Aminopyrazine derivatives and medications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

 

The technical field to which the invention relates.

[0001] the Present invention relates to new derivatives of aminopyrazine and pharmaceutical compositions containing the derivatives of aminopyrazine as the active ingredient.

The level of technology

[0002] Myeloproliferative neoplasm (chronic myeloid proliferative disease) is a class of diseases, mainly involving abnormal growth of hemocytes, which is called aberrant hematopoietic stem cells. More specifically, the known diseases such as polycythemia Vera, essential thrombocythemia and idiopathic myelofibrosis (see, for example, non-patent document 1). At the present time there is no available treatment for myeloproliferative neoplasms (chronic myeloid proliferative diseases), and there is therefore a need in therapeutic agent for the treatment of such diseases.

In 2005, it was reported on activated mutations of JAK2, JAK type collection tyrosinekinase (JAK2 V617F mutation), in a patient suffering from myeloproliferative neoplasm (chronic myeloid proliferative disease) (see, for example, non-patent document 2). Upon further investigation of the existence of an activated mutation was confirmed in 95% of patients with true is th polycythemia, in about 50% of patients with essential trombozitemia and in about 50% of patients with idiopathic myelofibrosis (see, for example, non-patent document 3). In addition, was found another activated mutation of JAK2 (JAK2 D620E mutation) in a few cases in patients with true polycythemia (see, for example, non-patent document 4). Moreover, the activated mutation of c-Mpl in the receptor thrombopoietin (MPL W515L mutation and MPL W515K mutation) were detected in about 10% of patients with idiopathic myelofibrosis, which JAK2 V617F was negative.

As JAK2 is located in the forward direction from the intracellular pathway of signal transduction c-Mpl, it is expected that the compounds having inhibitory activity against JAK2 tyrosine kinase, is the active ingredient in therapeutic tools for the treatment of diseases caused not only JAK2-aktivirovannyj mutations, but also c-Mpl mutations, for example, myeloproliferative neoplasms (chronic myeloid proliferative diseases) (see, for example, non-patent documents 5 and 6).

JAK2 is activated mutations have also been found in other, different from myeloproliferative, malignancy (chronic myeloid proliferative diseases). For example, it was reported that JAK2 V617F mutation was detected in a significant number of patients belonging to the class of the Miele is dysplastic syndrome (RARS-T) (see, for example, non-patent document 7). JAK2 is activated mutation (JAK2 R683S/G mutation, and so on) was also detected in 16 (about 9%) of the 187 patients with infantile acute lymphocytic leukemia (see, for example, non-patent document 8), and approximately 20% of patients with infantile acute lymphocytic leukemia with down syndrome (see, for example, non-patent document 9).

It was also reported that activation of JAK2 tyrosine kinase generated by hybrid JAK2 gene, is involved in the process of occurrence of pathologies. For example, TEL-JAK2 protein was detected in patients with myeloproliferative neoplasms acute myeloid proliferative disease) and acute myeloid leukemia, BCR-JAK2 protein and PCM1-JAK2 protein were detected in patients with chronic myeloid like leukemia hematologic cancer (see, for example, non-patent document 10). JAK2 path signal transduction is involved in the growth of Bcr-Ab1-positive cells of chronic myeloid leukemia, suggesting that the compounds having inhibitory activity against JAK2 tyrosine kinase, will be effective in the treatment of imatinib-resistant chronic myeloid leukaemia (see, for example, non-patent document 11). As a rule, JAK2 path signal transduction is one of the important pathways of cell growth of hematologyoncology, and, therefore, expect that the compounds having inhibitory activity against JAK2 tyrosine kinase, is to have a therapeutic effect against various hematological cancers (see, for example, non-patent document 10).

JAK2 tyrosinekinase also involved in the intracellular signal transduction of cytokine receptors or hormone receptors. Interleukin-6 (IL-6) is an inflammatory cytokine that plays an important role in inflammation, immune responses and cancer (see, for example, non-patent documents 12, 13 and 14), and the signal of IL-6 is transmitted through the JAK2 tyrosinekinase (see, for example, non-patent document 15). Diseases involving IL-6, include inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis), hematological cancers (e.g., multiple myeloma), solid cancer (e.g. prostate cancer) and diseases (e.g., pulmonary hypertension, arteriosclerosis, aneurysm, varicose veins) (see, for example, non-patent documents 16, 17 and 18). In addition, it is known that the JAK2 tyrosinekinase contributes in intracellular signal transduction prolactinoma receptors, and expressed the number prolactinoma receptors increases in cancer milk the gland, which leads to increased proliferation of cancer cells due to prolactin (see, for example, non-patent document 19).

Thus expect that the compounds having inhibitory activity against JAK2 tyrosine kinase, will demonstrate a therapeutic effect against various diseases, such as inflammatory diseases, hematological cancers, solid cancers and diseases, as JAK2 tyrosinekinase involved in the transmission of extracellular stimulation.

JAK3 is tyrosinekinase, which plays an important role in signal transduction of cytokines, and attracted considerable attention as a target molecule of immunosuppressants 10 or more years ago. Indeed, compounds having inhibitory activity against JAK3 tyrosine kinase, have been subjected to clinical trials as a drug for organ transplant and rheumatoid arthritis (see, for example, non-patent document 20)

References to prior art

Non-patent documents

[0003] non-Patent document 1: Van Etten, et al., 2004, Cancer Cell, 6, 547-552

Non-patent document 2: Robert Kralovics et al., 2005, New England Journal of Medicine, 352, 1779-1790

Non-patent document 3: Peter J. Campbell, et al., 2006, New England Journal of Medicine, 355, 2452-2466

Non-patent document 4: L. Richeldi, et al., 2006, Leukemia, 20, 2210-2211

Not atentry document 5: Yana Pikman, et al., 2006, PLoS Medicine, 3, 1140-1151

Non-patent document 6: Animesh D, et al., 2006, Blood, 108, 3472-3476

Non-patent document 7: M. M. Ceesay, et al., 2006, Leukemia, 20, 2060-2061

Non-patent document 8: C. Mullighan et al., 2009, Proceedings of the National Academy of Science u s A, 106, 9414-9418

Non-patent document 9: A. Gaikwad, et al., 2008, British Journal of Haematology, 144, 930-932

Non-patent document 10: Lyne Valentino, et al., 2006, Biochemical Pharmacology, 71, 713-721

Non-patent document 11: Ajoy K. Samanta, et al., 2006, Cancer Research, 66, 6468-6472

Non-patent document 12: H. Yu, et al., 2009, Nature Reviews Cancer, 9, 798-809

Non-patent document 13: H. Ogura, et al., 2008, Immunity, 29, 628-636

Non-patent document 14: R. Catlett-Falcone, et al., 1999, Immunity, 10, 105-115

Non-patent document 15: M. Narazaki, et al., 1994, Proceedings of the National Academy of Science u s A, 91, 2285-2289

Non-patent document 16: P. Heinrich, et al., 2003, Biochemical Journal, 374, 1-20

Non-patent document 17: M. Steiner, et al., 2009, Circulation Research, 104, 236-244

Non-patent document 18: H. Alexander, et al., 2009, Biochemical Pharmacology, 78, 539-552

Non-patent document 19: L. Neilson, et al., 2007, Molecular Endocrinology, 21, 2218-2232

Non-patent document 20: Paul S. Changelian et al., 2003, Science, 302, 875-878

The invention

The problem to be solved in the invention

[0004] the Main purpose of the present invention to provide new derivatives of aminopyrazine. Another objective of the present invention is to provide pharmaceutical compositions which contain these derivatives aminopyrazine as active ingredi the NTA.

Means for solving the above problems

[0005] In the present invention, the compound represented by the following General formula [1] (hereinafter referred to as ”compound of the present invention”), or its pharmaceutically acceptable salt represented by examples in which the specified connection is defined by the following values (I) or (II).

(I):

X represents CH or N;

R1is a halogen;

R2represents:

(1) H,

(2) halogen,

(3) cyano,

(4) a group represented by the following General formula [2]:

(where * indicates the position of the linkage; and RC, RDand REare the same or different and each represents (a) H or (b) alkyl, optionally substituted by hydroxy or alkoxy, or, alternatively, two of RC, RDand REtaken together with the adjacent C atom, represent N-containing saturated heterocyclic group, and the remaining represents H, saturated heterocyclic group, optionally substituted by alkylsulfonyl),

(5) a group represented by the following General formula [3]:

(where * is the value as defined above; and RFand RGare the same or different and each submitted is a (a) H, (b) alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, dialkylamino saturated cyclic amino group, alkylcarboxylic, alkylsulfonyl, aryl, heteroaryl, optionally substituted alkyl, tetrahydrofuranyl and carbamoyl, (c) alkylsulphonyl, (d) alkylsulfonyl, (e) carbarnoyl or (f) heteroaryl, optionally substituted alkyl, or, alternatively, RFand RGtaken together with the adjacent N atom represent a saturated cyclic amino group which may be optionally substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, alkoxy, amino, alkoxycarbonyl, alkylsulfonyl, alkylcarboxylic, (e) cycloalkyl, (f) halogenoalkane, (g) alkoxy, (h) oxo, (i) group, represented by the following General formula [4]:

(where * is the value as defined above; and RHrepresents alkyl or aryl), (j) a group represented by the following General formula [5]:

(where * is the value as defined above; and RIand RJare the same or different and each represents H, alkyl, who carbamoyl, alkylsulphonyl or alkylsulfonyl), (k) the group represented by the following General formula [6]:

(where * is the value as defined above; and RKrepresents alkyl, hydroxy, amino, alkylamino, dialkylamino, cyclooctylamine, (cycloalkyl)alkylamino, (hydroxyalkyl)amino, (alkoxyalkyl)amino, alkoxy, alkylsulfonyl or saturated cyclic amino group), and (l) saturated cyclic amino group, optionally substituted hydroxy-group; and saturated cyclic amino group, which was formed through the merger of RF, RGand the neighboring N, and may form a Spiro-linkage group represented by the following General formula [7A] and [7B]:

(where * is the value as defined above)),

(6) a group represented by the following General formula [8]:

(where * is the value as defined above; and RLrepresents (a) alkyl, (b) hydroxy, (c) alkoxy, (d) saturated cyclic amino group, optionally substituted by alkyl or alkylsulfonyl, or (e) amino, optionally substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, halogenoalkane, dialkylaminoalkyl, alkoxyalkyl and hydroxyalkyl),

(7) the group before the purposes of the following General formula [9]:

(where * is the value as defined above; and RM, RNand ROare the same or different and each represents H, halogen, cyano, alkoxy, carbarnoyl, sulfamoyl, monoalkylamines or alkylsulfonyl, or, alternatively, two of RM, RNand ROtaken together, represent methylenedioxy),

(8) -ORP(RPrepresents alkyl, optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl and cycloalkyl, or optional O-containing saturated cyclic group, optionally substituted by hydroxy) or

(9) heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl;

R3represents H or hydroxy;

R4represents H or alkyl; and

R5represents H or alkyl;

(II):

X represents-CRA;

RArepresents a group represented by the following General formula [10]:

(where * is the value as defined above; and RBrepresents (a) amino, long is correctly substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl and alkoxyalkyl, (b) alkoxy, (c) hydroxy, or (d) saturated cyclic amino group);

R1is a halogen;

R2represents H;

R3represents H or hydroxy;

R4represents H or alkyl; and

R5represents H or alkyl.

[0006] Among the compounds of the present invention preferred compounds represented by the General formula [1], especially the connection, as specified by the following values [i] or [ii], or their pharmaceutically acceptable salts:

[i]:

X represents CH or N; and

R2represents:

(1) a group represented by the following General formula [11]:

(where * matter, as defined above points; and RF1and RG1are the same or different and each represents (a) H, (b) alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, dialkylamino saturated cyclic amino group, alkylcarboxylic, alkylsulfonyl, aryl, heteroaryl, optionally substituted alkyl, tetrahydrofuranyl and carbamoyl, (c) alkylsulphonyl, (d) alkylsulfonyl, (e) carbarnoyl or (f) heteroaryl, optionally substituted alkyl, or al is ternative, RFand RGtaken together with the adjacent N atom represent a saturated cyclic amino group which may be optionally substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, alkoxy, amino, alkoxycarbonyl, alkylsulfonyl, alkylcarboxylic, (e) cycloalkyl, (f) halogenoalkane, (g) alkoxy, (h) oxo, (i) group, represented by the following General formula [4]:

(where * and RHhave the meanings as defined above), (j) a group represented by the following General formula [5]:

(where *, RIand RJhave the meanings as defined above), and (k) the group represented by the following General formula [6]:

(where * and RKhave the meanings as defined above)

(2) a group represented by the following General formula [8]:

(3) a group represented by the following General formula [9]:

(where *, RM, RNand ROhave the meanings as defined above)

(4) -ORP1(where RP1represents alkyl, optionally substituted by a group selected from the group consisting of the hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl and cycloalkyl), or

(5) heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl;

[ii]:

X represents-CRA;

RArepresents a group represented by the following General formula [10]:

(where * and RBhave the meanings as defined above), and

R2represents H.

[0007] Among the compounds of the present invention, such compounds where:

X represents CH;

R2represents:

(1) a group represented by the following General formula [11]:

(where *, RF1and RG1have the meanings as defined above)

(2) a group represented by the following General formula [8]:

(where * and RLhave the meanings as defined above)

(3) a group represented by the following General formula [9]:

(where *, RM, RNand ROhave the meanings as defined above)

(4) -ORP1(where RP1matter, as defined above), or

(5) heteroaryl, optionally substituted with one or two is a group, selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl;

or their pharmaceutically acceptable salts are particularly preferred.

[0008] Among the compounds of the present invention, the following specific compounds or their pharmaceutically acceptable salts are preferred:

(1) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-it,

(2) N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}acetamide", she

(3) (S)-6-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(4) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(5) (S)-N2'-[1-(4-forfinal)ethyl]-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine,

(6) (S)-N2'-[1-(4-forfinal)ethyl]-6-methoxy-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine,

(7) (S)-2'-[1-(4-forfinal)ethylamino]-6'-(pyrazin-2-ylamino)-3,4'-bipyridine-6-ol,

(8) (S)-N2-[1-(4-forfinal)ethyl]-4-(oxazol-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(9) (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(10) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)phenyl]-N4(pyrazin-2-Yeremey-2,4-diamine,

(11) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine,

(12) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yloxy}ethanol

(13) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,

(14) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,

(15) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,

(16) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-it,

(17) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2,6-dione,

(18) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}tetrahydropyrimidin-2(1H)-he,

(19) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,

(20) (S)-N2-[1-(4-forfinal)ethyl]-6-morpholino-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(21) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}imidazolidin-2-it,

(22) (S)-N2-[1-(4-forfinal)ethyl]-6-(oxazol-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(23) (S)-N2-[1-(4-forfinal)ethyl]-6-(6-methoxypyridine-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(24) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-3-yl)pyrimidine-2,4-diamine,

(25) (S)-4-{2-[1-(4-fortemelatonin]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol,

(26) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol,

(27) N-((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)acetamide", she

(28) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-4-yl)pyridine-2,6-diamine,

(29) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-3-yl)pyridine-2,6-diamine,

(30) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(31) (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)phenyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(32) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(33) N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyridine-4-yl]pyrrolidin-3-yl}acetamide", she

(34) (S)-N2-[1-(4-forfinal)ethyl]-4-morpholino-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(35) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-thiomorpholine-2,6-diamine,

(36) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propan-1-ol,

(37) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)acetamide", she

(38) (S)-6-(azetidin-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(39) (S)-6-(3-torasemide-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-is Jamin,

(40) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-it,

(41) (S)-4-(1-ethyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(42) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(43) (S)-4-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(44) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,

(45) 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ol,

(46) (S)-N2-[1-(4-forfinal)ethyl]-N4-(5-methylthiazole-2-yl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine,

(47) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4,5'-bipyrimidin-2,6-diamine,

(48) (S)-N2-[1-(4-forfinal)ethyl]-6-(2-methoxythiazole-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(49) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,

(50) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides,

(51) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxamide,

(52) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinate,

(53) 4-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-carboxamid is,

(54) 6-(3-aminopyrrolidine-1-yl)-N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(55) N-(1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)methanesulfonamide,

(56) (S)-2-({2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}(2-hydroxyethyl)amino)ethane-1-ol,

(57) (S)-N4-[2-(dimethylamino)ethyl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine,

(58) 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-carboxamide,

(59) (S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-carboxamid,

(60) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(61) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine,

(62) (R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-hydroxypyrrolidine-2-it,

(63) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[(tetrahydrofuran-2-yl)methyl]pyrimidine-2,4,6-triamine,

(64) ((S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol,

(65) ((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol,

(66) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-ol,

(67) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol,

(68) 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-ol,

(69) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide,

(70) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine,

(71) (S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine,

(72) (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)methanesulfonamide,

(73) (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)acetamide", she

(74) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ndimethylacetamide,

(75) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide,

(76) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzonitrile,

(77) (S)-N2-[1-(4-forfinal)ethyl]-6-(furan-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(78) ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxylate,

(79) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide,

(80) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-4-carboxylic acid,

(81) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(Piras is n-2-ylamino)pyrimidine-4-ylamino}-2-phenylethanol,

(82) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-phenylpropane-1-ol,

(83) (R)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-4-methylpentan-1-ol,

(84) (S)-6-[2-(dimethylamino)ethoxy]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(85) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylic acid,

(86) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide,

(87) (S)-6-(benzo[d]-1,3-dioxol-5-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(88) (S)-N2-[1-(4-forfinal)ethyl]-6-(2-herperidin-4-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(89) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4-diamine,

(90) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}ethanol

(91) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4,6-triamine,

(92) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide,

(93) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide,

(94) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-methylbutane-1-ol,

(95) (S)-N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulphonyl)PI is erasin-1-yl]-N 4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(96) (1S,2S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}cyclohexanol,

(97) (S)-N2-[1-(4-forfinal)ethyl]-N4-[(5-methylpyridin-2-yl)methyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine,

(98) (S)-N2-[1-(4-forfinal)ethyl]-N4-(furan-2-ylmethyl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine,

(99) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[1-(pyridine-3-yl)ethyl]pyrimidine-2,4,6-triamine,

(100) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol,

(101) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-2-ylmethyl)pyrimidine-2,4,6-triamine,

(102) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-3-ylmethyl)pyrimidine-2,4,6-triamine,

(103) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-4-ylmethyl)pyrimidine-2,4,6-triamine,

(104) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-hydroxypropanoic,

(105) (3S,4S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3,4-diol,

(106) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyrimidine-2,4-diamine,

(107) (S)-8-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1,3-dioxo-8 azaspiro[4.5]decane-2-it,

(108) (S)4-(1-benzyl-1H-pyrazole-4-yl)-N 2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(109) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(phenylsulfonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(110) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzamide,

(111) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine,

(112) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(113) (S)-N2-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(114) (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methoxyphenyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(115) (S)-4-(4-forfinal)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(116) (S)-N2-[1-(4-forfinal)ethyl]-4-methyl-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(117) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(methylsulphonyl)piperidine-4-carboxamide,

(118) (S)-N2-[1-(4-forfinal)ethyl]-4-(furan-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(119) (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(120) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-4-(hydroxymethyl)piperidine-4-ol,

(121) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzosulfimide,

(122) (S)-N2 -[1-(4-forfinal)ethyl]-4-methoxy-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(123) 4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1λ6,4-thiomorpholine-1,1-dione,

(124) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}piperidine-4-ol,

(125) (S)-1-(4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1,4-diazepan-1-yl)Etalon,

(126) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyrimidine-2-yl)pyridine-2,4,6-triamine,

(127) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyridin-2-yl)pyridine-2,4,6-triamine,

(128) N2-[(S)-1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyridine-2,6-diamine,

(129) methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate,

(130) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylbenzenesulfonamide,

(131) (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(132) (S)-N2-[1-(4-forfinal)ethyl]-N4N6di(pyrazin-2-yl)pyridine-2,4,6-triamine

(133) (S)-4-(cyclopropylmethoxy)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(134) (S)-N2-[1-(4-forfinal)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(135) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methane is,

(136) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate acid,

(137) (S)-N2-[1-(4-forfinal)ethyl]-4-(2-methoxyethoxy)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(138) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile,

(139) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(140) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(141) (S)-N2-[1-(4-forfinal)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(142) (S)-N2-[1-(4-forfinal)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(143) methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinate,

(144) (S)-2-[1-(4-forfinal)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,

(145) (S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(146) (S)-N-tert-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(147) (S)-N-ethyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(148) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}[4-(methanesulfonyl)piperazine-1-yl]metano,

(149) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(pyrrolidin-1-yl)methanon,

(150) (S)-2-[1-(4-forfinal)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,

