkenyl and (C2-C4)quinil provided that when Y in the direction shown by the arrow in the formula 1 is-NR4-CR3=CR3-, R3is CH3and R4is N, then R5is not group 4-CH3, 3,5-(CH3)2, 2,6-(CH3)2, 2-C2H5, 4-n-s4H9, 2-CL, 4-CL, 3,4-Cl2, 2-F or 3-CF3.

2. Connection on p. 1, in which Y in the direction shown by the arrow in the formula 1 is selected from-NR4-CR3=CR3-, -CH=CR3-N=CH-, -CR3=CR3-NR4-.

3. The connection is>, a R4represents hydrogen.

4. Connection on p. 1, where NR1R2is

< / BR>
and R5, R6, m and n have the meanings given above.

5. Connection on p. 4, in which each R5independently selected from 4-hydroxy, 4-amino, 5-fluorine, 5-hydroxy, 5-amino, 6-halogen-free, 6-methyl, 6-Attila, 6-ethinyl, 6-nitro-and 7-methyl and each of R6independently selected from hydroxy, amino, mono-N - or di-N,N-(C1-C4)alkylamino, sulfo or (C1-C4)alkoxy (provided that such groups are not attached to the carbon atom of the ring, which is directly adjacent to the nitrogen atom of the ring) or R6in each case independently represents carboxy, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino(C1-C4)alkyl, mono-N - or di-N, N-(C1-C4)alkylamino(C1-C4)alkyl, morpholino(C1-C4)alkyl, 4-(C1-C4)alkyl-piperazine-1-yl(C1-C4)alkyl, carboxy(C1-C4)alkyl, (C1-C4)al-kokstravel,

sulfo(C1-C4)alkyl, pyridyl(C1-C4)alkyl and (C1-C4)alkyl.

6. Connection on p. 1, in which R1pregnenelone above.

7. Connection on p. 6, in which each R5independently selected from 4-fluoro-3-chlorine, 3-trifloromethyl, 4-fluoro-3-trifloromethyl, 3-nitro-4-chloride, 3-nitro-4-fluorine, 4-fluoro-3-bromo, 3-iodine-5-amino, 3-methyl-4-fluorine, 4-amino, 3-fluorine, 3-hydroxy, 3-amino, 3-halogen, 3-methyl, 3-Attila, 3-ethinyl, 3-nitro and 4-methyl.

8. Connection on p. 1, in which R1is N, and R2Q. is

9. Connection on p. 8, in which Q is selected from 4-, 5-6-indolyl, 1H-benzimidazole-4-yl, 1H-benzimidazole-5-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-benzotriazol-4-yl, 1H-benzotriazol-5-yl, 1H-benzotriazol-6-yl, 5 - or 6-benzoxazolyl, 5 - or 6-benzothiazolyl, benzo[C][2, 1, 3]thiadiazole-4-Il, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-izochinolina, 4-, 5-, 6-, 7- or 8-indolinyl, 5-, 6-, 7 - or 8-hintline or 2, 5 - or 6-khinoksalinona, which may optionally bear one or two substituent selected from fluorine, bromine, chlorine, methyl, ethyl, Attila, ethinyl and methoxy.

10. Connection on p. 9, in which Q is selected from 5 - indolyl, 1H-indazol-5-yl, 1H-benzotriazol-5-yl, 6-benzothiazolyl, benzo[C] [2, 1 ,3]thiadiazole-4-yl, 5-chinoline, 6-chinoline, 8-chinoline, 5-izochinolina or 5-khinoksalinona, which may not necessarily not the x2">