(151) (S)-1-{2-[(S)-1-(4-Fortini is)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-carboxamid,

(152) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(tetrahydro-2H-Piran-4-yloxy)pyridine-2,6-diamine,

(153) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,

(154) (S)-2-[1-(4-forfinal)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,

(155) (S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,

(156) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(morpholino)methanon,

(157) (S)-N-benzyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(158) (S)-N-cyclopropyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(159) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(4-methylpiperazin-1-yl)methanon,

(160) (S)-2-[1-(4-forfinal)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,

(161) (S)-2-[1-(4-forfinal)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,

(162) (S)-N-cyclopropylmethyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(163) (S)-N-cyclobutyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(164) (S)-N-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(165) (S)-2-[1-(4-forfinal)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,

(166) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2-triptorelin)isonicotinamide,

(167) (S)--[1-(4-forfinal)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide,

(168) (S)-N-(2-ethoxyethyl)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,

(169) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylisatin-3-carboxamide,

(170) (S)-N2-[1-(4-forfinal)ethyl]-4-(methoxymethyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(171) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N,N-dimethylamide-3-carboxamide,

(172) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanesulfonamide,

(173) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carbonitril,

(174) 2-(4-forfinal)-2-[4-(1-methyl-1H-pyrazole-4-yl)-6-(pyrazin-2-ylamino)pyridine-2-ylamino]ethanol

(175) (S)-N-ethyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,

(176) (S)-N,N-diethyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,

(177) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}Etalon,

(178) (S)-N2-[1-(4-forfinal)ethyl]-6-(3-methoxyisatin-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(179) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-methylaziridine-3-ol,

(180) (S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,

(181) (S)-2-[1-(4-forfinal)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,

(182) (S)-2-[1-(4-�terphenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,

(183) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-3-yl}(morpholino)methanon,

(184) (S)-N-(cyclopropylmethyl)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,

(185) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)econsultant,

(186) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-Isopropylamine-3-carboxamide,

(187) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-(trifluoromethyl)azetidin-3-ol,

(188) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(pyrrolidin-1-yl)methanon,

(189) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-methoxyethyl)azetidin-3-carboxamide,

(190) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(piperidine-1-yl)methanon,

(191) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(morpholino)methanon,

(192) (S)-N-(cyclopropyl)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,

(193) (S)-N-(cyclopropylmethyl)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,

(194) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-hydroxyethyl)azetidin-3-carboxamide,

(195) (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-Ilam is but)pyrimidine-4-yl}azetidin-3-ol,

(196) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-Isopropylamine-3-ol,

(197) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol,

(198) (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol,

(199) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-Isopropylamine-3-ol,

(200) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-methylaziridine-3-ol,

(201) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-(trifluoromethyl)azetidin-3-ol,

(202) (S)-4-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(203) (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}acetamide", she

(204) (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanesulfonamide,

(205) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}urea,

(206) (S)-4-(3-cyclopropyl-3-methoxyisatin-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(207) (S)-N2-[1-(4-forfinal)ethyl]-4-(3-isopropyl-3-methoxyisatin-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(208) (S)-N2-[1-(4-forfinal)ethyl]-4-(3-methoxy-3-methylaziridine-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(209) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6-(5-methylpr the Zin-2-yl)pyridine-2,6-diamine,

(210) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methanesulfonyl)piperidine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(211) (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propionamide,

(212) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(213) (S)-4-(1-cyclopropyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(214) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methoxymethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,

(215) (S)-6-[3-(dimethylamino)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(216) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(217) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidine-2,4-diamine,

(218) (S)-N2-[1-(4-forfinal)ethyl]-6-(3-morpholinomethyl-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(219) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(220) (S)-(1-{1-[2-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)piperidine-4-ol,

(221) 4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1λ6,4-thiomorpholine-1,1-dione,

(222) (S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(feast of the zine-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)urea,

(223) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanol,

(224) of tert-butyl (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methylcarbamate,

(225) (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,

(226) (S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]econsultant,

(227) (S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]acetamide", she

(228) (S)-N2-[1-(4-forfinal)ethyl]-4-[3-morpholinomethyl-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine and

(229) (S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-yl)piperidine-4-ol.

[0009] the Compounds of the present invention or their pharmaceutically acceptable salts can be used as medicines.

The following details each of the terms used in the present invention.

The term “halogen” includes, for example, fluorine, chlorine, bromine and iodine.

The term “alkyl” means, for example, unbranched or branched alkyl containing 1-8 carbon atoms, more specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl and n-octyl. In particular, PR is pactically alkali, containing 1-6 carbon atoms and more preferred alkali containing 1-3 carbon atoms.

The alkyl fragment “alkylsulfonyl”, “alkylcarboxylic”, “hydroxyalkyl”, “(cycloalkyl)alkyl”, “alkoxyalkyl”, “alkylamino”, “(hydroxyalkyl)amino”, “(alkoxyalkyl)amino”, “dialkylamino”, "dialkylaminoalkyl”, “(cycloalkyl)alkylamino”, “alkylcarboxylic”, “alkylcarboxylic”, “alkylsulfonyl”, “alkylsulfonyl” and “monoalkylbenzenes” can be exemplified by the same examples as described above for “alkyl”.

The term “halogenated” means, for example, alkyl with an unbranched or branched chain, containing from 1 to 8 carbon atoms, one or more of which are substituted by halogen atoms in any optional substitutable position (positions). Alkyl and halogen fragments can be exemplified by the same examples as described above for the terms “alkyl” and “halogen”, respectively.

The term “cycloalkyl” means, for example, cycloalkyl containing 3-8 carbon atoms, more specifically, includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

Cycloalkenyl fragment “(cycloalkyl)alkyl”, “cycloalkenyl” and “(cycloalkyl)alkylamino” can be illustrated by such examples, ka is described above for the term “cycloalkyl”.

The term “alkoxy” means, for example, unbranched or branched alkoxy chain which contains 1 to 8 carbon atoms, more specifically, includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy and n-octyloxy.

Alkoxy fragment “alkoxyalkyl” and “(alkoxyalkyl)amino” can be exemplified by the same examples as described above for the term “alkoxy”.

The term “aryl” means aryl containing 6 to 10 carbon atoms, including, for example, phenyl, 1-naphthyl and 2-naphthyl. In particular, preferred is phenyl.

The term “aralkyl” means, for example, unbranched or branched alkyl chain containing 1-8 carbon atoms, which aryl containing 6 to 10 carbon atoms, optionally substituted at any substitutable position, including, for example, benzyl, phenylethyl (e.g., 1-phenylethyl, 2-phenylethyl, phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and so on) and naphthylmethyl (for example, 1-naphthylmethyl, 2-naphthylmethyl and so on).

The term “saturated cyclic amino group” means, for example, 4-7-membered saturated cyclic amino group which may contain one atom of O or S and one or two N atom as a forming ring atoms, more specifically, includes 1-azetidinol, 1 pyrrolidin the sludge, 1-imidazolidinyl, piperidino, 1-piperazinil, 1-tetrahydropyrimidine, morpholino, thiomorpholine and 1-homopiperazine.

The term “N-containing saturated heterocyclic group” means, for example, 5 - or 6-membered saturated heterocyclic group containing one N as a constituent ring atom, more specifically, includes, for example, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl.

The term “optional O-containing saturated cyclic group” means, for example, 5 - or 6-membered saturated cyclic group which may contain one O as a constituent ring atom, more specifically, includes, for example, cyclopentyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl.

The term “heteroaryl” means, for example, 5 - or 6-membered heteroaryl containing 1-4 atoms N, O and S as (a) components of the ring atoms, more specifically, includes, for example, furyl (e.g. 2-furyl, 3-furyl), thienyl (for example, 2-thienyl, 3-thienyl), pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl(for example, 1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-3-yl, 1,2,4-triazolyl-4-yl), tetrazolyl (for example, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g. the measures 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolin (for example, 3-isothiazole, 4-isothiazole, 5-isothiazolin), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) and pyrazinyl (for example, 2-pyrazinyl).

The term “tetrahydrofuranyl” includes, for example, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

The term “tetrahydropyranyl” includes, for example, 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl.

The preferred implementation of the present invention

[0010] the Compounds of the present invention can be obtained from known compounds or readily synthesized intermediates, for example, according to the following methods. Upon receipt of the compounds of the present invention, if the original substances are substituents which have a significant effect on the course of the reaction, this reaction is usually carried out after the preliminary protection of the source materials suitable protective groups, according to known methods. The protective group can be removed after the specified reaction, and using the known methods.

[0011]Method 1: when R2represents a halogen

(where R1and R5have the meanings as defined above; X1represents CH or N; and Hal1and Hal2are the same or different and each represents a halogen).

This reaction is a condensation reaction of compound [12] with the compound [13] using a palladium catalyst, and therefore, it can be doneper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but in particular there are no limits as long as the solvent does not render harmful influence on the course of the reaction. The above reaction is carried out at a temperature from 20°C to 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalizatorului, for example, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials, and the temperature of the specified reaction is usually the interval from 10 minutes to 24 hours.

Connection [12] as the starting material can be obtained using known methods (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252; Org. Lett., 6, 2004, 3671-3674).

[0012]Method 2: In the case when R2represents-ORP(where RPmatter, as defined above).

[0013]Method 2-1

(where X1, R1, R5and Hal2have the meanings as defined above; and R6represents alkyl, optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl and cycloalkyl, or optional O-containing saturated cyclic group).

The above reaction is carried out by condensing the compound [1a] with alcohol, compound [14], using a palladium catalyst is A. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. The above reaction is carried out at a temperature in the range from 20°C to 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl and easy-bis[2-(diphenylphosphino)phenyl] ether. Used bases include, for example, tert-piperonyl sodium and tribalistic. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 10 minutes to 24 hours.

[0014]How 2-2

(where X1, R1, R5, R6and Hal1have the meanings as defined above).

This reaction is a condensation reaction of compound [15] with the compound [13] using a palladium catalyst, and therefore, it can be carried out according to the method similar to example 1, as described above.

[0015] the Connection [15] as a starting compound can be obtained, for example, according to the following method.

(where X1, R1, R6Hal1and Hal2have the meanings as defined above).

Stage 1

Connection [18] can be obtained by the interaction of the compounds [16] with alcohol, compound [17], in a suitable solvent in the presence of a base at a temperature from -20°C to 100°C. is Used bases include, for example, sodium hydride, sodium hydroxide, etc., Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; and water; or mixtures thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually intervalt 30 minutes to 24 hours.

Stage 2

This reaction is a condensation reaction of compound [18] with the compound [19] using a palladium catalyst, and therefore, it can be doneper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. The above reaction is carried out at a temperature from 20°C to 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time of the criminal code is the current base rate of the reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 10 minutes to 24 hours.

[0016]Method 3: when R2represented by the following General formula [9]:

(where RMRNROand * have the meanings as defined above), or if R2is heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the binding site is restricted to C).

[0017]Method 3-1

(where X1, R1, R5and Hal2have the meanings as defined above; and R7and R8each represents hydroxy, or R7and R8taken together, represent-O-C(CH3)2-C(CH3)2-O-, -O-(CH2)3-O - or-O-CH2-C(CH3)2-CH2-O-; and

R9represents a group represented by the following General formula [9]:

(where RM, RN, ROand * have the meanings as defined above)

or heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)Ala is La, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the binding site is restricted to C).

This reaction is a reaction cross-combinations using the compound [1a] and compounds of organoborane [20], and therefore it can be performedper seaccording to known methods. The above reaction can be performed, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature of 20-200°C. Used palladium catalysts include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and a complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; water; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. Used bases include, for example, sodium hydroxide, potassium carbonate and sodium carbonate. The time specified reaction depends on the type of the source ve is esta and temperature specified reaction and is usually the interval from 30 minutes to 24 hours.

[0018]How 3-2

(where X1, R1, R5, R9and Hal1have the meanings as defined above).

This reaction is a condensation reaction of compound [21] with the compound [13] using a palladium catalyst and therefore it can be performedper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. The above reaction is carried out at a temperature from 20°C to 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-BINAP the sludge, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 10 minutes to 24 hours.

[0019] the Connection [21] as a starting compound can be obtained, for example, according to the following 3 ways.

[0020]The way A

(where X1, R1, R7, R8, R9Hal1and Hal2have the meanings as defined above; and Hal3represents a halogen).

Stage 1

This reaction is a reaction cross combinations using connection [22] and compounds of organoborane [20], and therefore it can be performedper seaccording to known methods. The above reaction can be performed, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20-200°C. Used palladium catalysts include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and a complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane. The number of palla is avago catalyst is preferably, the interval from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; water; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. Used bases include, for example, sodium hydroxide, potassium carbonate and sodium carbonate. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 30 minutes to 24 hours.

Stage 2

This reaction is a condensation reaction of compound [23] with the compound [19] using a palladium catalyst, and therefore, it can be doneper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. The above reaction is carried out at a temperature from 20°C d is 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 10 minutes to 24 hours.

[0021]Method B

(where X1, R1, R9Hal1and Hal2have the meanings as defined above; and R10, R11and R12are the same or different and each represents an alkyl).

This reaction is a reaction cross combinations using connection [12], and the connection of organoborane [24], and therefore it can be performedper seaccording to known methods. The above reaction can execute the ü, for example, in the presence of palladium catalyst in a suitable solvent at a temperature in the range of 20-200°C. Used palladium catalysts include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane and palladium acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; or mixtures thereof, but there is no specific limitation only if the solvents do not affect the course of the reaction. You can also use additives, such as copper oxide or silver oxide. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually a range from 1 to 24 hours.

[0022]The method C

(where X1, R1, R7, R8, R9Hal1and Hal2have the meanings as defined above).

This reaction is a reaction cross combinations using connection [12], and the connection is of organoborane [20], and so it can be doneper seaccording to known methods. The above reaction can be performed, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20-200°C. Used palladium catalysts include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium and a complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used the reaction solvent includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; water; or a mixture thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. Used bases include, for example, sodium hydroxide, potassium carbonate and sodium carbonate. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 30 minutes to 24 hours.

[0023]Method 4: In the case when R2represented by the following General formula [3]:

(where RFand RGeveryone has values, as defined above).

[0024]How 4-1

(where X1, R1, R5and Hal2everyone has values, as defined above; and R13represents a group represented by the following General formula [3]:

(where RFand RGeveryone has values, as defined above).

This reaction is a reaction cross-combinations using the compound [1a] and the compound [25], and therefore it can be performedper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. The above reaction can be performed, for example, in the presence of a palladium catalyst and a base in a suitable solvent at a temperature in the range of 20-200°C. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The number ispolzuemogo the palladium catalyst is preferably, the interval from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually the interval from 30 minutes to 24 hours.

[0025]How 4-2

(where X1, R1, R5, R13and Hal1everyone has values, as defined above).

This reaction is a condensation reaction of compound [26] with the compound [13] using a palladium catalyst, and therefore, it can be doneper seaccording to known methods. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; or a mixture thereof, but in particular there are no limits to those on the, until the solvents have no effect on the course of the reaction. The above reaction is carried out at a temperature from 20°C to 200°C in the presence of a base. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually the interval from 10 minutes to 24 hours.

[0026] the Connection [26] as a starting compound can be obtained, for example, by the following 2 methods.

(where X1, R1, R13Hal1and Hal2everyone has values, as defined above).

[0027]The way a

Connection [26] can be obtained by the interaction of the compound [12] with the compound [25] in a suitable solvent in the presence of a base at a temperature from 20°C to 200°C. Used bases include, for example, pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate and sodium bicarbonate. Used solvents include alcohols, such as 1-butanol, 2-methoxyethanol; ethers, such as tetrahydrofuran, 1,4-dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; acetonitrile; or a mixture thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually preferably in the range from 1 to 24 hours.

[0028]Method b

Connection [26] can be obtained by condensation reaction of compound [12] with the compound [25] using a palladium catalystper seaccording to a known method. Used solvents include, for example, hydrocarbons, such as toluene, xylene; ethers such as 1,4-dioxane, tetrahydrofuran; or mixtures thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. The above reaction can be performed in the Pris is under the base at a temperature from 20°C to 200°C. Used palladium catalysts include, for example, Tris(dibenzylideneacetone)(chloroform)dipalladium(0), Tris(dibenzylideneacetone)dipalladium(0) and palladium(II) acetate. The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. Used ligands for palladium catalysts include, for example, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, easy-bis[2-(diphenylphosphino)phenyl] ether, and tri-tert-butylphosphine. Used bases include, for example, tert-piperonyl sodium, tribalistic and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually the interval from 10 minutes to 24 hours.

[0029]Method 5: In the case when R2is heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the binding site is limited to N).

(where X1, R1, R5 and Hal1everyone has values, as defined above; and R14is heteroaryl, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylsulphonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl (but the binding site is limited to N)).

This reaction is a condensation reaction of compound [27] with the compound [13] using a palladium catalyst, and it can be carried out according to the method similar to example 4-2, as described above.

[0030] the Connection [27] as a starting compound can be obtained according to the following method.

(where X1, R1, R14Hal1and Hal2everyone has values, as defined above).

This reaction is a reaction cross combinations using connection [12] and the compound [28], and it can be doneper seaccording to known methods. The above reaction can be performed, for example, in the presence or absence of a copper catalyst in a suitable solvent at a temperature of from 20 to 200°C. Used copper catalysts include, for example, copper iodide and copper acetate. The amount of copper catalyst composition is yet, preferably, the interval from 0.01 to 0.2 mol per 1 mol of arylalkenes. As ligands for copper, you can use such ligands, TRANS-N,N'-dimethylcyclohexane-1,2-diamine, TRANS-1,2-cyclohexanediamine, 1,10-phenanthrolin, etc. Used in the reaction solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; or mixtures thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. Used bases include, for example, tribalistic, potassium carbonate, sodium carbonate and cesium carbonate. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually preferably in the range from 30 minutes to 24 hours.

[0031]Method 6: In the case when R2is alkoxycarbonyl

(where X1, R1, R5and Hal1everyone has values, as defined above; and R15represents alkyl).

This reaction is a condensation reaction of compound [29] with the compound [13] using a palladium catalyst, and it can be done on m is todica, similar to example 4-2, as described above.

[0032] the Compound [29] as a starting compound can be obtained according to the following method.

(where X1, R1, R15and Hal1everyone has values, as defined above).

This reaction is a condensation reaction of compound [30] with the compound [19] using a palladium catalyst, and it can be carried out according to the method similar to that described in stage 2 of the method for obtaining compounds [15] as a starting compound, as described above.

[0033]Method 7: In the case when R2is hydroxycarbonyl

(where X1, R1, R5and R15everyone has values, as defined above).

This reaction is a hydrolysis reaction of the compound [1f], and it can be doneper seaccording to a known method. Typically, this reaction can be carried out by hydrolysis of the compound [1f] in the presence of acid or base, to obtain the compound [1g]. Acids which can be used in this reaction include, for example, inorganic acids such as hydrochloric acid and sulfuric acid; bases include, for example, inorganic bases such as sodium hydroxide and guide the oxide of potassium. Solvents that can be used in this reaction include, for example, alcohols such as methanol, ethanol; ethers, such as tetrahydrofuran, 1,4-dioxane; water; or mixtures thereof. The above reaction is carried out at a temperature from 0°C to 100°C, usually for a period of time from 30 minutes to 24 hours.

[0034]Method 8: In the case when R2represents (a) a saturated cyclic amino group, optionally substituted by alkyl or alkylsulfonyl; or (b) aminocarbonyl, optionally substituted by one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, halogenoalkane, dialkylaminoalkyl, alkoxyalkyl and hydroxyalkyl

(where X1, R1and R5everyone has values, as defined above; R16and R17are the same or different and each represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, halogenated, dialkylaminoalkyl, alkoxyalkyl or hydroxyalkyl, or taken together with the adjacent N atom, they represent a saturated cyclic amino group; and the specified saturated cyclic amino group may be optionally substituted by alkyl or alkylsulfonyl).

This reaction is a condensation reaction of compound [1g] what Obedinenie [31], and it can be carried out per se, according to known methods. The compound [1h] can be synthesized by reacting compound [1g] in the form of a carboxylic acid or its reactive derivative with the compound [31]. Reactive compound [1g] include those which are usually used in the condensation reactions of amides, for example, halides (e.g. acid chloride, bromohydrin), mixed acid anhydrides, imidazolides, active amides, etc., In the case of using the compound [1g] the above reaction is carried out in the presence or absence of the substrate, using a condensing agent at a temperature of from -20 to 100°C. Condensing agents which can be used in this reaction include, for example, 1,1'-oxalylamino, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylthiophosphate, hexaflurophosphate O-(benzotriazole-1-yl)-N,N,N',N'-tetramethylurea and hexaphosphate 1H-benzotriazolyl-1-electropermeabilization. Bases that can be used in this reaction include organic bases, such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine and 1,8-diazabicyclo[5.4.0]-7-undecene. Used solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether; amides such as N,N-dimethylformamid is d, N,N-dimethylacetamide; NITRILES such as acetonitrile, propionitrile; hydrocarbons, such as benzene, toluene; halogenated hydrocarbons such as chloroform, methylene chloride; or mixtures thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. If necessary, you can use supplements. Additives include, for example, 1-hydroxybenzotriazole and 1-hydroxy-7-isobenzofuranyl. The time specified reaction depends on the type of source materials and temperature specified reaction and is usually preferably in the range from 10 minutes to 24 hours. The number of compounds [31] and the condensing agent is preferably, for example, in the range of 1-3 equimolar amounts of 1 mol of compound [1g].

[0035]Method 9: In the case when R2represents H, alkylsulphonyl, N-containing saturated heterocyclic group, optionally substituted by alkylsulfonyl or alkyl, optionally substituted by hydroxy or alkoxy

(where X1, R1, R5and Hal1everyone has values, as defined above; and R18represents H or alkyl, optionally substituted alkoxy).

This reaction is a condensation reaction of compound [32] with the compound [13] IP is the use of palladium catalyst, and it can be carried out according to the method similar to that described above in method 1.

[0036]Method 10: In the case when R2represents a cyano

(where X1, R1, R5and Hal2everyone has values, as defined above).

This reaction is a reaction cyanation of the compound [1a], and it can be carried out per se, according to known methods. The above reaction can be carried out using cenocoeliinae, for example, in the presence or absence of a palladium catalyst at a temperature of from 20 to 200°C., optionally using microwave irradiation. Used palladium catalysts include, for example, tetrakis(triphenylphosphine)palladium complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane and Tris(dibenzylideneacetone)dipalladium(0). The amount of palladium catalyst is preferably in the range from 0.001 to 0.1 mol per 1 mol of arylalkenes. If necessary, you can use the ligands of palladium, such as 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, etc. Used cyanocobalamine include cyanide, copper(I) cyanide zinc(II), potassium cyanide and sodium cyanide. Used will dissolve the do include, for example, ethers such as tetrahydrofuran, 1,4-dioxane; alcohols such as methanol, ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone; hydrocarbons, such as benzene, toluene; dimethylbenzenesulfonic; water; or a mixture thereof, but in particular there are no limits as long as the solvent does not affect the course of the reaction. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually preferably in the range from 30 minutes to 24 hours.

[0037]Method 11: when X represents-CRAand RAis alkoxycarbonyl

(where R1, R5and Hal1everyone has values, as defined above; and R19represents alkyl).

This reaction is a condensation reaction of the compound [33] with the compound [13], using a palladium catalyst, and it can be carried out according to the method similar to example 4-2, as described above.

[0038] the Compound [33] as a starting compound can be obtained according to the following method.

(where R1, R19Hal1and Hal3everyone has values, as defined above).

This reaction is particularly the condensation reaction of compound [34] with the compound [19] using a palladium catalyst, and it can be carried out by the procedure similar to step 2 of method A, method 3-2, as described above.

[0039]Method 12: In the case when X represents-CRAand RAis hydroxycarbonyl

(where R1, R5, R19Hal1and Hal3everyone has values, as defined above).

This reaction is a hydrolysis reaction of the compound [1k], and it can be carried out according to the method similar to example 7, as described above.

[0040]Way 13: In the case when X represents-CRA; and RArepresents a group represented by the General formula [35]:

(where * is the value as defined above; R20and R21are the same or different and each represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl or alkoxyalkyl, or, taken together with the adjacent N atom, they represent a saturated cyclic amino group).

(where R1, R5, R20and R21everyone has values, as defined above).

This reaction is a condensation reaction of compound [1j] with the compound [36], and it can be carried out according to the method similar to example 8, as described is use.

[0041]Way 14: In the case when R4represents an alkyl

(where X, R1, R2, R3, R5and Hal1everyone has values, as defined above; and R22represents alkyl).

This reaction is a condensation reaction of compound [37] with the compound [13] using a palladium catalyst, and it can be carried out according to the method similar to example 4-2, as described above.

[0042] the Compound [37] as a starting compound can be obtained according to the following method.

(where X, R1, R2, R5, R22and Hal1everyone has values, as defined above; and Hal4represents a halogen).

At this stage the connection [38] provide an opportunity to interact with the compound [39] in a suitable solvent in the presence of a base at a temperature from 20°C to 200°C, optionally using microwave irradiation. Used bases include, for example, sodium hydride, diisopropylamide lithium and n-utillity. Used solvents include, for example, ethers such as tetrahydrofuran, 1,4-dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; hydrocarbons, such as benzene, toluene; acetonitrile; or a mixture thereof, but specific about what the controls do not exist until until the solvents have no effect on the course of the reaction. The time specified reaction depends on the type of source materials and temperature specified reactions, and is usually preferably in the range from 10 minutes to 24 hours.

[0043]Way 15: In the case when R3represents a hydroxy

(where X1, R1, R2, R5and Hal1everyone has values, as defined above).

This reaction is a condensation reaction of compound [40] with the compound [13] using a palladium catalyst, and it can be carried out according to the method similar to example 1, as described above. As for the base, which can be used in this reaction, it is appropriate tert-piperonyl sodium.

[0044] the Compound [40] as a starting compound can be obtained according to the following method.

(where X1, R1, R2, R5Hal1and Hal3everyone has values, as defined above).

Stage 1

Connection [42] can be obtained using known methods (J. Org. Chem., 65, 2000, 9059-9068).

Stage 2

At this stage the connection [42] is subjected to the condensation reaction with the compound [43] using a palladium catalyst, and the above reaction can about what westwith according to the method similar to example 1, as described above.

[0045] Although the compounds of the present invention can be used as medicines as such, they can also be used in the form of pharmaceutically acceptable salts according to known methods. Such salts include salts of mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, or salts of organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluensulfonate acid, benzosulfimide acid, methanesulfonic acid and so on

For example, hydrochloride compounds of the present invention can be obtained by dissolving the compounds of the present invention in a solution of hydrogen chloride in alcohol or ethyl acetate, or diethyl ether.

[0046] since some compounds of the present invention contain asymmetric carbon, all optical isomers and their mixtures are included in the present invention. The optical isomers can be obtained by optical separation of racemates obtained as described above, with an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid and so on), using their basicity, according to known methods, or, alternati is but the optical isomers can be obtained from optically active starting compounds obtained in advance. On the other hand, they can be obtained by optical separation using a chiral column or asymmetric synthesis.

When the compounds of the present invention exist in the form of geometric isomers or tautomers, not only each of these isomers and their mixtures are included in the present invention.

[0047] the Compounds of the present invention or their pharmaceutically acceptable salts can be used as medicines. Pharmaceutical compositions containing the compounds of the present invention or their pharmaceutically acceptable salts as active ingredients, can be used in preventive or therapeutic medicines for cancer (for example, when hematological cancer (e.g., when the true polycythemia, essential of thrombocythemia, myeloproliferative tumors, such as idiopathic myelofibrosis (chronic myeloid proliferative disease) syndrome osteomielitis, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma), in solid cancers (such as prostate cancer, breast cancer), inflammatory Soboleva is Yah (for example, in rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis) and angiopathy (for example, pulmonary hypertension, arteriosclerosis, aneurysm, varicose veins).

[0048] When the compounds of the present invention or their pharmaceutically acceptable salts are administered as pharmaceuticals, they can be administered as such or in the form of pharmaceutical compositions containing, for example, from 0.001% to 99.5%, preferably from 0.1% to 90% of the active ingredient (a) pharmaceutically acceptable non-toxic and inactive media (media) mammals, including humans.

As for the media, you can use one or more of the members of solid, semi-solid or liquid excipients, fillers and other auxiliary agents for pharmaceutical compositions. The pharmaceutical compositions of the present invention preferably administered in unit dosage form. The pharmaceutical composition can be introduced through the fabric, orally, intravenously, topically (dermal, in the form of eye drops and so on) or rectally. The composition can be entered in a dosage form appropriate for the selected route of administration.

Dosage as a medicine, it is desirable to determine, depending on the condition of the patient, such as age, weight, type and condition of the disease and the method of administration, and usually, this dose corresponds to the introduction in the range of 0.1 mg to 5 g/day, preferably 1 mg to 500 mg/day for adults in the form of compounds of the present invention or its pharmaceutically acceptable salt as the active ingredient when administered orally. In some cases, this dose may be lower than the above intervals, or if necessary, may be higher. Usually dose can be administered in a single dose or in divided doses, or by continuous injection within 1 to 24 hours.

EXAMPLES

[0049] Hereinafter the present invention will be described in more detail using the comparative examples, examples, test examples and examples of compositions of the compounds of the present invention that the present invention is not limited.

Comparative example 1

(S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine

2.4 g of 2,4,6-trichloropyridine dissolved in 24 ml of tetrahydrofuran, add 2.0 ml of triethylamine at room temperature and added dropwise a solution of 2.0 g (S)-(-)-1-(4-forfinal)ethylamine in 12 ml of tetrahydrofuran, then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtered to remove the precipitate, and then the resulting filtrate is concentrated under reduced pressure. The resulting residue is purified colonoscopy because it allows the Noah chromatography on silica gel, obtaining 1,77 g specified in the connection header.

MS (ESI, electrospray ionization) m/z 286 (M+H)+

Comparative example 2

(S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

(S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyridine-2-amine

7.2 g of 2,4,6-trichloropyridine and to 2.74 g (S)-(-)-1-(4-forfinal)ethylamine are dissolved in 25 ml of 1-butanol, to the solution is added to 13.7 ml of N,N-diisopropylethylamine and the resulting mixture is stirred at a temperature of 120°C for 42 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, with getting to 2.57 g specified in the title compound as a yellow oil.

MS (ESI) m/z 285 (M+H)+

Stage 2

(S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

To 734 mg (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyridine-2-amine, 343 mg of 2-aminopyrazine, 1.39 g of tribalista, 190 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene and 170 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 17 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with argon and the mixture is stirred at a temperature of 100°C for 19 hours. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 654 mg specified in the title compound as a brown powder.

MS (ESI) m/z 344 (M+H)+

[0050]Example 1

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-he

Stage 1

(S)-4-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}piperazine-2-he

To a solution of 150 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine and 58 mg piperazine-2-it 1.5 ml of 1-butanol add 183 μl of N,N-diisopropylethylamine and the resulting mixture was stirred at 60°C for 20 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 196 mg specified in the title compound as a white powder.

MS (ESI) m/z 355 (M+H)+

Stage 2

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-he

196 mg (S)-4-{6-chloro-2-[1-(4-forfinal)atrami is a]pyrimidine-4-yl}piperidine-2-it, 55 mg of 2-aminopyrazine, 50 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 101 mg of tert-butoxide sodium and 27 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 6 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 196 mg specified in the title compound as pale brown powder.

MS (ESI) m/z 409 (M+H)+

Example 2

The hydrochloride of N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}ndimethylacetamide

N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}ndimethylacetamide receive according to the method similar to example 1, using (S)-N-(pyrrolidin-3-yl)ndimethylacetamide instead of piperazine-2-it. The compound obtained is dissolved in methanol, the resulting solution was added 1N hydrochloric acid and then the solvent is removed, obtaining specified in the title compound as a white powder.

MS (ESI) m/z 437 (M+H)+

Example 3

Hydrochlori the (S)-6-(3,3-diversecity-1-yl)-N 2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-6-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethylamino]-N4(pyrazin-2-ylamino)pyrimidine-2,4-diamineget the method similar to example 1, using the hydrochloride of 3,3-diversityin instead of piperazine-2-it. The compound obtained is dissolved in methanol, add 1N hydrochloric acid and then the solvent is removed, obtaining specified in the title compound as a white powder.

MS (ESI) m/z 402 (M+H)+

Example 4

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

2,6-dichloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine

500 mg of 2,6-dichloro-4-iodopyridine, 379 mg of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 753 mg of potassium carbonate and 74 mg of the complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane is added in order to degassed solvent mixture consisting of 7.5 ml of 1,4-dioxane and 2.5 ml of water, and the resulting mixture was stirred at 90°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is Argonaut under reduced pressure, then the obtained residue is purified column chromatography on silica gel, to obtain 257 mg specified in the connection header.

MS (ESI) m/z 228 (M+H)+

Stage 2

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine

257 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine obtained in stage 1, 164 mg (S)-(-)-1-(4-forfinal)ethylamine, 66 mg of 2-(di-tert-butylphosphino)biphenyl, 271 mg of tert-butoxide sodium and 25 mg of palladium acetate is added in order to 6 ml of degassed toluene, and the resulting mixture was stirred at 85°C for 2 hours in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 240 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 331 (M+H)+

Stage 3

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

235 mg (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine, 74 mg of 2-aminopyrazine, 68 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 95 mg of tert-butoxide sodium and 37 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 6 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1.5 hours in an argon atmosphere. Reaktionarsten diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 204 mg of (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine as a pale yellow powder. The compound obtained is dissolved in ethanol, add 1N hydrochloric acid and then the solvent is removed, obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 390 (M+H)+

Example 5

Hydrochloride (S)-N2'-[1-(4-forfinal)ethyl]-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine

(S)-N2'-[1-(4-forfinal)ethyl]-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine receive according to the method similar to example 4 using 3-(1,3,2-dioxaborinane-2-yl)pyridine instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The compound obtained is dissolved in ethanol, add 1N hydrochloric acid, then the solvent is removed, obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 387 (M+H)+

[0051] Example 6

(S)-N2'-[1-(4-forfinal)ethyl]-6-methoxy-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine

Specified in the agolove compound obtained as pale yellow powder by the method, similar to example 4, using 2-methoxy-5-pyridineboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

MS (ESI) m/z 417 (M+H)+

Example 7

Hydrochloride (S)-2'-[1-(4-forfinal)ethylamino]-6'-(pyrazin-2-ylamino)-3,4'-bipyridine-6-ol

108 mg of (S)-N2'-[1-(4-forfinal)ethyl]-6-methoxy-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine dissolved in 3 ml of acetonitrile, add 116 mg of sodium iodide and 99 μl of tributyltinchloride and the resulting mixture was stirred at 70°C for 3.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate and water and the pH of the mixture was adjusted to 9 using saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified column chromatography on silica gel, to obtain 78 mg (S)-2'-[1-(4-forfinal)ethylamino]-6'-(pyrazin-2-ylamino)-3,4'-bipyridine-6-ol as a pale yellow powder. The compound obtained is dissolved in methanol, to the solution was added 1N hydrochloric acid and then the solvent is removed, obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 403 (M+H)+

Example 8

(S)-N2-[1-(4-forfinal)ethyl]-4-(oxazol-5-yl)-N (pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

5-(2,6-dichloropyridine-4-yl)oxazol

528 mg of 2,6-dichlorosalicylaldehyde (this compound was obtained by the method described in J. Chem. Soc., Chem. Commun., 1998, 1567-1568) dissolved in 10 ml of methanol, add 586 mg p-toluensulfonate and 415 mg of potassium carbonate and the resulting mixture is stirred at 50°C for 30 minutes. The reaction solution is concentrated and then diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 630 mg specified in the title compound as a white powder.

MS (ESI) m/z 215 (M+H)+

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-4-(oxazol-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

630 mg of 5-(2,6-dichloropyridine-4-yl)oxazole obtained in stage 1, 408 mg (S)-(-)-1-(4-forfinal)ethylamine, 182 mg of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and 1.9 g of cesium carbonate and 66 mg of palladium acetate is added in order to 30 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1.5 hours in an argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 600 mg (S)-6-chloro-N-[1-(4-forfinal)ethyl]4-(oxazol-5-yl)pyridin-2-amine as a pale yellow powder. 10 ml of degassed toluene are added to the obtained powder and 180 mg of 2-aminopyrazine, 180 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 254 mg of tert-butoxide sodium and 98 mg of Tris(dibenzylideneacetone)diplodia add in this order, the resulting mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 390 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 377 (M+H)+

Example 9

(S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

1.37 g (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 460 mg of 2-aminopyrazine, 277 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2,04 g tribalista and 248 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 30 ml of 1,4-dioxane, the mixture was subjected to degassing, then the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 2 hours. The reaction solution was diluted with ethyl acetate. The resulting solution washed the t successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 960 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 345 (M+H)+

Example 10

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

100 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 145 mg of 4-(methylsulphonyl)phenylboronic acid, 123 mg of sodium carbonate and 17 mg of tetrakis(triphenylphosphine)palladium is added in order to degassed solvent mixture consisting of 3 ml of 1,4-dioxane and 1.2 ml of water, and the resulting mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 124 mg of (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine as a white powder. The compound obtained is dissolved in methanol, add 1N hydrochloric acid and the solvent is then delete the Ute, obtaining specified in the title compound as a white powder.

MS (ESI) m/z 465 (M+H)+

[0052]Example 11

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10, using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carbamate instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 377 (M+H)+

Example 12

Hydrochloride (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yloxy}ethanol

To 150 mg (S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine, 187 mg of tribalista, 84 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl and 46 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and the resulting mixture is stirred at a temperature of 100°C for 13 hours. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and neymann the m salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 62 mg of (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yloxy}ethanol as a pale brown powder. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 52 mg specified in the title compound as a yellow powder.

MS (ESI) m/z 370 (M+H)+

Example 13

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine

Stage 1

(S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(pyridin-3-yl)pyrimidine-2-diamine

500 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 314 mg of 3-(1,3,2-dioxaborinane-2-yl)pyridine, 927 mg of sodium carbonate and 202 mg of tetrakis(triphenylphosphine)palladium is added in order to degassed solvent mixture consisting of 15 ml of toluene, 7 ml of ethanol and 10 ml of water, and the resulting mixture was stirred at 110°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column of chromatographie the on silica gel, to obtain 218 mg specified in the title compound as a white powder.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine

To 100 mg (S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(pyridin-3-yl)pyrimidine-2-diamine, 35 mg of 2-aminopyrazine, 18 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 129 mg tribalista and 16 mg of Tris(dibenzylideneacetone)(chloroform)diplodia, add 2 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 1 hour. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 54 mg specified in the title compound as a white powder.

MS (ESI) m/z 388 (M+H)+

Specific rotation [α]D20=-29,60° (c=0.5, methanol)

Example 14

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine

Stage 1

(S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(pyridin-2-yl)pyrimidine-2-diamine

200 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1) and 0.22 ml of 2-(Tr is butylstannyl)pyridine, 55 mg of copper oxide and 81 mg of tetrakis(triphenylphosphine)palladium is added in order to degassed toluene, and the resulting mixture was stirred at 110°C for 4 hours in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 63 mg specified in the title compounds as colorless oils.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine

To 62 mg of (S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(pyridin-2-yl)pyrimidine-2-diamine, 22 mg of 2-aminopyrazine, 22 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 80 mg tribalista and 20 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 2 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 2 hours. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 25 mg specified in the title compound as a white powder.

MS (ESI) m/z 388 (M+H)+

Specific rotation [α]D20=-61,20° (c=0.5, methanol)

Example 15

S)-N 2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 14, using 4-(tributylstannyl)pyridine instead of 2-(tributylstannyl)pyridine.

MS (ESI) m/z 388 (M+H)+

[0053]Example 16

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-he

Stage 1

(S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}pyrrolidin-2-he

100 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 33 mg of 2-pyrrolidone, 20 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 149 mg of tribalista and 19 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 3 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The reaction solution is filtered to remove rainfall, the solvent is distilled off under reduced pressure and then the resulting residue is purified column chromatography on silica gel, to obtain 106 mg specified in the title compound as a yellow oil.

Stage 2

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-he

104 mg of (S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}pyrrolidin-2-about the and, 33 mg of 2-aminopyrazine, 18 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 132 mg tribalista and 17 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 3 ml of degassed 1,4-dioxane, and then the resulting mixture is stirred at a temperature of 100°C for 11 hours in an argon atmosphere. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 74 mg specified in the title compound as pale brown powder.

MS (ESI) m/z 394 (M+H)+

Specific rotation [α]D20=-19,60° (c=0.5, methanol)

Example 17

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2,6-dione

Stage 1

(S)-4-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}piperazine-2,6-dione

182 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1) and 80 mg piperazine-2,6-dione is dissolved in 2 ml of tetrahydrofuran and 2 ml of N,N-dimethylformamide, to the solution was added 122 μl of N,N-diisopropylethylamine and the resulting mixture is stirred at a temperature of 80°C for 32 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and, to obtain 136 mg specified in the title compound as a white powder.