11. Connection on p. 1, selected from the group consisting of the following compounds: (3-ethynylphenyl)-(7H-pyrrolo[2, 3-d] pyrimidine-4-yl)-amine hydrochloride; (3-course)-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydro-indol-1-yl)7H-pyrrolo[2,3-d] pyrimidine hydrochloride; (7H-pyrrolo[2,3-d] pyrimidine-4-yl)-m-tolylamino hydrochloride; (1H-indol-5-yl)-(7H-pyrrolo[2, 3-d]pyrimidine-4-yl)-amine hydrochloride; (6 methylindolin-1-yl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine hydrochloride; (benzo[b]Tien-5-yl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (6-chloro-5-floridain-1-yl)-(7H-pyrrolo[2, 3-d] pyrimidine-4-yl)-amine; (1H-indazol-5-yl)-(7H-pyrrolo[2, 3-d] pyrimidine-4-yl)-amine; 1-(4-m-tolylamino-pyrrolo [2, 3-d]pyrimidine-7-yl)-ethanone hydrochloride; (5-iodo-7H-pyrrolo[2, 3-d]pyrimidine-4-yl)m-tolylamino; (3-chlorophenyl)-(1H-[1,2,3]triazole[4, 5-d]pyrimidine-7-yl)-amine hydrochloride; (3-chlorophenyl)-pyrido[4, 3-d]pyrimidine-4-yl-amine hydrochloride; (1H-indol-5-yl)-pyrido[4,3-d] pyrimidine-4-yl-amine hydrochloride; (3-ethynylphenyl)-(7 methylpyridin[4,3-d] pyrimidine-4-yl)-amine hydrochloride; (3-chlorophenyl)(7 methylpyridin[4,3-d] pyrimidine-4-yl)-amine hydrochloride; (3-ethynylphenyl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine hydrochloride; (6-bromo-5-floridain-1-yl)-(pyrido[4, 3-d] pyrimidine-4-yl)-amine; (6-chloro-5-floridain-1-yl)-(pyrido[4, 3-d]pyrimidine-4-yl-4-hydroxyphenyl)(6 methylpyridin[4,3-d] pyrimidine-4-yl)-amine; (6-joindomain-1-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (benzo[b] Tien-5-yl)-(pyrido[4,3-d] pyrimidine-4-yl)-amine; (3-ethinyl-phenyl)-(N-purine-6-yl)-amine; (1H-indol-5-yl)-(N-purine-6-yl)-amine hydrochloride; (3-chloro-phenyl)-(N-purine-6-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydroindol-1-yl)-pyrido[3,4-d] pyrimidine; (pyrido[3,4-d]pyrimidine-4-yl)-(m-tolyl)amine; (1H-indazol-5-yl)-(pyrido[3,4-d] pyrimidine-4-yl)-amine; (1H-indol-5-yl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine; (phenyl)-(pyrido[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(pyrido[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(pyrido[3,4-d]pyrimidine-4-yl)-amine; (3-bromophenyl)-(pyrido[3,4-d] pyrimidine-4-yl)-amine; (phenyl)-(pyrido[3,4-d] pyrimidine-4-yl)-amine; 4-(6-chloro-2,3-dihydroindol-1-yl)-pyrido[3,4-d] pyrimidine; (pyrido[3,4-d]pyrimidine-4-yl)-(m-tolyl)-amine; (1H-indazol-5-yl)-pyrido[3,4-d] pyrimidine-4-yl-amine; (1H-indol-5-yl)-pyrido[3,4-d] pyrimidine-4-yl-amine; phenyl-pyrido[2,3-d]pyrimidine-4-yl-amine; 3-chlorophenyl-pyrido[2,3-d] pyrimidine-4-yl-amine; 3-chlorophenyl-pyrido[3,4-d]pyrimidine-4-yl-amine; 3-bromophenyl-pyrido[3,4-d]pyrimidine-4-yl-amine; phenyl-(pyrido[3,4-d]pyrimidine-4-yl)-amine; (7-benzazolyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethinyl-phenyl)-amine; 4-(6-chloro-2,3-dihydroindol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-6-ol; (3-ethynylphenyl)-[7-(2-morpholine-4-yl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)]-amine; (3-ethynylphenyl)-[7-(2-Mdina-4-yl} -amine; (7-arylpyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethynylphenyl)-amine hydrochloride; (3-ethynylphenyl)-(7-methylpyrrole[2,3-d]pyrimidine-4-yl)-amine hydrochloride; (5-bromo-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(5-iodine-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid; (3-ethynylphenyl)-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine hydrochloride; N-(5-iodine-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-N-m-tolylacetic; 4-(3-ethinyl-phenylamino)-7H-pyrrolo[2,3-d] pyrimidine-5-carboxylic acid methyl ester hydrochloride; (1H-indazol-5-yl)-(6-methyl-pyrido[3,4-d]pyrimidine-4-yl)-amine hydrochloride; benzo[b]thiophene-5-yl-(6-methylpyridin[3,4-d]pyrimidine-4-yl)-amine hydrochloride; (3-ethinyl-4-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; 2-methyl-4-(6-methylpyridin[3,4-d]pyrimidine-4-ylamino)-phenol dihydrochloride; 4-(4-bromo-7-methyl-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine hydrochloride; 4-(6-bromo-7-methyl-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine hydrochloride; 4-(6-bromo-5-fluoro-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine hydrochloride; (3-chloro-4-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; (6 methylpyridin[3,4-d] pyrimidine-4-yl)-(3-trifluoromethyl-phenyl)-amine hydrochloride; (4-fluoro-3-were)-(6-methylpyridin[3,4-d]phenyl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; 4-(6,7-dimethyl-2,3-dihydroindol-1-yl)-pyrido[3,4-d] pyrimidine hydrochloride; (3-ethynylphenyl)-pyrido[3,4-d]pyrimidine-4-yl-aminohydroxylation; benzo[b]thiophene-5-yl-pyrido[3,4-d] pyrimidine-4-yl)-amine hydrochloride; (3-ethynylphenyl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine hydrochloride; 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methylpyridin[3,4-d] pyrimidine; (3-ethynylphenyl)-(5-methylsulfanyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d] pyrimidine-5-yl-carbonitrile; (1H-indol-5-yl)-(6 methylpyridin[3,4-d]pyrimidine-4-yl-amine methanesulfonate.

12. Connection on p. 11, selected from the group consisting of the following compounds: (1H-indol-5-yl)-(6 methylpyridin[3,4-d]pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (3-chlorophenyl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester; 4-(3-ethynylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; (1H-indol-5-yl)-pyrido[3,4-d]pyrimidine-4-yl-amine; (3-chloro-4-forfinal)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; benzo[b] thiophene-5-yl(6-methyl-pyrido[3,4-d] pyrimidine-4-yl)-amine; (3-idenifier)-pyrido[3,4-d] pyrimidine-4-yl-amine; (4-fluoro-3-were)-(6-Meile)-(m-tolyl)amine; (6 methylpyridin[3,4-d]pyrimidine-4-yl)-(3-triptoreline)-amine hydrochloride; (1H-indazol-5-yl)-(6 methylpyridin[3,4-d] pyrimidine-4-yl)-amine; (3-ethynylphenyl)-(5-methylsulfanyl-7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (1H-indol-5-yl)-(7H-pyrrolo[2,3-d] pyrimidine-4-yl)-amine; (5-bromo-7H-pyrrolo[2,3-d]pyrimidine-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7H-pyrrolo[2,3-d]pyrimidine-5-yl-carbonitrile.

 

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