Stage 2

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2,6-dione

119 mg (S)-4-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}piperazine-2,6-dione, 34 mg of 2-aminopyrazine, 19 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 139 mg of tribalista and 17 mg of Tris(dibenzylideneacetone)(chloroform)diplodia added to 2.5 ml of degassed 1,4-dioxane, and then the resulting mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 26 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 423 (M+H)+

Example 18

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}tetrahydropyrimidin-2(1H)-he

Specified in the title compound obtained as pale yellow powder by the method similar to example 16, using tetrahydro-2-pyrimidine instead of 2-pyrrolidone.

MS (ESI) m/z 409 (M+H)+

Example 19

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyrrolidin-1-yl)PI is kidin-2,4-diamine

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 1, using pyrrolidine instead of piperazine-2-it.

MS (ESI) m/z 380 (M+H)+

Example 20

(S)-N2-[1-(4-forfinal)ethyl]-6-morpholino-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 1, using morpholine instead of piperazine-2-it.

MS (ESI) m/z 396 (M+H)+

Specific rotation [α]D20=-25,19° (c=0.5, methanol)

[0054] Example 21

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}imidazolidin-2-it

150 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 9), 224 mg of 2-imidazolidinone, 26 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 185 mg of tribalista and 23 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 5 ml of degassed 1,4-dioxane, and the resulting mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, then the remainder of cleansing the t column chromatography on silica gel, to obtain 80 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}imidazolidin-2-it is in the form of a white powder. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 56 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 395 (M+H)+

Elemental analysis (for C19H19FN8O·HCl+0.5 H2O+0.1 C2H5OH)

Calculated (%) C: 51,88, H: 4,90, N: 25,21

Found (%) C: 51,71, H: 4,77, N: 24,87

Example 22

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(oxazol-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Stage 1

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine

150 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 9), 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (synthesized according to the method described in WO2007/17096) and 25 mg of tetrakis(triphenylphosphine)palladium is added in order to 5 ml of degassed dimethylformamide, and the resulting mixture is stirred at a temperature of 100°C for 2.5 hours in an argon atmosphere. To the mixture is added 246 mg of 5-(tributylstannyl)-2-(triisopropylsilyl)oxazole and the resulting mixture was continued to stir for four hours. The reaction is first solution was diluted with water and then extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 153 mg of (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine as a pale orange oil.

Stage 2

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(oxazol-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

122 mg (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[2-(triisopropylsilyl)oxazol-5-yl]pyrimidine-2,4-diamine are dissolved in 1.2 ml of tetrahydrofuran and add 0.5 ml of 1M tertrahydrofuran ring solution tetrabutylammonium. The reaction solution was stirred at room temperature for 20 min and then diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 60 mg (S)-N2-[1-(4-forfinal)ethyl]-6-(oxazol-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine as a white powder. The compound obtained is subjected to hydrochloridebuy using the normal method, with p is the receiving 45 mg specified in the title compounds as a pale orange powder.

MS (ESI) m/z 378 (M+H)+

Elemental analysis (for C19H16FN7O·HCl)

Calculated (%) C: 55,14, H: 4,14, N: 23,69

Found (%) C: 54,94, H: 3,92, N: 23,81

Example 23

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(6-methoxypyridine-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-(6-methoxypyridine-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10, using 2-methoxy-5-pyridineboronic acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 418 (M+H)+

Elemental analysis (for C22H20FN7O·HCl)

Calculated (%) C: 58,21, H: 4,66, N: 21,60

Found (%) C: 57,80, H: 4,48, N: 21,54

Specific rotation [α]D20=-24,80° (c=0.5, methanol)

Example 24

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-3-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-3-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10, using 1H-pyrazole-3-Bronevoy acid instead of 4-(methylsulphonyl)phenylboronic acid. Furthermore, the obtained compound was subjected to the home hydrochloridebuy, using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 377 (M+H)+

Elemental analysis (for C19H17FN8·HCl+0,8 H2O)

Calculated (%) C: 53,41, H: 4,62, N: 26,23

Found (%) C: 53,21, H: or 4.31, N: 26,25

Specific rotation [α]D20=-86,40° (c=0.5, methanol)

Example 25

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol

Stage 1

(S)-N2-[1-(4-forfinal)ethyl]-6-(2-herperidin-4-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the header connection receive according to the method similar to example 5, using 2-herperidin-4-Bronevoy acid instead of 4-(methylsulphonyl)phenylboronic acid.

Stage 2

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol

1 ml of 1,2-dimethoxyethane and 10% hydrochloric acid is added to 80 mg (S)-N2-[1-(4-forfinal)ethyl]-6-(2-herperidin-4-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine and the mixture was stirred at 85°C for 2 hours. Then add 0.5 ml of 10% hydrochloric acid and the resulting mixture was continued to stir for 2 hours. The reaction solution was diluted with ethyl acetate and alkalinized saturated aqueous sodium bicarbonate. The resulting mixture ex is reginout and the organic layer is dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting solid product is washed with diethyl ether, filtered off and then dried under reduced pressure, to obtain 54 mg specified in the title compound as a white powder.

MS (ESI) m/z 404 (M+H)+

[0055] Example 26

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol

Specified in the title compound obtained as a pale-brown powder according to the method similar to example 7 using (S)-N2-[1-(4-forfinal)ethyl]-6-(6-methoxypyridine-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 23) instead of (S)-N2'-[1-(4-forfinal)ethyl]-6-methoxy-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine.

MS (ESI) m/z 404 (M+H)+

Specific rotation[α]D20=-39,60° (c=0.5, methanol)

Example 27

The hydrochloride of N-((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)ndimethylacetamide

N-((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)ndimethylacetamide receive according to the method similar to example 1, using (R)-N-(pyrrolidin-3-yl)ndimethylacetamide instead of piperazine-2-it. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 437 (M+H)+

Elementaires (C 22H25FN8O·HCl)

Calculated (%) C: 55,87, H: 5,54, N: 23,69

Found (%) C: 55,49, H: a total of 5.21, N: 23,59

Specific rotation [α]D20=113,59° (c=0.5, methanol)

Example 28

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-4-yl)pyridine-2,6-diamine

Stage 1

2,6-dichloro-4-(1H-pyrazole-4-yl)pyridine

188 mg of 2,6-dichloro-4-iodopyridine, 201 mg of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carbamate, 284 mg of potassium carbonate and 56 mg of the complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane is added in order to a degassed mixed solution consisting of 3 ml of 1,4-dioxane and 1 ml of water, and then the resulting mixture was stirred at 90°C for 5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 90 mg specified in the connection header.

Stage 2

2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy)methyl}-1H-pyrazole-4-yl)pyridine

In the atmosphere of argon 90 mg of 2,6-dichloro-4-(1H-pyrazole-4-yl)pyridine dissolved in 2 ml of tetrahydrofuran, add 20 mg of 60% sodium hydride at 0° and the mixture is stirred at 0°C for 15 minutes. Then to the resulting mixture add 82 μl (2 chloromethoxy)ethyltrimethoxysilane, the mixture was left to warm to room temperature and stirred for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 106 mg specified in the connection header.

Stage 3

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-yl)pyridine-2-amine

100 mg of 2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-yl)pyridine obtained in stage 2, 44 mg (S)-(-)-1-(4-forfinal)ethylamine, 17 mg of 2-(di-tert-butylphosphino)biphenyl, 70 mg of tert-butoxide sodium and 6 mg of palladium acetate is added in order to 3 ml of degassed toluene, and then the resulting mixture was stirred at 85°C for 1.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 70 mg of the decree is tion in the title compounds as colorless oils.

Stage 4

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-yl)pyridine-2,6-diamine

68 mg (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-yl)pyridine-2-amine, obtained in stage 3, 17 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 21 mg of tert-butoxide sodium and 8 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in that order and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 70 mg specified in the title compounds as colorless oils.

Stage 5

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-4-yl)pyridine-2,6-diamine

To 53 mg of (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-yl)pyridine-2,6-diamine obtained in stage 4, add a mixed solvent consisting of 1 ml triperoxonane acid and 0.1 ml of water, and the resulting mixture was stirred at room temperature for 3 hours. The solvent is distilled off under reduced pressure, and the resulting residue diluted with water and alkalinized with a saturated aqueous solution of sodium bicarbonate. The reaction is actor extracted with ethyl acetate, the organic layer is washed with water and then dried over magnesium sulfate. The solvent is distilled off, and then the obtained residue is purified column chromatography on silica gel, to obtain 15 mg specified in the title compound as an amorphous pale yellow solid.

MS (ESI) m/z 376 (M+H)+

Specific rotation [α]D20=-103,59° (c=0.5, methanol)

Example 29

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-3-yl)pyridine-2,6-diamine

Stage 1

2,6-dichloro-N-methoxy-N-methylethanolamine

586 mg of 2,6-dichlorophenylamino acid dissolved in 10 ml of dimethylformamide, added 690 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 490 mg of 1-hydroxybenzotriazole, 440 mg of the hydrochloride of N,O-dimethylhydroxylamine and 1.67 ml of triethylamine and the resulting mixture was stirred at room temperature for 17 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution and the mixture is diluted with ethyl acetate. The resulting mixture was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 500 mg specified in the connection header.

Stage 2

1-(2,6-dichloropyridine-4-yl)alanon

490 mg of 2,6-dichloro-N-methoxy-N-methylethanolamine dissolved in tetrahydrofuran, are added dropwise 2.1 ml 3M tertrahydrofuran ring solution methylacrylamide at 0°C and the resulting mixture is stirred at 0°C for 1 hour. To the reaction solution was added an aqueous solution of ameriglide and the mixture is diluted with ethyl acetate. The resulting mixture was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 325 mg specified in the connection header.

Stage 3

2,6-dichloro-4-(1H-pyrazole-3-yl)pyridine

5 ml of N,N-dimethylformamidine add to 325 mg of 1-(2,6-dichloropyridine-4-yl)ethanone and the resulting mixture is heated to boiling under reflux for 30 minutes. N,N-dimethylformamidine distilled off under reduced pressure, to the obtained residue, add 5 ml of ethanol and 91 μl of hydrazinoacetate and the resulting mixture is heated to boiling under reflux for 1 hour. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 320 mg specified in the connection header.

Stage 4

2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy)methyl}-1H-pyrazole-3-yl)pyridine

In argon atmosphere, 250 mg of 2,6-dichloro-4-(1H-pyrazole-3-is l)of pyridine are dissolved in 6 ml of tetrahydrofuran, small portions add 56 mg of 60% sodium hydride at 0°C and the resulting mixture is stirred at 0°C for 30 minutes. Then 0.25 ml (2 chloromethoxy)ethyltrimethoxysilane added to the obtained mixture, the mixture is left to warm to room temperature and stirred for 2 hours. To the reaction solution was added water. The resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 440 mg specified in the connection header.

Stage 5

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-6-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-yl)pyridine-2-amine

100 mg of 2,6-dichloro-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-yl)pyridine obtained in stage 4, 45 mg (S)-(-)-1-(4-forfinal)ethylamine, 17 mg of 2-(di-tert-butylphosphino)biphenyl, 70 mg of tert-butoxide sodium and 7 mg of palladium acetate is added in order to 3 ml of degassed toluene, then the resulting mixture was stirred at 85°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue purified colonoscopy because it allows the Noah chromatography on silica gel, to obtain 130 mg specified in the title compound as a brown oil.

Stage 6

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-yl)pyridine-2,6-diamine

130 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-6-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-yl)pyridine-2-amine, obtained in stage 5, 35 mg of 2-aminopyrazine, 30 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 42 mg of tert-butoxide sodium and 18 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in that order and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 95 mg specified in the title compound as a brown oil.

Stage 7

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-3-yl)pyridine-2,6-diamine

A mixed solvent consisting of 3 ml triperoxonane acid and 0.3 ml of water, add to 95 mg (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-yl)pyridine-2,6-diamine obtained in stage 6, and the mixture is stirred at 60°C for 1 hour. The solvent is distilled off under reduced pressure, and the resulting residue diluted with water and alkalinized asystem aqueous solution of sodium bicarbonate. The reaction solution is extracted with ethyl acetate, the organic layer washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 20 mg indicated in the title compounds as pale yellow powder.

MS (ESI) m/z 376 (M+H)+

Example 30

Maleate (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

of 1.34 g (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine synthesized according to a similar methodology phases 1 and 2 of example 4, 423 mg of 2-aminopyrazine, 154 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 544 mg of tert-butoxide sodium and 74 mg of Tris(dibenzylideneacetone)diplodia add in order to 13 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 1.26 g (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine as a pale yellow powder. Then 1.0 g of the obtained (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6- (irain-2-yl)pyridine-2,6-diamine dissolved in 1 ml of methanol and add 300 mg of maleic acid. To the reaction solution was added 6 ml of ethyl acetate and stirred at room temperature for 2 hours. Resulting solid precipitate is filtered, obtaining 1.1 g specified in the title compound as a white powder.

MS (ESI) m/z 390 (M+H)+

Elemental analysis (for C25H24FN7O4)

Calculated (%) C: 59,40, H: 4,79, N: 19,40

Found (%) C: 59,19, H: 4,58, N: 19,36

Specific rotation[α]D20=68,40° (c=0.5, methanol)

[0056] Example 31

Maleate (S)-N2-[1-(4-forfinal)ethyl]-6-morpholino-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-morpholino-N4(pyrazin-2-yl)pyrimidine-2,4-diamine synthesized in example 20, is converted into malate by the procedure analogous to example 30.

MS (ESI) m/z 396 (M+H)+

Elemental analysis (for C24H26FN7O5)

Calculated (%) C: 56,35, H: 5,12, N: 19,17

Found (%) C: 56,42, H: 5,07, N: 19,41

Specific rotation [α]D20=81,20° (c=0.5, methanol)

Example 32

1/2 maleate (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine

(S)-N2-([1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine synthesized in example 15, is converted into malate by the procedure analogous to example 30.

MS (ESI) m/z 388 (M+H)+

Element the th analysis (for C 23H20FN7O2)

Calculated (%) C: 62,02, H: 4,53, N: 22,01

Found (%) C: 61,79, H: 4,50, N: 22,14

Specific rotation [α]D20=-42,00° (c=0.5, methanol)

Example 33

Maleate of N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}ndimethylacetamide

N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}acetamide", she synthesized in example 2, is converted into malate by the procedure analogous to example 30.

MS (ESI) m/z 437 (M+H)+

Elemental analysis (for C26H29FN8O5)

Calculated (%) C: 56,52, H: of 5.29, N: to 20.28

Found (%) C: 56,49, H: 5,24, N: 20,45

Specific rotation [α]D20=26,39° (c=0.5, methanol)

Example 34

Maleate (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine

(S)-N2-([1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine synthesized in example 11, is converted into malate by the procedure analogous to example 30.

MS (ESI) m/z 377 (M+H)+

Elemental analysis (for C23H21FN8O4+0,2 H2O)

Calculated (%) C: 55,69, H: 4,35, N: 22,59

Found (%) C: 55,32, H: 4,33, N: 22,61

Specific rotation [α]D20=-51,60° (c=0.5, methanol)

Example 35

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylsulphonyl)f the Nile]-N 4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10 using 3-(methylsulphonyl)phenylboronic acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 465 (M+H)+

Elemental analysis (for C23H21FN6O2S·HCl+0.5 H2O)

Calculated (%) C: 54,17, H: 4,55, N: 16,48

Found (%) C: 54,04, H: 4,35, N: 16,10

Specific rotation [α]D20=-12,40° (c=0.5, methanol)

[0057]Example 36

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)phenyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)phenyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 4 using 4-(methylsulphonyl)phenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 464 (M+H)+

Elemental analysis (for C24H22 5O2S·HCl+0,2 H2O)

Calculated (%) C: 57,24, H: 4,68, N: 13,91

Found (%) C: 56,97, H: 4,35, N: 13,71

Specific rotation [α]D20=74,00° (c=0.5, methanol)

Example 37

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

4-iodine-1-isopropyl-1H-pyrazole

In the atmosphere of argon 96 mg of 60% sodium hydride are suspended in 6 ml of N,N-dimethylformamide, add 388 mg 4-iodine-1H-pyrazole at 0°C and the resulting mixture is stirred at 0°C for 30 minutes. Then add to 0.21 ml of 2-bromopropane and the resulting reaction mixture is stirred at a temperature of 100°C for 2 hours. To the reaction solution was added water. The resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 328 mg specified in the connection header.

Stage 2

2,6-dichloro-4-(1-isopropyl-1H-pyrazole-4-yl)pyridine

251 mg of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (synthesized by the method described in J. Am. Chem. Soc., 2003, 125, 7792-7793), 325 mg 4-iodine-1-isopropyl-1H-pyrazole, 381 mg of potassium carbonate and 22 mg of the complex of 1,1'-bis(diphenylphosphino)fer azopardi(II)dichloride-dichloromethane is added in order to a degassed mixture of solvents, consisting of 6 ml of 1,4-dioxane and 2 ml of water, and the resulting mixture was stirred at 90°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 145 mg specified in the connection header.

Stage 3

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)pyridine-2-amine

145 mg of 2,6-dichloro-4-(1-isopropyl-1H-pyrazole-4-yl)pyridine obtained in stage 2, 87 mg (S)-(-)-1-(4-forfinal)ethylamine, 34 mg of 2-(di-tert-butylphosphino)biphenyl, 109 mg of tert-butoxide sodium and 13 mg of palladium acetate is added in order to 6 ml of degassed toluene, and then the resulting mixture was stirred at 85°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 59 mg specified in the title compounds as pale yellow powder.

Stage 4

Hydro is Lorig (S)-N 2-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

59 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)pyridine-2-amine, 19 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 22 mg of tert-butoxide sodium and 9 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 5 ml of degassed toluene, and the resulting mixture was stirred at 85°C for 1.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 40 mg (S)-N2-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine as a pale yellow powder. The compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 30 mg specified in the title compound as a brown powder.

MS (ESI) m/z 418 (M+H)+

Specific rotation [α]D20=76,40° (c=0.5, methanol)

Example 38

The hydrochloride of N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyridine-4-yl]pyrrolidin-3-yl}ndimethylacetamide

100 mg of (S)-4-PI is the p-N 2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine (comparative example 2), 112 mg of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide, 69 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 92 mg of tert-butoxide of sodium and 30 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 6 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 115 mg of N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyridine-4-yl]pyrrolidin-3-yl}ndimethylacetamide in the form of a pale brown powder. The compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 67 mg specified in the title compound as a brown powder.

MS (ESI) m/z 436 (M+H)+

Specific rotation [α]D20=63,20° (c=0.5, methanol)

Example 39

(S)-N2-[1-(4-forfinal)ethyl]-4-morpholino-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, is using morpholine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 395 (M+H)+

Specific rotation [α]D20=-38,80° (c=0.5, methanol)

Example 40

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-thiomorpholine-2,6-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, using thiomorpholine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 411 (M+H)+

[0058]Example 41

Hydrochloride (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propan-1-ol

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 12, using 1,3-propandiol instead of ethylene glycol.

MS (ESI) m/z 384 (M+H)+

Example 42

(S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)ndimethylacetamide

100 mg of tert-butyl, azetidin-3-ylcarbamate dissolved in 5 ml of methylene chloride and add 225 mg of N,N-diisopropylethylamine. Under ice cooling to the reaction mixture are added 68 mg of acetylchloride and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, the organic layer is washed successively with 5% aqueous citric acid solution and saturated salt solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 146 mg masla the East brown substance. The resulting residue is dissolved in 2.5 ml of methylene chloride, was added 1 ml of triperoxonane acid and the resulting mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, to obtain 66 mg of N-(azetidin-3-yl)acetamidoacrylate. Then 33 mg trifenatate N-(azetidin-3-yl)ndimethylacetamide, 148 mg of triethylamine, 100 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 28 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 56 mg of tert-butoxide of sodium and 30 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 3 ml of degassed 1,4-dioxane and the resulting mixture was stirred at 90°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 17 mg specified in the connection header in the form of a bright Golden-yellow powder.

MS (ESI) m/z 423 (M+H)+

Example 43

(S)-6-(azetidin-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as an amorphous Belogorodka substances according to the method similar to example 1, using the hydrochloride of azetidine instead of piperazine-2-it.

MS (ESI) m/z 366 (M+H)+

Example 44

(S)-6-(3-torasemide-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 1, using the hydrochloride of 3-foreseeing instead of piperazine-2-it.

MS (ESI) m/z 384 (M+H)+

Specific rotation [α]D20=84,00° (c=0.5, methanol)

Example 45

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-he

100 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 9), 41 mg of 2-azetidinone, 34 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 123 mg of tribalista and 30 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 3 ml of degassed 1,4-dioxane and the resulting mixture was stirred at 90°C for 5 hours in an argon atmosphere. The reaction mixture was filtered to remove the precipitate, the solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 58 mg specified in the title compound as a white powder.

MS (ESI) m/z 380 (M+H)+

Specific rotation [α] 20=-62,40° (c=0.5, methanol)

[0059] Example 46

(S)-4-(1-ethyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 37, using Iodate instead of 2-bromopropane.

MS (ESI) m/z 404 (M+H)+

Specific rotation [α]D20=-83,60° (c=0.5, methanol)

Example 47

(S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as a white powder by the method similar to example 4, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

MS (ESI) m/z 390 (M+H)+

Example 48

(S)-4-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as ocher-yellow powder by the procedure analogous to example 37, using (methyl bromide)cyclopropane instead of 2-bromopropane.

MS (ESI) m/z 430 (M+H)+

Example 49

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine

Stage 1

(S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(thiazol-yl)pyrimidine-2-amine

286 mg (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 411 mg of 5-(tributylstannyl)thiazole and 115 mg of tetrakis(triphenylphosphine)palladium is added in that order to the degassed dimethylformamide and then the resulting mixture is stirred at a temperature of 100°C for 5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 175 mg of (S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine as a white solid.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine

To 155 mg of (S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine, 53 mg of 2-aminopyrazine, 72 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 196 mg tribalista and 81 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 4 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 5 hours. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated concrete is salt and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 105 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 394 (M+H)+

Example 50

Hydrochloride of 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ol

Stage 1

1-{6-chloro-2-[(S)-1-(4-forfinal)ethylamino]pyrimidine-4-yl}pyrrolidin-3-ol

Specified in the title compound obtained as a white powder by the method similar to example 1, step 1, using DL-3-pyrrolidino instead of piperazine-2-it.

Stage 2

Hydrochloride of 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ol

119 mg of 1-{6-chloro-2-[(S)-1-(4-forfinal)ethylamino]pyrimidine-4-yl}pyrrolidin-3-ol, 40 mg of 2-aminopyrazine, 20 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 150 mg tribalista and 19 mg of Tris(dibenzylideneacetone)diplodia add in order to 3 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 2.5 hours in an argon atmosphere. Specified, the reaction mixture was filtered to remove the precipitate, the resulting filtrate is concentrated under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 47 mg of 1-{2-[(S)-1-(4-CFT is henyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ol. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 32 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 396 (M+H)+

Elemental analysis (for C20H22FN7O·HCl+0,25 H2O)

Calculated (%) C: 55,04, H: 5,43, N: 22,47

Found (%) C: 55,06, H: 5,12, N: 22,50

[0060]Example 51

(S)-N2-[1-(4-forfinal)ethyl]-N4-(5-methylthiazole-2-yl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine

Specified in the title compound obtained as pale yellow powder by the method similar to example 16 using 2-amino-5-methylthiazole instead of 2-pyrrolidone.

MS (ESI) m/z 423 (M+H)+

Example 52

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4,5'-bipyrimidin-2,6-diamine

Stage 1

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4,5'-bipyrimidin-2-amine

210 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 91 mg pyrimidine-5-Bronevoy acid, 304 mg of potassium carbonate and 60 mg of the complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane is added in order to a degassed mixed solution consisting of 3 ml of 1,4-dioxane and 1 ml of water, and the resulting mixture was stirred at 90°C for 6 hours in an argon atmosphere. The reaction solution was diluted with what dilatatum. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 73 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4,5'-bipyrimidin-2-amine in the form of an amorphous white solid.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4,5'-bipyrimidin-2,6-diamine

To 90 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4,5'-bipyrimidin-2-amine, 31 mg of 2-aminopyrazine, 31 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 116 mg tribalista and 28 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 2 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 3 hours. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel with 30 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 389 (M+H)+

Example 53

(S)-N2-[1-(4-forfinal)ethyl]-6-(2-methoxythiazole-5-yl)-N4-(pirati the-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as a pale orange powder by the procedure analogous to example 49, using 2-methoxy-5-(tributylstannyl)thiazole instead of 5-(tributylstannyl)thiazole.

MS (ESI) m/z 424 (M+H)+

Example 54

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine

Stage 1

Tert-butyl((S)-4,6-dichloropyrimidine-2-yl)[1-(4-forfinal)ethyl]carbamate

300 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine are dissolved in 7 ml of tetrahydrofuran and added dropwise to 0.70 ml of di-tert-BUTYLCARBAMATE and 58 mg of 4-dimethylaminopyridine and then the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 285 mg specified in the title compounds as colorless oils.

Stage 2

Tert-butyl((S)-4-chloro-6-(thiazol-2-yl)pyrimidine-2-yl)[1-(4-forfinal)ethyl]carbamate

270 mg of tert-butyl((S)-4,6-dichloropyrimidine-2-yl)[1-(4-forfinal)ethyl]carbamate, 314 mg of 2-(tributylstannyl)thiazole and 81 mg of tetrakis(triphenylphosphine)palladium type specified in the order to 5 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The solvent of the reaction solution is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 150 mg specified in the title compound as a yellow oil.

Stage 3

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine

130 mg of tert-butyl((S)-4-chloro-6-(thiazol-2-yl)pyrimidine-2-yl)[1-(4-forfinal)ethyl]carbamate, 34 mg of 2-aminopyrazine, 35 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 127 mg of tribalista and 31 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 4 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 90 mg of pale yellow oil. To the resulting oil is added 2 ml triperoxonane acid and stirred at room temperature for 2 hours. Triperoxonane acid is distilled off under reduced pressure, and the resulting residue diluted with water and alkalinized saturated concrete water is sodium bicarbonate. The reaction solution is extracted with ethyl acetate, the organic layer is successively washed with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 25 mg specified in the title compound as a white powder.

MS (ESI) m/z 394 (M+H)+

Example 55

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 52, using pinacolyl ester 2-cyano-5-Bronevoy acid instead of pyrimidine-5-Bronevoy acid.

MS (ESI) m/z 413 (M+H)+

[0061]Example 56

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxamide

Specified in the header connection receive according to the method similar to example 1, using isonipecotamide instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 437 (M+H)+

Example 57

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinate

To 38 mg (S)-5-{2-[1-(4-forfinal) is thylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides add tert-butanol and 60 mg of potassium fluoride on a substrate of activated alumina and the resulting mixture was stirred at 90°C for 4 hours. The reaction solution is filtered to remove the precipitate, then the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography on silica gel, to obtain 25 mg specified in the title compound as amorphous solid.

MS (ESI) m/z 431 (M+H)+

Example 58

4-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-carboxamide

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 1, using piperazine-2-carboxamide instead of piperazine-2-it.

MS (ESI) m/z 438 (M+H)+

Example 59

6-(3-aminopyrrolidine-1-yl)-N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Tert-butyl 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ylcarbamate receive according to the method similar to example 1, using 3-(tert-butoxycarbonylamino)pyrrolidin instead of piperazine-2-it. 2 ml triperoxonane acids are added to the obtained compound, and the mixture is stirred at room temperature for 1 hour. Triperoxonane acid is distilled off, and then the obtained residue was diluted with water and alkalinized with a saturated aqueous solution of sodium bicarbonate. The reaction solution is extracted with ethyl acetate, the organic with the Oh washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain specified in the title compounds as pale yellow powder.

MS (ESI) m/z 395 (M+H)+

Example 60

The hydrochloride of N-(1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)methanesulfonamide

110 mg of 6-(3-aminopyrrolidine-1-yl)-N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 59) was dissolved in 3 ml of tetrahydrofuran and 91 μl of N,N-diisopropylethylamine add 21 µl of methanesulfonanilide at 0°C and the resulting mixture is stirred at 0°C for 1 hour. To the reaction solution was added water, then the reaction solution is extracted with ethyl acetate, the organic layer is successively washed with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 92 mg of N-(1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)methanesulfonamide in the form of an amorphous pale yellow solid. The compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 70 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 473 (M+H)+

Elemental analysis (for C21H25 FN8O2S·HCl+0.5 H2O+0,2 CH3CO2C2H5)

Calculated (%) C: 48,88, H: 5,38, N: 20,92

Found (%) C: 48,64, H: 5,17, N: 20,73

[0062]Example 61

Hydrochloride (S)-2-({2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}(2-hydroxyethyl)amino)ethane-1-ol

(S)-2-({2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}(2-hydroxyethyl)amino)ethane-1-ol get by the method similar to example 1, using diethanolamine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 414 (M+H)+

Elemental analysis (for C20H24FN7O2·HCl+H2O)

Calculated (%) C: 52,97, H: 5,65, N: 21,62

Found (%) C: 52,91, H: the 5.45, N: 21,37

Example 62

The dihydrochloride (S)-N4-[2-(dimethylamino)ethyl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue

(S)-N4-[2-(dimethylamino)ethyl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine receive according to the method similar to example 1, using N,N-dimethylethylenediamine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as a pale-coric is avago powder.

MS (ESI) m/z 397 (M+H)+

Elemental analysis (for C20H25FN82HCl+1,5 H2O)

Calculated (%) C: 48,39, H: 6,09, N: 22,57

Found (%) C: 48,30, H: 5,81, N: 22,45

Example 63

Hydrochloride of 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-carboxamide

1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-carboxamide receive according to the method similar to example 1, using nipecotate instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 437 (M+H)+

Example 64

Hydrochloride (S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-carboxamide

(S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-carboxamid receive according to the method similar to example 1, using L-prolinamide instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 423 (M+H)+

Elemental analysis (for C21H23FN8O·HCl+1,5 H2O)

Calculated (%) C: better than anticipated at 51.90, H: ceiling of 5.60, N: 23,06

Found (%) C: 51.89ˆ, H: 5,26, N: 22,97

Example 65

2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 1, using 1-methanesulfonylaminoethyl instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 473 (M+H)+

Elemental analysis (for C21H25FN8O2S·HCl+1,6 H2O)

Calculated (%) C: 46,90, H: 5,47, N: 20,83

Found (%) C: 46,52, H: 5,09, N: 20,69

[0063]Example 66

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine

Stage 1

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine

Specified in the header connection receive according to the method similar to example 52, using 1-(triisopropylsilyl)-1H-pyrrol-3-Bronevoy acid instead of pyrimidine-5-Bronevoy acid.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine

305 mg of (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-H-pyrrol-3-yl]pyrimidine-2,4-diamine are dissolved in 3 ml of tetrahydrofuran, add 0,86 ml of 1M solutiontetrabutylammonium/tetrahydrofuran while cooling with ice water and the resulting mixture was stirred at room temperature for 15 minutes. To the reaction solution was added water. The resulting solution was extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 199 mg specified in the title compound as pale brown powder.

MS (ESI) m/z 376 (M+H)+

Example 67

(R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-hydroxypyrrolidine-2-he

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 16, using (R)-(+)-4-hydroxy-2-pyrrolidine instead of 2-pyrrolidone.

MS (ESI) m/z 410 (M+H)+

Example 68

N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[(tetrahydrofuran-2-yl)methyl]pyrimidine-2,4,6-triamine

Specified in the title compound obtained as an amorphous solid by the procedure analogous to example 1, using tetrahydrofurfurylamine instead of piperazine-2-it.

MS (ESI) m/z 410 (M+H)+

Example 69

Hydrochloride ((S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol

((S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol receive according to the method similar to example 1, using L-prolinol instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 410 (M+H)+

Elemental analysis (for C21H24FN7O·HCl+0,4 H2O+0,5 CH3OH)

Calculated (%) C: 55,04, H: 5,97, N: 20,90

Found (%) C: 55,05, H: 5,75, N: 20,57

Example 70

Hydrochloride ((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol

((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol receive according to the method similar to example 1, using D-prolinol instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 410 (M+H)+

Elemental analysis (for C21H24FN7O·HCl+0,4 H2O+0,5 CH3OH)

Calculated (%) C: 55,04, H: 5,97, N: 20,90

Found (%) C: 54,74, H: 5,70, N: 20,70

[0064]Example 71

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-ol receive according to the method similar to example 1, using 4-hydroxypiperidine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 410 (M+H)+

Elemental analysis (for C21H24FN7O·HCl)

Calculated (%) C: 56,56, H: 5,65, N: 21,99

Found (%) C: 56,23, H: of 5.53, N: 21,99

Example 72

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol receive according to the method similar to example 1, using the hydrochloride of 3-hydroxyazetidine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 382 (M+H)+

Elemental analysis (for C19H20FN7O/HCl+1,2 H2O+0,2 CH3OH)

Calculated (%) C: 51,72, H: 5,47, N: 21,99

Found (%)C: 51,45, H: 5,14, N: 22,29

Example 73

Hydrochloride of 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(p is the Razin-2-ylamino)pyrimidine-4-yl}piperidine-3-ol

1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-ol receive according to the method similar to example 1, using 3-hydroxypiperidine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 410 (M+H)+

Elemental analysis (for C21H24FN7O·HCl+0,9 H2O+0,4 CH3OH)

Calculated (%) C: 54,12, H 6.03, N: 20,64

Found (%) C: 53,90, H: 5,78, N: 20,93

Example 74

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide

Stage 1

5-(tributylstannyl)nicotinamide

300 mg of 5-bromo-3-cyanopyridine, 750 mg hexamethyldisilane and 185 mg of tetrakis(triphenylphosphine)palladium is added in order to 5 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The solvent of the reaction solution is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 178 mg specified in the title compounds as colorless oils.

Stage 2

(S)-5-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}nicotinamide

187 mg (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine is (comparative example 1), 175 mg of 5-(tributylstannyl)nicotinanilide, 25 mg of copper iodide and 75 mg of tetrakis(triphenylphosphine)palladium is added in order to 3 ml of degassed toluene, and the resulting mixture was stirred at 110°C for 17 hours in an argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 58 mg of (S)-5-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}nicotinanilide in the form of a colorless oil.

Stage 3

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide

55 mg (S)-5-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}nicotinanilide, 16 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 21 mg of tert-butoxide sodium and 8 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 2 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 21 mg specified in the title compound as a white powder.

MS (ESI) m/z 413 (M+H)+

Example 75

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine

Stage 1

(S)-6-[2-(benzoyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-forfinal)ethyl]-Nsup> 4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-6-[2-(benzoyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 74, using 2-(benzoyloxymethyl)-5-(tributylstannyl)-2H-tetrazol (synthesized according to the method described in hedron Lett., 2000, 41, 2805-2809) instead of 5-(tributylstannyl)nicotinanilide.

Stage 2

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine

50 mg of (S)-6-[2-(benzoyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine are dissolved in 1.5 ml of methanol, add 1.5 ml of 10% hydrochloric acid and the resulting mixture is stirred at a temperature of 80°C for 20 hours. The reaction solution is cooled in air to room temperature, then diluted with ethyl acetate and the pH of the mixture was adjusted to 4 using a saturated aqueous solution of sodium bicarbonate. The organic layer is extracted, washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is washed with methanol, filtered and dried under reduced pressure to obtain 15 mg specified in the title compound as a white powder.

MS (ESI) m/z 379 (M+H)+

[0065]Por the measures 76

The dihydrochloride (S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue

(S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine receive according to the method similar to example 59, using tert-butyl N-(2-amino-ethyl)carbamate instead of 3-(tert-butoxycarbonylamino)pyrrolidine. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 369 (M+H)+

Elemental analysis (for C18H21FN8.2HCl+0,5 H2O)

Calculated (%) C: 48,01, H: lower than the 5.37, N: are 24.88

Found (%) C: 47,72, H: 5,51, N: 24,70

Example 77

Hydrochloride (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)methanesulfonamide

(S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)methanesulfonamide receive according to the method similar to example 60, using (S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine instead of 6-(3-aminopyrrolidine-1-yl)-N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the header is soedineniya in the form of a pale yellow powder.

MS (ESI) m/z 447 (M+H)+

Elemental analysis (for C19H23FN8O2S·HCl+H2O)

Calculated (%) C: 45,55, H: 5,23, N: 22,37

Found (%) C: 45,61, H: 5,07, N: 22,24

Example 78

Hydrochloride (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)ndimethylacetamide

Saturated aqueous sodium bicarbonate solution and chloroform is added to 141 mg of the dihydrochloride (S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue (example 76) and the resulting mixture is extracted. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 3 ml of tetrahydrofuran, add 223 μl of diisopropylethylamine and 23 ál acetylchloride at 0°C and the resulting mixture is stirred at 0°C for 30 minutes. The reaction solution is added to water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 95 mg of (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)ndimethylacetamide in the form of a white powder. The compound obtained is subjected to hydrochloridebuy, IP is by using a conventional method, to obtain 74 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 411 (M+H)+

Elemental analysis (for C20H23FN8O·HCl)

Calculated (%) C: 53,75, H: 5,41, N: 25,07

Found (%) C: 53.47 USD, H: 5,55, N: 24,87

Example 79

Hydrochloride (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ndimethylacetamide

(S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ndimethylacetamide receive according to the method similar to example 1, using 2-aminoacetate instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as pale brown powder.

MS (ESI) m/z 383 (M+H)+

Elemental analysis (for C18H19FN8O·HCl+1,2 H2O)

Calculated (%) C: 49,08, H: 5,13, N: 25,44

Found (%) C: 49,33, H: the 5.45, N: 25,14

Example 80

Hydrochloride (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide receive according to the method similar to example 10, using 4-carbamoilirovaniem acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in sialometaplasia in the form of a white powder.

MS (ESI) m/z 430 (M+H)+

Elemental analysis (for C23H20FN7O·HCl+H2O)

Calculated (%) C: 57,09, H: 4,79, N: 20,26

Found (%) C: 57,16, H: 4,68, N: 20,45

[0066]Example 81

(S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzonitrile

Specified in the title compound obtained as an amorphous pale yellow solid according to the method similar to example 10 using 3-cyanoaniline acid instead of 4-(methylsulphonyl)phenylboronic acid.

MS (ESI) m/z 412 (M+H)+

Example 82

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(furan-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-(furan-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10 using 3-Puilboreau acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 377 (M+H)+

Elemental analysis (for C20H17FN6O·HCl)

Calculated (%) C: 58,18, H: 4,39, N: 20,36

Found (%) C: 57,88, H: 4,58, N: 20,24

Example 83

Ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxylate

Specified in reception is e compound obtained as an amorphous pale yellow solid according to the method similar to example 1, using utilizedabated instead of piperazine-2-it.

MS (ESI) m/z 466 (M+H)+

Example 84

(S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide

Specified in the title compound obtained as amorphous solid compound by the procedure analogous to example 57, using (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide instead of (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides.

MS (ESI) m/z 431 (M+H)+

Example 85

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-4-carboxylic acid

128 mg of ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxylate (example 83) was dissolved in 3 ml of ethanol, add, and 0.28 ml of 12% aqueous sodium hydroxide solution and the resulting mixture was stirred at room temperature for 6 hours. The ethanol is distilled off, and then the obtained residue was diluted with water and the aqueous layer washed with diethyl ether. The aqueous layer was neutralized with 10% hydrochloric acid to pH 7, extracted with ethyl acetate, the organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and then the obtained residue was washed with diethyl ether, filter the Ute and dried under reduced pressure, to obtain 58 mg specified in the title compound as a white powder.

MS (ESI) m/z 438 (M+H)+

[0067]Example 86

(S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-2-phenylethanol

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using (S)-(+)-2-phenylglycinol instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 446 (M+H)+

Example 87

(S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-phenylpropane-1-ol

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using L-phenylalaninol instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 460 (M+H)+

Example 88

(R)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-4-methylpentan-1-ol

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using D-leucinol instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z426 (M+H) +

Example 89

The dihydrochloride (S)-6-[2-(dimethylamino)ethoxy]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

To 172 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 212 mg of tribalista, 95 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl and 52 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 4 ml of 2-dimethylaminoethanol, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 1 hour. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 118 mg (S)-6-[2-(dimethylamino)ethoxy]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 101 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 398 (M+H)+

Elemental analysis (for C20H24FN7O·2HCl+1,2 H2O)

Calculated (%) C: 48,83, H: of 5.82, N: 19.93 per

Found (%) C: 48,89, H: 5,63, N: 19,86

Example 90

(S)-1-{2-[1-(4-forfinal)atilim is but]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylic acid

Stage 1

Ethyl (S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}-1H-pyrazole-4-carboxylate

500 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine (comparative example 1), 270 mg of ethyl 4-pyrazolecarboxylate, 0,20 ml of TRANS-N,N'-dimethylcyclohexane-1,2-diamine, 780 mg of tribalista and 100 mg of copper iodide is added in order to 10 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 6 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 51 mg specified in the title compound as a white powder.

MS (ESI) m/z 390 (M+H)+

Stage 2

Ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylate

50 mg of ethyl (S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}-1H-pyrazole-4-carboxylate, 15 mg of 2-aminopyrazine, 12 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 17 mg of tert-butoxide sodium and 7 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 10 ml of degassed toluene, and the resulting mixture was stirred at pace is the atur 100°C for 2 hours in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 45 mg specified in the title compound as a white powder.

MS (ESI) m/z 449 (M+H)+

Stage 3

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylic acid

2 ml of ethanol, 1 ml of tetrahydrofuran and 80 μl of a 12% aqueous solution of sodium hydroxide is added to 35 mg of ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylate and the mixture was stirred at room temperature for 18 hours. To the mixture add 160 ál of 12% aqueous sodium hydroxide solution and the resulting mixture was continued to stir for 3 hours. The ethanol is distilled off. The obtained residue was diluted with ethanol, diluted with water and the pH of the mixture was adjusted to 7 using 10% hydrochloric acid; the resulting mixture was extracted with ethyl acetate, the organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 14 mg specified in the title compound as a white powder.

MS (ESI) m/z 421 (M+H)+

[0068]Example 91

(S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide

192 mg (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzonitrile (example 81) on billaut to 5 ml of tert-butanol and add 384 mg of potassium fluoride, deposited on activated alumina, and the resulting mixture is stirred at a temperature of 80°C for 2 hours. Add 384 mg of potassium fluoride deposited on activated alumina, and the resulting mixture was continued to stir for 15 hours. The reaction solution is filtered to remove the precipitate, then the filtrate concentrated under reduced pressure and the resulting residue is purified column chromatography on silica gel, to obtain 158 mg specified in the title compound as a white powder.

MS (ESI) m/z 430 (M+H)+

Example 92

Hydrochloride (S)-6-(benzo[d]1,3-dioxol-5-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-6-(benzo[d]1,3-dioxol-5-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 10, using 3,4-(methylendioxy)phenylboronic acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 431 (M+H)+

Elemental analysis (for C23H19FN6O2·HCl+H2O)

Calculated (%) C: 56,97, H: 4,57, N: 17,33

Found (%) C: 56,58, H: of 4.38, N: 17,45

Example 93

(S)-N2-[1-(4-forfinal)ethyl]-6-2-herperidin-4-yl)-N 4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as a white powder by the method similar to example 10, using 2-herperidin-4-Bronevoy acid instead of 4-(methylsulphonyl)phenylboronic acid.

MS (ESI) m/z 406 (M+H)+

Example 94

N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4-diamine

To 200 mg (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 246 mg tribalista, 111 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl and 60 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add 4 ml tetrahydrofurfuryl alcohol and 2 ml of 1,4-dioxane, the mixture Tegaserod, the volume is filled with gaseous argon and then stirred at a temperature of 100°C for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 77 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 411 (M+H)+

Example 95

Hydrochloride (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}ethanol

()-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}ethanol according to the method analogous to example 94, using ethylene glycol instead of tetrahydrofurfuryl alcohol. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 371 (M+H)+

Elemental analysis (for C18H19FN6O2·HCl)

Calculated (%) C: 53,14, H: 4,95, N: 20,66

Found (%) C: 52,94, H: 4,95, N: to 20.52

[0069]Example 96

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using 1-(2-amino-ethyl)pyrrolidin instead of piperazine-2-it.

MS (ESI) m/z 423 (M+H)+

Example 97

(S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide

150 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 235 mg neopentylglycol ether 4-cyano-3-Bronevoy acid, 184 mg of sodium carbonate and 25 mg of tetrakis(triphenylphosphine)palladium is added in order to a degassed mixed solution consisting of 3.5 ml of 1,4-dioxane and 1.5 ml of water, and the resulting mixture is stirred at a temperature of 100°C for 5 hours in an argon atmosphere. The reaction solution was diluted with atilas what tatom. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, then the resulting powder was washed with ethyl acetate, filtered and dried under reduced pressure to obtain 31 mg of (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide in the form of a white powder.

MS (ESI) m/z 431 (M+H)+

Example 98

(S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide

The filtrate obtained in example 97 distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 15 mg (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide in the form of a white powder.

MS (ESI) m/z 413 (M+H)+

Example 99

Hydrochloride (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-methylbutane-1-ol

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 1, using L-valinol instead of piperazine-2-it.

MS (ESI) m/z 412 (M+H)+

Elemental analysis (for C21H26FN7O·HCl+H2O)

Calculated (%) C: 54,13, H: 6,27, N: 21,04

Found (%) C: 54,18, H: 5,91, N: 21,14

Example 100

Hydrochloride (S)-N2-[1-(4-chlorophenyl)ethyl]-6-[-(methylsulphonyl)piperazine-1-yl]-N 4(pyrazin-2-yl)pyrimidine-2,4-diamine

Stage 1

(S)-6-chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine-2-amine

200 mg of (S)-4,6-dichloro-N-[1-(4-chlorophenyl)ethyl]pyrimidine-2-amine and 119 mg of 1-methysulfonylmethane dissolved in 3 ml of 1-butanol add to 0.23 ml of N,N-diisopropylethylamine and the resulting mixture was stirred at 60°C for 20 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 196 mg specified in the title compound as a white powder.

MS (ESI) m/z 430 (M+H)+

Stage 2

Hydrochloride (S)-N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulphonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

210 mg of (S)-6-chloro-N-[1-(4-chlorophenyl)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine-2-amine, 56 mg of 2-aminopyrazine, 47 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 66 mg of tert-butoxide sodium and 25 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 6 ml of degassed toluene, and the resulting mixture premesis the Ute at a temperature of 100°C for 4 hours in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 120 mg (S)-N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulphonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 489 (M+H)+

Elemental analysis (for C21H25ClFN8O2S·HCl+0,4 H2O)

Calculated (%) C: 47,35, H: 5,07, N: 21,04

Found (%) C: is 47.24, H: 4,79, N: 20,97

[0070]Example 101

Hydrochloride, (1S,2S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}cyclohexanol

(1S,2S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}cyclohexanol receive according to the method similar to example 94, using (1S,2S)-TRANS-1,2-cyclohexanediol instead tetrahydrofurfuryl alcohol. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 425 (M+H)+

Elemental analysis (for C22H25FN6O2·HCl+0,2 H2O)

Calculated (%) C: a 56.88, H: 5,73, N: 18,09

Found (%) C: 56,94, H: of 5.53, N: 18,14

Example 102

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N4-[(5-methylpr the Zin-2-yl)methyl]-N 6(pyrazin-2-yl)pyrimidine-2,4,6-analogue

(S)-N2-[1-(4-forfinal)ethyl]-N4-[(5-methylpyridin-2-yl)methyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine receive according to the method similar to example 1, using 2-(aminomethyl)-5-methylpyrazine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 432 (M+H)+

Elemental analysis (for C22H22FN9·HCl+H2O+0,5 CH3OH)

Calculated (%) C: 53,84, H: 5,42, N: 25,11

Found (%) C: 53,44, H: of 5.05, N: 25,40

Example 103

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N4-(furan-2-ylmethyl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue

(S)-N2-[1-(4-forfinal)ethyl]-N4-(furan-2-ylmethyl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-triamine receive according to the method similar to example 1, using furfurylamine instead of piperazine-2-it. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 406 (M+H)+

Elemental analysis (for C21H20FN7O·HCl+1,5 H2O)

Calculated (%) C: 53,79, H: 5,16, N: to 20.91

Found (%) C: 53,85, H: 4,84, N: 20,85

Example 104

(S)-N 2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[1-(pyridine-3-yl)ethyl]pyrimidine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using 1-(3-pyridyl)ethylamine instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 431 (M+H)+

Example 105

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol

Stage 1

The hydrochloride of 4-(hydroxymethyl)piperidine-4-ol

500 mg of 1-benzyl-4-(hydroxymethyl)piperidine-4-ol (synthesized according to the method described in J. Med. Chem., 1988, 486-491), dissolved in 10 ml of ethanol, add 300 mg of 10% palladium-on-carbon and 0.38 ml of concentrated hydrochloric acid and the resulting mixture was subjected to hydrogenation at room temperature over night. Specified, the reaction mixture was filtered to remove the precipitate, the precipitate washed with ethanol and water and the filtrate concentrated under reduced pressure. The resulting residue is triturated in diethyl ether, obtaining 374 mg specified in the title compound as a white powder.

Stage 2

(S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol

150 mg of (S)-4,6-di the ENT-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine and 97 mg of the hydrochloride of 4-(hydroxymethyl)piperidine-4-ol are dissolved in 3 ml of 2-ethoxyethanol, add 274 μl of N,N-diisopropylethylamine and the resulting mixture is stirred at a temperature of 135°C for 20 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 194 mg specified in the title compound as a brown oil.

Stage 3

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol

100 mg of (S)-1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol, 32 mg of 2-aminopyrazine, 45 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 38 mg of tert-butoxide sodium and 27 mg of Tris(dibenzylideneacetone)(chloroform)palladium is added in order to a degassed mixed solution, consisting of 3 ml of toluene and 2 ml of 1,4-dioxane, and the resulting mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel with receiving the receiving 80 mg specified in the title compound as a brown powder.

MS (ESI) m/z 440 (M+H)+

[0071]Example 106

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-2-ylmethyl)pyrimidine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using 2-(aminomethyl)pyridine instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 417 (M+H)+

Example 107

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-3-ylmethyl)pyrimidine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1 using 3-(aminomethyl)pyridine instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 417 (M+H)+

Example 108

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-4-ylmethyl)pyrimidine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using 4-(aminomethyl)pyridine instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to usaimage the action at 135°C.

MS (ESI) m/z 417 (M+H)+

Example 109

(S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-hydroxypropanoic

Specified in the title compound obtained as a white powder by the method similar to example 1, using L-Suriname instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 413 (M+H)+

Example 110

(3S,4S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3,4-diol

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 1, using (3S,4S)-3,4-pyrrolidine instead of piperazine-2-it.

MS (ESI) m/z 412 (M+H)+

[0072]Example 111

N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 1 using 1,4-dioxa-8 azaspiro[4.5]decane instead of piperazine-2-she and ethoxyethanol as the reaction solvent in stage 1, which is subjected to interaction at 135°C.

MS (ESI) m/z 452 (M+H)+

Example 112

(S)-8-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1,3-dioxo-8 azaspiro[4.5]decane-2-he

50 mg (S)-1-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol (example 105) and 24 mg of N,N'-carbonyldiimidazole dissolved in 2 ml of methylene chloride and the resulting mixture was stirred at room temperature within 15 minutes. The reaction solution was purified column chromatography on silica gel, to obtain 52 mg specified in the title compound as pale brown powder.

MS (ESI) m/z 466 (M+H)+

Example 113

(S)-4-(1-benzyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as pale yellow powder by the method similar to example 3 using 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

MS (ESI) m/z 466 (M+H)+

Example 114

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(phenylsulfonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-[4-(phenylsulfonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 50, using 1-phenolsulfonephthalein instead of DL-3-pyrrolidinone. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 535 (M+H)+

Elemental analysis (for C26H27FN8O2S·HCl+1,3 H2O)

Calculated (%) C: 52,53, H: 5,19, N: 18,85

Found (%) C: 52,65, H: 5,02, N: 18,54

Example 115/p>

The dihydrochloride (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzamide

150 mg of (S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine (comparative example 2), 108 mg of 4-carbamoilirovaniem acid, 567 mg of cesium carbonate, 21 mg, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 13 mg of Tris(dibenzylideneacetone)diplodia add in order to a degassed mixed solution consisting of 3 ml of 1,4-dioxane and 0.6 ml of water, and the resulting mixture is stirred at a temperature of 100°C for 17 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 39 mg (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzamide. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 31 mg specified in the title compound as an orange powder.

MS (ESI) m/z 429 (M+H)+

Elemental analysis (for C24H21FN6O·2HCl+H2O)

Calculated (%) C: 55,50, H: 4,85, N: 16,18

Found (%) C: 55,57, H: 4,70, N: 16,25

[0073]Example 116

The dihydrochloride (S)-N2 -[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine receive according to the method similar to example 115 using 1-(triisopropylsilyl)-1H-pyrrol-3-Bronevoy acid instead of 4-carbamoilirovaniem acid. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as an orange powder.

MS (ESI) m/z 375 (M+H)+

Elemental analysis (for C21H19FN6·2HCl+0,4 H2O)

Calculated (%) C: 55,49, H: a 4.83, N: be 18.49

Found (%) C: 55,70, H: 4,80, N: 18,11

Example 117

The dihydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

(S)-6-chloro-N-[1-(4-forfinal)ethyl]pyridine-2-amine

300 mg of 2,6-dichloropyridine, 296 mg (S)-(-)-1-(4-forfinal)ethylamine, 119 mg of 2-(di-tert-butylphosphino)biphenyl, 487 mg of tert-butoxide sodium and 45 mg of palladium acetate is added in order to 6 ml of degassed toluene, and the resulting mixture was stirred at 85°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled with igenom pressure, then the obtained residue is purified column chromatography on silica gel, to obtain 210 mg specified in the title compounds as a pale yellow oil.

Stage 2

The dihydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

207 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]pyridine-2-amine, 86 mg of 2-aminopyrazine, 79 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 111 mg of tert-butoxide sodium and 43 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 4 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 202 mg of (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine as a pale yellow powder. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 128 mg specified in the title compounds as a pale orange powder.

MS (ESI) m/z 310 (M+H)+

Example 118

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Stage 1

(S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)pyrimidine-2-amine

200 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)e is Il]pyrimidine-2-amine and 63 mg of 4-methylimidazole dissolved in 2 ml of dimethylformamide, add 193 mg of potassium carbonate and the resulting mixture is stirred at a temperature of 100°C for 17 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 62 mg specified in the title compound as a white solid.

Stage 2

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

60 mg (S)-4-chloro-N-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)pyrimidine-2-amine, 19 mg of 2-aminopyrazine, 17 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 35 mg of tert-butoxide sodium and 9 mg of Tris(dibenzylideneacetone)diplodia add in order to 2 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 2 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 9 mg (S)-N 2-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 48 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 391 (M+H)+

Example 119

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methoxyphenyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-(4-methoxyphenyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 37 using 4-bromoanisole instead of 4-iodine-1-isopropyl-1H-pyrazole. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 416 (M+H)+

Elemental analysis (for C24H22FN5O·HCl+1,5 H2O)

Calculated (%) C: 60,19, H: 5,47, N: 14,62

Found (%) C: 60,37, H: 5,08, N: 14,71

Example 120

Hydrochloride (S)-4-(4-forfinal)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-4-(4-forfinal)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 37 using 4-bramptonbest instead of 4-iodine-1-isopropyl-1H-pyrazole. The compound obtained is subjected to hidrocloruro the tion, using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 404 (M+H)+

[0074]Example 121

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-methyl-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-methylpyridin-2-amine

500 mg of 2,6-dichloro-4-iodopyridine, 0.51 ml trimethylboroxine, 1.0 g of potassium carbonate and 208 mg of tetrakis(triphenylphosphine)palladium is added in order to 6 ml of degassed dimethylformamide and the resulting mixture was stirred at 110°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 330 mg of pale yellow solid. The obtained solid product is dissolved in 6 ml of degassed toluene, add in this order 253 mg (S)-(-)-1-(4-forfinal)ethylamine, 147 mg simple bis[2-(diphenylphosphino)phenyl] ether, 244 mg of tert-butoxide sodium and 40 mg of palladium acetate and the resulting mixture is stirred at a temperature of 80°C for 1 hour in argon atmosphere. The reaction solution was diluted with et is lacerata. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 100 mg specified in the title compounds as colorless oils.

Stage 2

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-methyl-N6(pyrazin-2-yl)pyridine-2,6-diamine

95 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-methylpyridin-2-amine, 40 mg of 2-aminopyrazine, 34 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 48 mg of tert-butoxide sodium and 19 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 6 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 85 mg of (S)-N2-[1-(4-forfinal)ethyl]-4-methyl-N6(pyrazin-2-yl)pyridine-2,6-diamine. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 38 mg specified in the title compound as a yellow powder.

MS (ESI) m/z 324 (M+H)+

Elemental analysis (for C18H18FN5·HCl+0.5 H2O)

Calculated (%) C: 58,62, H: 5,47, N: 18,99

Found (%) C: 58,86, H: 5,68, N: 18,61

Example 12

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(methylsulphonyl)piperidine-4-carboxamide

In an argon atmosphere 92 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxylic acid (example 85) was dissolved in 2 ml of tetrahydrofuran, added 41 mg of N,N'-carbonyldiimidazole and the resulting mixture was stirred at 70°C for 1 hour. The reaction solution is cooled in air to room temperature, add 80 mg of methanesulfonamide and 63 μl of 1,8-diazabicyclo[5,4,0]-7-undecene and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water and the pH of the mixture was adjusted to 4 using acetic acid. The reaction solution is extracted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled under reduced pressure to obtain 42 mg specified in the title compound as a white powder.

MS (ESI) m/z 515 (M+H)+

Example 123

(S)-N2-[1-(4-forfinal)ethyl]-4-(furan-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 37 using 3-bromofuran instead of 4-iodine-1-isopropyl-1H-pyrazole.

MS (ESI) m/z 376 (M+H)

Example 124

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 38, using 1-methanesulfonylaminoethyl instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 472 (M+H)+

Example 125

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-4-(hydroxymethyl)piperidine-4-ol

(S)-4-(2,2-dimethyl-1,3-dioxa-8 azaspiro[4.5]Decan-8-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 38, using 2,2-dimethyl-1,3-dioxa-8 azaspiro[4.5]decane instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent. 46 mg of the obtained compound was dissolved in 1 ml of chloroform, add 0.5 ml of 50% aqueous solution triperoxonane acid at 0°C and the resulting mixture is stirred. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography naselesele, to obtain 21 mg specified in the title compound as a brown powder.

MS (ESI) m/z 439 (M+H)+

[0075]Example 126

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzosulfimide

Specified in the title compound obtained as brown powder by the procedure analogous to example 37 using 4-bromobenzaldehyde instead of 4-iodine-1-isopropyl-1H-pyrazole.

MS (ESI) m/z 465 (M+H)+

Example 127

(S)-N2-[1-(4-forfinal)ethyl]-4-methoxy-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as a white powder by the method similar to example 4, using 2,6-dichloro-4-methoxypyridine (synthesized according to the method described in WO2007/21710A1) instead of 2,6-dichloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine.

MS (ESI) m/z 340 (M+H)+

Example 128

4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1λ6,4-thiomorpholine-1,1-dione

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, using thiomorpholine-1,1-dioxide instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent.

MS (ESI) m/z 443 (M+H)+

Example 129

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}piperidine-4-ol

Specified in is the head of the compound obtained as brown powder by the method, analogous to example 38 using 4-hydroxypiperidine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent.

MS (ESI) m/z 409 (M+H)+

Example 130

(S)-1-(4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1,4-diazepan-1-yl)alanon

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, using N-acetylcoumarin instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 450 (M+H)+

[0076]Example 131

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyrimidine-2-yl)pyridine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38 using 2-aminopyrimidine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent.

MS (ESI) m/z 403 (M+H)+

Example 132

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyridin-2-yl)pyridine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38 using 2-aminopyridine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent.

MS (ESI) m/z 402 (M+H)+

Example 133

N2-[(S)-1-(4-ftoh the Nile)ethyl]-N 6(pyrazin-2-yl)-4-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyridine-2,6-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, using 1,4-dioxa-8 azaspiro[4.5]decane instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide and 1,4-dioxane as a reaction solvent.

MS (ESI) m/z 451 (M+H)+

Example 134

Methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate

Stage 1

Methyl (S)-2-chloro-6-[1-(4-forfinal)ethylamino]isonicotinate

of 8.3 g of methyl 2,6-dichloroaniline, 6,1 ml (S)-(-)-1-phenethylamine, 20,5 g of cesium carbonate, and 2.1 g of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 505 mg of palladium acetate is added in order to 100 ml of degassed 1,4-dioxane and the resulting mixture was stirred at 70°C for 7 hours in an argon atmosphere. Specified, the reaction mixture was purified column chromatography on silica gel, to obtain 4.4 g specified in the title compounds as pale yellow powder.

Stage 2

Methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate

4.4 g of methyl (S)-2-chloro-6-[1-(4-forfinal)ethylamino]isonicotinate, 1.3 g of 2-aminopyrazine, 2.67 g of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 5.0 g of tribalista and 1.28 g of Tris(dibenzylideneacetone)diplodia add in order to 10 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 24 hours in an argon atmosphere. Specified, the reaction mixture was filtered through celite, the filtrate concentrated under reduced pressure and the resulting residue is purified column chromatography on silica gel, to obtain 4.9 g specified in the title compound as a white powder.

MS (ESI) m/z 368 (M+H)+

Example 135

Hydrochloride (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylbenzenesulfonamide

(S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylbenzenesulfonamide receive according to the method similar to example 10, using pinacolyl ester of 4-(N-methylsulfonyl)phenylboronic acid instead of 4-(methylsulphonyl)phenylboronic acid. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 480 (M+H)+

Elemental analysis (for C23H22FN7O2S·HCl+0,2 H2O)

Calculated (%) C: 53,17, H: 4,54, N: 18,87

Found (%) C: 52,98, H: 4,34, N: 18,84

[0077]Example 136

The dihydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

1.10 g of 2,6-dichloro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 164 mg of 4-methylimidazole, of 0.56 ml of triethylamine and 0.32 ml of pyridine are dissolved in 4 ml of methylene chloride, add 545 Gazette copper and the resulting mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with water and chloroform, add concentrated aqueous ammonia solution and the resulting mixture is extracted. The aqueous layer was then extracted with chloroform, the organic layers combined and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 117 mg of 2,6-dichloro-4-(4-methyl-1H-imidazol-1-yl)pyridine. Then (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine get the technique similar to stages 2 and 3 of example 4, using 2,6-dichloro-4-(4-methyl-1H-imidazol-1-yl)pyridine instead of 2,6-dichloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 390 (M+H)+

Example 137

(S)-N2-[1-(4-forfinal)ethyl]-N4N6di(pyrazin-2-yl)pyridine-2,4,6-triamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38 using 2-aminopyrazine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 403 (M+H)+

Example 138

(S)-4-(cyclopropylmethoxy)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

2,6-dichloro-4-(cyclopropylmethoxy)pyridine

109 mg of cyclopropylamine dissolved in 2 ml of dimethylformamide, add 60 mg of 60% sodium hydride while cooling with ice water and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction solution was added 400 mg of 2,4,6-trichloropyridine and stirred at room temperature for 30 minutes. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 133 mg specified in the title compounds as colorless oils.

Stage 2

(S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-forfinal)ethyl]pyridine-2-amine

130 mg of 2,6-dichloro-4-(cyclopropylmethoxy)pyridine, 92 mg (S)-(-)-1-(4-forfinal)ethylamine, 36 mg of 2-(di-tert-butylphosphino)biphenyl, 144 mg of tert-butoxide sodium and 14 mg of palladium acetate is added in order to 2 ml of degassed toluene, and the mixture is stirred at a temperature of 80°C for 15 minutes in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over Sul is blockhead magnesium. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 122 mg specified in the title compounds as colorless oils.

Stage 3

(S)-4-(cyclopropylmethoxy)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

112 mg of (S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-forfinal)ethyl]pyridine-2-amine, 43 mg of 2-aminopyrazine, 67 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 51 mg of tert-butoxide sodium and 36 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 2 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 1.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 103 mg specified in the title compound as a brown powder.

MS (ESI) m/z 380 (M+H)+

Example 139

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

(S)-6-chloro-N-[1-(4-perfe who yl)ethyl]-N-methyl-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine

92 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine are dissolved in 1.5 ml of tetrahydrofuran, added 17 mg of 60% sodium hydride and the resulting mixture was stirred at room temperature for 10 minutes. Added 26 μl under the conditions and the reaction solution is subjected to microwave irradiation at 100°C for 5 minutes. To the reaction solution was added 8 mg of 60% sodium hydride and 26 μl under the conditions and the reaction solution is stirred at a temperature of 130°C for 10 minutes, also added 17 mg of 60% sodium hydride and 26 μl under the conditions and the resulting mixture is stirred at a temperature of 130°C for 10 minutes. To the reaction solution was added water and extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 62 mg specified in the title compounds as a pale yellow oil.

Stage 2

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

60 mg (S)-6-chloro-N-[1-(4-forfinal)ethyl]-N-methyl-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine, 18 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2',4',6'-treetop is pilifera, 24 mg of tert-butoxide sodium and 9 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 2 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 60 mg (S)-N2-[1-(4-forfinal)ethyl]-N2-methyl-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine as a pale yellow oil. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 29 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 404 (M+H)+

Elemental analysis (for C22H22FN7·HCl+2,2 H2O)

Calculated (%) C: 55,10, H: 5,76, N: 20,45

Found (%) C: 55,27, H: 5,44, N: 20,09

Example 140

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanol

100 mg of methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate dissolved in 1 ml of tetrahydrofuran, small portions add 20 mg of sociallyengaged and the resulting mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with tetrahydrofuran, cooled to 0°C and then add 25 ál of water, 25 μl of 2n aqueous sodium hydroxide, then 75 μl of water and the resulting reaction from the ect dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 60 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 340 (M+H)+

[0078]Example 141

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate acid

To 500 mg of methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate (example 134) add 5 ml of methanol and then added to 2.7 ml of 2n aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate and water, extracted and added 2n hydrochloric acid to the aqueous layer. The obtained solid residue is filtered off and dried under reduced pressure to obtain 160 mg specified in the title compound as a white powder.

MS (ESI) m/z 354 (M+H)+

Example 142

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(2-methoxyethoxy)-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-(2-methoxyethoxy)-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 12 using 2-methoxyethanol instead of ethylene glycol. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way, with recip is tion specified in the title compound as a brown powder.

MS (ESI) m/z 384 (M+H)+

Example 143

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile

To 500 mg (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example 9), 197 mg of cyanide zinc, 66 mg of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 66 mg of Tris(dibenzylideneacetone)diplodia add a mixed solution of dimethylformamide and water (99/1), bubbled gaseous argon through the solution for three minutes and subjected to microwave irradiation at 150°C for 15 minutes. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, with getting 323 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 336 (M+H)+

Example 144

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 143, using (S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine in place of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine (example is 9).

MS (ESI) m/z 335 (M+H)+

Example 145

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

To 500 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate acid (example 141) add 15 ml of a 7n solution of ammonia/methanol and the resulting mixture is stirred at a temperature of 100°C for 3 days in a sealed ampoule. The solvent of the reaction solution is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 310 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 353 (M+H)+

[0079]Example 146

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

150 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile (example 143) dissolved in 5 ml of anhydrous ethanol and 156 mg of the hydrochloride hydroxyamine add 309 μl of triethylamine and the resulting mixture is refluxed for 2 hours. The reaction solution was diluted with water and the resulting mixture extracted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on forces is the Kagel, to obtain 140 mg of an amorphous brown solid. To the specified reaction solution add 5 ml of triethylorthoformate and 7 mg p-toluensulfonate acid and the resulting mixture was stirred at 60°C for 4 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 141 mg of (S)-N2-[1-(4-forfinal)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine. The compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 67 mg specified in the title compound as a yellow powder.

MS (ESI) m/z 379 (M+H)+

Elemental analysis (for C18H15FN8O·HCl)

Calculated (%) C: 52,12, H: 3,89, N: 27,01

Found (%) C: 52,33, H: 3,97, N: 26,90

Example 147

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 146 using (S)-2-[1-(4-forfinal) is thylamino]-6-(pyrazin-2-ylamino)isonicotinamide instead of (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 378 (M+H)+

Example 148

Methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinate

Stage 1

Methyl (S)-6-chloro-2-[1-(4-forfinal)ethylamino]nicotinate

5.0 g of methyl 2,6-dichloronicotinic dissolved in 50 ml of dimethylformamide and add 4,39 g (S)-(-)-1-(4-forfinal)ethylamine, 6,27 g diisopropylethylamine and 150 mg of 4-dimethylaminopyridine and the resulting mixture was stirred at 60°C for 24 hours. The reaction solution is cooled, then diluted with ethyl acetate, washed successively with water and saturated salt solution and the organic layer is dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 2.83 g specified in the title compound as a white powder.

Stage 2

Methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinate

2.83 g of methyl (S)-6-chloro-2-[1-(4-forfinal)ethylamino]nicotinate, 870 mg of 2-aminopyrazine, 1.06 g of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 4.09 g of tribalista and 475 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 15 ml degaser the bath 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 3,14 g specified in the title compound as an orange powder.

MS (ESI) m/z 368 (M+H)+

Example 149

(S)-2-[1-(4-forfinal)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide

70 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid (example 141) was dissolved in 0.5 ml of dimethylformamide, added 81 mg of dimethylamine hydrochloride, 37 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 32 mg of 1-hydroxy-7-isobenzofuranyl and 0.18 ml of diisopropylethylamine and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off, and then the obtained residue is purified column chromatography on silica gel, to obtain 45 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 381 (M+H)+

Example 150

(S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-forfinal)ethylamino]-6-(pyrazin--ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 149, using N,N-dimethylethylenediamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 424 (M+H)+

[0080]Example 151

(S)-N-tert-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a white powder by the method similar to example 149, using tert-butylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 409 (M+H)+

Example 152

(S)-N-ethyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

To dimethylformamide solution of 450 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid (example 141) and 2.2 ml of Diisopropylamine add 1,32 g hexaphosphate 1H-benzotriazolyl-1-electroporation and the resulting mixture is stirred for 15 minutes. Add 520 mg of ethylamine hydrochloride and the resulting mixture stirred for 2 days. The reaction solution was diluted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off, and then the obtained residue is purified column chromatography on silica gel, to obtain 390 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 381 (M+H)+

Example 153

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}[4-(methanesulfonyl)piperazine-1-yl]metano

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 152 using 1-methanesulfonylaminoethyl instead of dimethylamine hydrochloride.

MS (ESI) m/z 500 (M+H)+

Example 154

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(pyrrolidin-1-yl)methanon

As a side product of example 153 (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(pyrrolidin-1-yl)methanon obtained as pale yellow powder.

MS (ESI) m/z 407 (M+H)+

Example 155

(S)-2-[1-(4-forfinal)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 149, using Isopropylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 395 (M+H)+

[0081]Example 156

(S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-carboxamide

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using (S)-azetidin-2-carboxamide (synthesized according to the method described in Chem. Phram. Bull., 1998, 787-796) instead of Pipa is Azin-2-it, and using 1,4-dioxane as a reaction solvent in stage 2.

MS (ESI) m/z 409 (M+H)+

Example 157

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(tetrahydro-2H-Piran-4-yloxy)pyridine-2,6-diamine

(S)-N2-([1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(tetrahydro-2H-Piran-4-yloxy)pyridine-2,6-diamine receive according to the method similar to example 138 using tetrahydro-2H-Piran-4-ol instead of cyclopropylamine. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 410 (M+H)+

Example 158

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide

Specified in the title compound obtained as brown powder by the procedure analogous to example 1, using 3-azetidinone instead of piperazine-2-she and 1,4-dioxane as a reaction solvent in stage 2.

MS (ESI) m/z 409 (M+H)+

Example 159

(S)-2-[1-(4-forfinal)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a red-brown powder by the procedure analogous to example 149, using 2-Isopropylamine instead of dimethylamine hydrochloride.

<> MS (ESI) m/z 397 (M+H)+

Example 160

(S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 149, using methylamine hydrochloride instead of dimethylamine hydrochloride.

MS (ESI) m/z 367 (M+H)+

[0082]Example 161

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(morpholino)metano

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 149, using morpholine instead of dimethylamine hydrochloride.

MS (ESI) m/z 423 (M+H)+

Example 162

Hydrochloride (S)-N-benzyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

(S)-N-benzyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide receive according to the method similar to example 152 using benzylamine instead of dimethylamine hydrochloride. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 443 (M+H)+

Example 163

(S)-N-cyclopropyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the method, obtained the primary example 149, using cyclopropylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 393 (M+H)+

Example 164

Hydrochloride (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(4-methylpiperazin-1-yl)methanone

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(4-methylpiperazin-1-yl)methanon receive according to the method similar to example 152 using 1-methylpiperazine instead of dimethylamine hydrochloride. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 436 (M+H)+

Example 165

(S)-2-[1-(4-forfinal)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 152 using methoxyethylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 411 (M+H)+

[0083]Example 166

(S)-2-[1-(4-forfinal)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a pink powder by the procedure analogous to example 152 using 1-Propylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 395 (M+H)+

Example 167

(S)-N-cyclopropylmethyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 152 using cyclopropylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 407 (M+H)+

Example 168

(S)-N-cyclobutyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a red-brown powder by the procedure analogous to example 152 using cyclobutylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 407 (M+H)+

Example 169

(S)-N-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 152 using n-butylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 409 (M+H)+

Example 170

(S)-2-[1-(4-forfinal)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 152 using isobutylamine instead of dimethylamine hydrochloride.

MS (ESI) m/z 409 (M+H)+

[0084]Example 171

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2-triptorelin)isonicotinamide

Specified in the title compound obtained as pale yellow powder by the procedure similar the th example 152, using 2,2,2-triptorelin instead of dimethylamine hydrochloride.

MS (ESI) m/z 435 (M+H)+

Example 172

(S)-2-[1-(4-forfinal)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 152 using 3-hydroxypropylamino instead of dimethylamine hydrochloride.

MS (ESI) m/z 411 (M+H)+

Example 173

(S)-N-(2-ethoxyethyl)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide

Specified in the title compound obtained as a yellow powder by the procedure analogous to example 152 using 2-amoxicillin instead of dimethylamine hydrochloride.

MS (ESI) m/z 425 (M+H)+

Example 174

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylisatin-3-carboxamide

Stage 1

1-benzhydryl-N-methylisatin-3-carboxamide

400 mg 1-benzhydrylamine-3-carboxylic acid (synthesized according to the method described in WO2005/49602), dissolved in 4 ml of dimethylformamide, to the solution was added 683 mg of triethylamine, 122 mg of methylamine hydrochloride, 304 mg of 1-hydroxybenzotriazole and 431 mg of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with utilize the atom. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 158 mg specified in the connection header.

Stage 2

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylisatin-3-carboxamide

150 mg of 1-benzhydryl-N-methylisatin-3-carboxamide are dissolved in 6 ml of methanol, to the solution was added 535 μl of 4n an ethyl acetate solution of hydrogen chloride and 150 mg of 20% palladium hydroxide and the resulting mixture was subjected to hydrogenation at a pressure of 4 atmospheres at room temperature over night. The palladium hydroxide is filtered off, the filtrate is concentrated under reduced pressure, to obtain 150 mg of pale yellow oil. 81 mg of the obtained compound was dissolved in 5 ml of degassed 1,4-dioxane, added 81 mg of triethylamine, 184 mg (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 51 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 103 mg of tert-butoxide sodium and 55 mg of Tris(dibenzylideneacetone)(chloroform)diplodia in that order and the mixture was stirred at 90°C for 3.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate, etc is myauth successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 24 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylisatin-3-carboxamide as a yellow powder.

MS (ESI) m/z 423 (M+H)+

Example 175

(S)-N2-[1-(4-forfinal)ethyl]-4-(methoxymethyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

20 mg (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanol (example 140) was dissolved in methylene chloride, added 59 mg chetyrehpostovye carbon and 47 mg of triphenylphosphine under ice cooling and the resulting mixture is stirred for 30 minutes. Then add 90 ál of 9.8 M methanol solution of sodium methoxide and the resulting mixture is stirred over night. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 7 mg specified in the title compound as a yellow powder.

MS (ESI) m/z 354 (M+H)+

[0085]Example 176

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N,N-dimethylamide-3-carboxamide

Specified in the header connection produces the t in the form of a white powder by the method, similar to example 174 using hydrochloride, dimethylamine instead of methylamine hydrochloride.

MS (ESI) m/z 437 (M+H)+

Example 177

(S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanesulfonamide

100 mg of 1-(tert-butoxycarbonyl)-3-aminoacridine dissolved in 5 ml of methylene chloride and add 225 mg diisopropylethylamine. Then add 100 mg of methanesulfonamide under ice cooling, the mixture was left to warm to room temperature and stirred over night. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with 5% aqueous citric acid solution and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 199 mg of a colorless oil. The oil obtained is dissolved in 2.5 ml of methylene chloride, was added 1 ml of triperoxonane acid and the resulting mixture was stirred at room temperature overnight. The solvent is distilled under reduced pressure to obtain a yellow oil. The oil obtained is dissolved in 6 ml of degassed 1,4-dioxane and add 200 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 55 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 111 mg of tert-butoxide sodium, 294 mg of triethylamine and 60 mg the rice(dibenzylideneacetone)(chloroform)diplodia in that order and the mixture was stirred at 90°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 12 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 459 (M+H)+

Example 178

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carbonitril

216 mg of 1-(tert-butoxycarbonyl)-3-cyanoacetylene dissolved in 2.5 ml of methylene chloride, was added 1 ml of triperoxonane acid and the resulting mixture was stirred at room temperature overnight. The solvent is distilled under reduced pressure to obtain brown oil. The oil obtained is dissolved in 4 ml of degassed 1,4-dioxane and add 302 mg of triethylamine, 205 mg of (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine, 57 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 229 mg of tert-butoxide sodium and 62 mg of Tris(dibenzylideneacetone)(chloroform)diplodia in that order and the mixture was stirred at 90°C for 3 hours in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and neymann the m salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 58 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 391 (M+H)+

Example 179

2-(4-forfinal)-2-[4-(1-methyl-1H-pyrazole-4-yl)-6-(pyrazin-2-ylamino)pyridine-2-ylamino]ethanol

Stage 1

4-(4-forfinal)oxazolidin-2-he

600 mg 2-amino-2-(4-forfinal)Ethan-1-ol and 80 mg of potassium carbonate are suspended in 914 mg diethylmalonate, the resulting mixture is stirred at a temperature of 130°C for 2.5 hours and then stirred at 100°C for 2.5 hours, removing, at the same time, the formed ethanol. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 610 mg specified in the title compounds as a pale yellow oil.

Stage 2

3-[6-chloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl]-4-(4-forfinal)oxazolidin-2-he

379 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine, 300 mg of 4-(4-forfinal)oxazolidin-2-it, 192 mg of 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 705 mg tribalista and 172 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 10 ml of degassed 1,4-dioxane and the resulting mixture was stirred at 90°C for 5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 212 mg specified in the title compound as a yellow powder.

Stage 3

2-(4-forfinal)-2-[4-(1-methyl-1H-pyrazole-4-yl)-6-(pyrazin-2-ylamino)pyridine-2-ylamino]ethanol

80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl]-4-(4-forfinal)oxazolidin-2-it, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 41 mg of tert-butoxide of sodium and 22 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 2.5 ml of degassed 1,4-dioxane and the resulting mixture was stirred at 90°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 34 mg specified in the title compound as a white powder.

MS (ESI) m/z 406 (M+H)+

Example 180

(S)-N-ethyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pirati the-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 174 using hydrochloride, ethylamine instead of methylamine hydrochloride.

MS (ESI) m/z 437 (M+H)+

[0086]Example 181

(S)-N,N-diethyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide

Specified in the title compound obtained as a white powder by the method similar to example 174 using diethylamine instead of methylamine hydrochloride.

MS (ESI) m/z 465 (M+H)+

Example 182

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}ethanone

Stage 1

(S)-1-{2-chloro-6-[1-(4-forfinal)ethylamino]pyridine-4-yl}alanon

535 mg of 1-(2,6-dichloropyridine-4-yl)ethanone (stages 1 and 2 of example 29), 391 mg (S)-(-)-1-(4-forfinal)ethylamine, 262 mg (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1.28 g of cesium carbonate and 63 mg of palladium acetate is added in order to 10 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 3 hours in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 132 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 293 (M+H)+

Stage 2

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)the feast of the DIN-4-yl}ethanone

150 mg of (S)-1-{2-chloro-6-[1-(4-forfinal)ethylamino]pyridine-4-yl}ethanone, 51 mg of 2-aminopyrazine, 49 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 59 mg of tert-butoxide sodium and 23 mg of Tris(dibenzylideneacetone)diplodia add in order to 6 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 20 minutes in an argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 77 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}ethanone. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 352 (M+H)+

Elemental analysis (for C19H18FN5O·HCl+0,8 H2O)

Calculated (%) C: 56,73. H: 5,16, N: 17,41

Found (%) C: 57,06, H: 5,20, N: 17,02

Example 183

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-6-(3-methoxyisatin-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

(S)-N2-[1-(4-forfinal)ethyl]-6-(3-methoxyisatin-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine receive according to the method similar to example 1, using the hydrochloride of 3-methoxyaniline instead of piperazine-2-it. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the header joint is in the form of a pale yellow powder.

MS (ESI) m/z 396 (M+H)+

Elemental analysis (for C20H22FN7O·HCl+0,3 H2O)

Calculated (%) C: 54,93, H: 5,44, N: are 22.42

Found (%) C: 55,14, H: 5,44, N: 22,16

Example 184

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-methylaziridine-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-methylaziridine-3-ol receive according to the method similar to example 1, using the hydrochloride of 3-methylisatin-3-ol instead of piperazine-2-it. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 396 (M+H)+

Example 185

(S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide

Stage 1

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinic acid

1.0 g of methyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinate was dissolved in 60 ml of methanol, the resulting solution was added 20 ml of 10% aqueous sodium hydroxide solution and the reaction solution heated to boiling under reflux for 4 hours. The reaction solution is distilled under reduced pressure to remove methanol. The resulting aqueous layer washed with diethyl ether and the pH of the mixture was adjusted to 3 using 10% hydrochloric acid. Receive the config solid precipitate is filtered and washed with water. The obtained solid product is dried under reduced pressure, to obtain 880 mg specified in the title compounds as pale yellow powder.

Stage 2

(S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide

80 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinic acid was dissolved in 1 ml of tetrahydrofuran, to the solution was added 86 mg of hexaflurophosphate O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium (HBTU) and 59 mg of triethylamine. The resulting mixture was stirred at room temperature for 30 minutes, then add 119 μl of 2M solution of methylamine/tetrahydrofuran and the resulting mixture is stirred for 5 hours. The reaction solution was purified column chromatography on silica gel, to obtain 45 mg specified in the title compound as a white powder.

MS (ESI) m/z 367 (M+H)+

[0087]Example 186

(S)-2-[1-(4-forfinal)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide

Specified in the title compound obtained as a white powder by the method similar to example 185 using dimethylamine hydrochloride instead of a 2M solution of methylamine/tetrahydrofuran.

MS (ESI) m/z 381 (M+H)+

Example 187

(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide

2 ml of oxalicacid add to 82 mg (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nor is otinovaa acid (stage 1 of example 185) and the resulting mixture is heated to boiling under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, to the obtained residue, add 5 ml of concentrated aqueous ammonia and the resulting mixture is stirred at a temperature of 100°C for 30 minutes. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 13 mg specified in the title compound as a brown powder.

MS (ESI) m/z 353 (M+H)+

Example 188

The dihydrochloride (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-3-yl}(morpholino)methanone

(S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-3-yl}(morpholino)methanon receive according to the method similar to example 185, by using morpholine instead of a 2M solution of methylamine/tetrahydrofuran. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a white powder.

MS (ESI) m/z 423 (M+H)+

Elemental analysis (for C22H23FN6O2·2HCl)

Calculated (%) C: 53,34, H: 5,09, N: 16,96

Found (%) C: 53,18, H: a 4.86, N: 16,99

Example 189

(S)-N-(cyclopropylmethyl)-2-[1-(4-Fortini is)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide

Specified in the title compound obtained as a white powder by the method similar to example 185, by using cyclopropylamine instead of a 2M solution of methylamine/tetrahydrofuran.

MS (ESI) m/z 407 (M+H)+

Example 190

(S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)econsultant

Specified in the title compound obtained as a pale orange powder by the procedure analogous to example 177 using acanaloniidae instead of methanesulfonamide.

MS (ESI) m/z 473 (M+H)+

[0088]Example 191

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-Isopropylamine-3-carboxamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 174 using Isopropylamine instead of methylamine hydrochloride.

MS (ESI) m/z 451 (M+H)+

Example 192

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-(trifluoromethyl)azetidin-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-(trifluoromethyl)azetidin-3-ol receive according to the method similar to example 1, using the hydrochloride of 3-(trifluoromethyl)azetidin-3-ol (synthesized according to the method described in US 2007/275930) instead of piperazine-2-it. The compound obtained is subjected to hydrochlor the formation, using the normal way of obtaining specified in the title compounds as pale yellow powder.

MS (ESI) m/z 450 (M+H)+

Elemental analysis (for C20H19F4N7O·HCl+H2O)

Calculated (%) C: 47,67, H: 4,40, N: 19,46

Found (%) C: 48,05, H: 4,11, N: 19,23

Example 193

(S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(pyrrolidin-1-yl)methanon

Specified in the title compound obtained as a white powder by the method similar to example 174 using pyrrolidine instead of methylamine hydrochloride.

MS (ESI) m/z 463 (M+H)+

Example 194

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-methoxyethyl)azetidin-3-carboxamide

Specified in the title compound obtained as a white powder by the method similar to example 174 using 2-methoxyethylamine instead of methylamine hydrochloride.

MS (ESI) m/z 467 (M+H)+

Example 195

(S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(piperidine-1-yl)methanon

Specified in the title compound obtained as a white powder by the method similar to example 174 using piperidine instead of methylamine hydrochloride.

MS (ESI) m/z 477 (M+H)+

[0089]Example 196

(S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}AZE is one-3-yl)(morpholino)metano

Specified in the title compound obtained as a white powder by the method similar to example 174 using morpholine instead of methylamine hydrochloride.

MS (ESI) m/z 479 (M+H)+

Example 197

(S)-N-(cyclopropyl)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide

Specified in the title compound obtained as a white powder by the method similar to example 174 using cyclopropylamine instead of methylamine hydrochloride.

MS (ESI) m/z 449 (M+H)+

Example 198

(S)-N-(cyclopropylmethyl)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide

Specified in the title compound obtained as a white powder by the method similar to example 174 using cyclopropylamine instead of methylamine hydrochloride.

MS (ESI) m/z 463 (M+H)+

Example 199

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-hydroxyethyl)azetidin-3-carboxamide

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 174 using 2-hydroxyethylamine instead of methylamine hydrochloride.

MS (ESI) m/z 453 (M+H)+

Example 200

Hydrochloride (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol

(S)-3-cyclo is ropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol get method similar to example 1, using the hydrochloride of 3-cyclopropylamino-3-ol (synthesized according to the method described in US 2007/275930) instead of piperazine-2-it. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 422 (M+H)+

Elemental analysis (for C22H24FN7O·HCl+0.5 H2O)

Calculated (%) C: 56,59, H: 5,61, N: 21,00

Found (%) C: 56,35, H: 5,24, N: 20,97

[0090]Example 201

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-Isopropylamine-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-Isopropylamine-3-ol receive according to the method similar to example 1, using the hydrochloride of 3-isopropylpyridine-3-ol (synthesized according to the method described in US 2007/275930) instead of piperazine-2-it. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 424 (M+H)+

Elemental analysis (for C22H26FN7O·HCl+0,4 H2O)

Calculated (%) C: 56,56, H 6.00, N: 20,99

Found (%) C: 56,81, H: of 5.82, N: 20,94

Example 202

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol

100 mg of the hydrochloride of 3-GI is roxatidine dissolved in 2 ml of methanol, to the solution was added 43 mg of tert-butoxide sodium and the solvent is distilled off under reduced pressure. To the obtained residue, add 4 ml of degassed 1,4-dioxane, then 105 mg (S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine (comparative example 2), 57 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 96 mg of tert-butoxide sodium and 32 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in that order and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with a saturated aqueous solution of ameriglide and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 78 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol. In addition, the compound obtained is subjected to hydrochloridebuy, using a conventional method, to obtain 60 mg specified in the title compound as a brown powder.

MS (ESI) m/z 381 (M+H)+

Example 203

Hydrochloride (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol

(S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethyl) - Rev. Ino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol get method similar to example 202 using the hydrochloride of 3-cyclopropylamino-3-ol instead of hydrochloride of 3-hydroxyazetidine. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 421 (M+H)+

Example 204

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-Isopropylamine-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-Isopropylamine-3-ol receive according to the method similar to example 202 using the hydrochloride of 3-isopropylpyridine-3-ol instead of hydrochloride of 3-hydroxyazetidine and toluene instead of 1,4-dioxane as solvent. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 423 (M+H)+

Example 205

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-methylaziridine-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-methylaziridine-3-ol receive according to the method similar to example 202 using the hydrochloride of 3-methylisatin-3-ol instead of hydrochloride of 3-hydroxyazetidine and toluene instead of 1,4-dioxane as solvent. The compound obtained is subjected Hydra is chlorination, using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 395 (M+H)+

[0091]Example 206

Hydrochloride (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-(trifluoromethyl)azetidin-3-ol

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-(trifluoromethyl)azetidin-3-ol receive according to the method similar to example 202 using the hydrochloride of 3-(trifluoromethyl)azetidin-3-ol instead of hydrochloride of 3-hydroxyazetidine and toluene instead of 1,4-dioxane as solvent. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 449 (M+H)+

Example 207

Hydrochloride (S)-4-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-4-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 202 using the hydrochloride of 3,3-diversityin instead of hydrochloride of 3-hydroxyazetidine and toluene instead of 1,4-dioxane as solvent. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

+

Example 208

(S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}ndimethylacetamide

Stage 1

Tert-butyl 2,6-dichloropyridine-4-ylcarbamate

1.0 g of 2,6-dichlorophenylamino acid dissolved in 20 ml of tert-butyl alcohol to the solution is added to 0.87 ml of triethylamine and 1.2 ml diphenylphosphinite and the resulting mixture is heated to boiling under reflux overnight. The solvent of the reaction mixture is distilled under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 969 mg specified in the title compound as a white powder.

Stage 2

Tert-butyl (S)-2-chloro-6-[1-(4-forfinal)ethylamino]pyridine-4-ylcarbamate

390 mg of tert-butyl 2,6-dichloropyridine-4-ylcarbamate, 220 ál (S)-(-)-1-(4-forfinal)ethylamine, 243 mg of bis[2-(diphenylphosphino)phenyl]ethyl ester, 199 mg of tert-butoxide sodium and 67 mg of palladium acetate is added in order to 10 ml of degassed 1,4-dioxane and the resulting mixture is stirred at a temperature of 100°C for 10 hours in an argon atmosphere. 118 μl of acetic acid is added to the reaction solution and then the resulting mixture was diluted with ethyl acetate. The reaction mixture was filtered through celite to remove the precipitate, the resulting filtrate is concentrated under reduced pressure, the obtained residue is purified is kolonochnoi chromatography on silica gel, to obtain 210 mg specified in the title compound as an amorphous white solid.

Stage 3

Tert-butyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-ylcarbamate

195 mg of tert-butyl (S)-2-chloro-6-[1-(4-forfinal)ethylamino]pyridine-4-ylcarbamate, 61 mg of 2-aminopyrazine, 152 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 71 mg of tert-butoxide sodium and 73 mg of Tris(dibenzylideneacetone)(chloroform)diplodia add in order to 10 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C overnight in an argon atmosphere. 43 μl of acetic acid is added to the reaction solution and the resulting mixture was diluted with ethyl acetate. Specified, the reaction mixture was filtered through celite to remove the precipitate, the filtrate is concentrated under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 203 mg specified in the title compound as an amorphous pale yellow solid.

Stage 4

(S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,4,6-triamine

210 mg of tert-butyl (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-ylcarbamate dissolved in 3 ml of methylene chloride, to the solution was added 1 ml triperoxonane acid and the resulting mixture was stirred at room te is the temperature for 5 hours. The reaction solution was poured into ice saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 151 mg specified in the title compound as an amorphous pale yellow solid.

Stage 5

(S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}ndimethylacetamide

50 mg of (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,4,6-triamine dissolved in 1 ml of methylene chloride and 43 μl of triethylamine to the solution was added 22 μl of acetic anhydride and 1 mg of 4-dimethylaminopyridine and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water. The resulting solution was extracted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 32 mg specified in the title compound as a yellow powder.

MS (ESI) m/z 367 (M+H)+

Example 209

Hydrochloride (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanesulfonamide

(S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanesulfonamide get the technique similar to stage 5 of example 208 using methanesulfonyl anhydride instead of acetic anhydride. The compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a yellow powder.

MS (ESI) m/z 403 (M+H)+

Example 210

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}urea

50 mg of (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,4,6-analogue dissolved in 2 ml of methylene chloride, to the solution was added 49 mg of N,N'-carbonyldiimidazole and the resulting mixture was stirred at room temperature overnight. To this reaction mixture are added a saturated methanolic ammonia solution and the resulting mixture was stirred at room temperature overnight. The solvent of the reaction solution is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 23 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 368 (M+H)+

[0092]Example 211

Hydrochloride (S)-4-(3-cyclopropyl-3-methoxyisatin-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

1-b is Sheryl-3-cyclopropylamino-3-ol

300 mg of 1-benzhydrylamine-3-one, dissolved in 3.8 ml of tetrahydrofuran, is added to 2 ml of 1M solution cyclopropylmagnesium/tetrahydrofuran while cooling with ice water, the resulting mixture was left to warm to room temperature and stirred for 30 minutes. The reaction solution was poured into a saturated aqueous solution of sodium carbonate, the resulting mixture was extracted with diethyl ether and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 334 mg specified in the connection header.

Stage 2

1-benzhydryl-3-cyclopropyl-3-methoxyisatin

334 mg of 1-benzhydryl-3-cyclopropylamino-3-ol is dissolved in dimethylformamide, to the solution was added 72 mg of 60% sodium hydride and the resulting mixture was stirred at room temperature for 30 minutes. Add 112 μl under the conditions and the resulting mixture was continued to stir at room temperature for 2 hours. To the reaction solution was added water, the mixture extracted with diethyl ether and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 280 mg specified in the connection header.

Stage 3

Hydrochloride (S)-4-(3-cyclopropyl-3-methoxyisatin-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

275 mg of 1-benzhydryl-3-cyclopropyl-3-methoxyacridine dissolved in 15 ml of methanol, to the solution is added to 0.70 ml of 2n hydrochloric acid and 150 mg of 20% palladium hydroxide and the resulting mixture was stirred at room temperature overnight under hydrogen pressure of 3.43 bar. The reaction mixture was filtered to remove the precipitate, then the filtrate concentrated under reduced pressure, to obtain 146 mg of a white powder. 62 mg of the obtained compound was dissolved in 2 ml of methanol and to the solution was added 41 mg of tert-butoxide sodium, and then the solvent is distilled off under reduced pressure. 4 ml of degassed toluene are added to the obtained residue, then add 100 mg of (S)-4-chloro-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine (comparative example 2), 55 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 41 mg of tert-butoxide sodium and 27 mg of Tris(dibenzylideneacetone)diplodia in that order and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with a saturated aqueous solution of ameriglide and saturated salt solution and then dried over Sul is an atom of magnesium. The solvent is distilled off under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 47 mg of (S)-4-(3-cyclopropyl-3-methoxyisatin-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 435 (M+H)+

Example 212

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(3-isopropyl-3-methoxyisatin-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-(3-isopropyl-3-methoxyisatin-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine receive according to the method similar to example 211, using 0,79 M solution isopropylacrylamide/tetrahydrofuran instead of 1M solution cyclopropylmagnesium/tetrahydrofuran. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 437 (M+H)+

Example 213

Hydrochloride (S)-N2-[1-(4-forfinal)ethyl]-4-(3-methoxy-3-methylaziridine-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine

(S)-N2-[1-(4-forfinal)ethyl]-4-(3-methoxy-3-methylaziridine-1-yl)-N6(pyrazin-2-yl)pyridine,6-diamine get method similar to example 211, using 3M solution isopropylacrylamide/tetrahydrofuran instead of 1M solution cyclopropylmagnesium/tetrahydrofuran. In addition, the compound obtained is subjected to hydrochloridebuy using the normal way of obtaining specified in the title compound as a brown powder.

MS (ESI) m/z 409 (M+H)+

Example 214

(S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6-(5-methylpyrazine-2-yl)pyridine-2,6-diamine

250 mg of 2-amino-5-bromopyrazine, and 0.40 ml of trimethylboroxine, 794 mg of potassium carbonate and 166 mg of tetrakis(triphenylphosphine)palladium is added in order to 4 ml of degassed dimethylformamide and the resulting mixture was stirred at 110°C in an argon atmosphere overnight. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 100 mg of pale yellow oil. The resulting residue is dissolved in 6 ml of degassed toluene and add 100 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)pyridine-2-amine, 29 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 41 mg of tert-butoxide sodium and 14 mg Tr is s(dibenzylideneacetone)diplegia in that order and the mixture is stirred at a temperature of 100°C for 1 hour in argon atmosphere. The reaction solution was purified column chromatography on silica gel, to obtain 90 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 404 (M+H)+

Example 215

(S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methanesulfonyl)piperidine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

Tert-butyl 4-(2,6-dichloropyridine-4-yl)-5,6-dihydropyridines-1(2H)-carbamate

874 mg of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 1.06 g of tert-butyl 4-(tripterocalyx)-5,6-dihydropyridines-1(2H)-carbamate, of 1.33 g of potassium carbonate and 26 mg of the complex of 1,1'-bis(diphenylphosphino)ferienparadies(II)dichloride-dichloromethane is added in order to 16 ml of degassed dimethylformamide and the resulting mixture is stirred at a temperature of 80°C for 1.5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 631 mg specified in the connection header.

Stage 2

2,6-dichloro-4-[1-(methylsulphonyl)-1,2,3,6-tetrahydropyridine-4-yl]pyridine

327 mg of tert-butyl 4-(2,6-dichloropyridine-4-yl)-5,6-dihydropyridines-1(2H)-ka is mamata dissolved in 4 ml of methylene chloride, to the solution add 2 ml triperoxonane acid and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 2n aqueous sodium hydroxide solution and the resulting mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 221 mg of brown solid. The obtained solid product is dissolved in 10 ml of methylene chloride, to the solution was added to 270 μl of triethylamine, 251 mg methanesulfonamido anhydride and 1 mg of 4-dimethylaminopyridine and the resulting mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution, then the mixture is extracted with ethyl acetate, the organic layer washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 236 mg specified in the title compound as pale brown powder.

Stage 3

(S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-[1-(methylsulphonyl)-1,2,3,6-tetrahydropyridine-4-yl]pyridine-2-amine

225 mg of 2,6-dichloro-4-[1-(methylsulphonyl)-1,2,3,6-tetr hydropyridine-4-yl]pyridine, 104 μl (S)-(-)-1-(4-forfinal)ethylamine, 68 mg of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 359 mg of cesium carbonate and 17 mg of palladium acetate is added in order to 5 ml of degassed tetrahydrofuran and the resulting mixture was stirred at 60°C for 10 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate, filtered to remove the precipitate, then the filtrate concentrated under reduced pressure, the obtained residue is purified column chromatography on silica gel, to obtain 118 mg specified in the title compounds as pale yellow powder.

Stage 4

(S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methylsulphonyl)-1,2,3,6-tetrahydropyridine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

115 mg of (S)-6-chloro-N-[1-(4-forfinal)ethyl]-4-[1-(methylsulphonyl)-1,2,3,6-tetrahydropyridine-4-yl]pyridine-2-amine, 40 mg of 2-aminopyrazine, 53 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 40 mg of tert-butoxide sodium and 26 mg of Tris(dibenzylideneacetone)diplodia add in order to 5 ml of degassed toluene, and the mixture is stirred at a temperature of 100°C for 5 hours in an argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled at below the nom pressure, then the obtained residue is purified column chromatography on silica gel, to obtain 89 mg specified in the title compound as pale brown powder.

Stage 5

(S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methanesulfonyl)piperidine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

88 mg (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methylsulphonyl)-1,2,3,6-tetrahydropyridine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine dissolved in 5 ml of methanol, add 599 mg of ammonium formate and 18 mg of palladium hydroxide (20% on carbon) and the mixture heated to boiling under reflux for 3 hours. 599 mg of ammonium formate and 18 mg of palladium hydroxide (20% on coal) is added to the reaction solution, the reaction solution is then heated to boiling under reflux for 2 hours. The reaction solution is filtered to remove the precipitate, then the filtrate concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 34 mg specified in the title compounds as pale yellow powder.

MS (ESI) m/z 471 (M+H)+

[0093 Example 216

(S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propionamide

Specified in the title compound obtained as a yellow amorphous solid substances by the method similar to stage 5 of example 208 using propionic anhydride instead of acetic anhydride.

MS (ESI) m/z 381 (M+H)+

Example 217

(S)-N2-[1-(4-forfinal)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 37 using 2-bromatology ether instead of 2-bromopropane.

MS (ESI) m/z 434 (M+H)+

Example 218

(S)-4-(1-cyclopropyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Stage 1

1-cyclopropyl-4-iodine-1H-pyrazole

100 mg of pyrazole, 253 mg of cyclopropylboronic acid and 312 mg of sodium carbonate is added to 2.5 ml of 1,2-dichloroethane, to the mixture are added dropwise 5 ml of 1,2-dichlorethane suspension containing 267 mgcopper acetate and 230 mg of 2,2-bipyridine, and the resulting mixture was stirred at 70°C for 4 hours. The specified reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with a saturated aqueous solution of ameriglide, water and nasyscennosti salt and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 148 mg of a yellow oil. The oil obtained is dissolved in 3 ml of acetonitrile, the solution was added 209 mg of iodine and 451 mg of nitrate deamonize(IV) under cooling with ice water and the resulting mixture was stirred at room temperature for 5 hours. Add 6 ml of 5% aqueous solution of sodium bisulfite and the mixture was stirred at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 167 mg specified in the title compounds as a pale yellow oil.

Stage 2

(S)-4-(1-cyclopropyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as pale yellow powder by the procedure analogous to example 37, using 1-cyclopropyl-4-iodine-1H-pyrazole instead of 4-iodine-1-isopropyl-1H-pyrazole.

MS (ESI) m/z 416 (M+H)+

Example 219

(S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methoxymethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the header of the group get as brown powder by the method, similar to example 37, using bromatology ether instead of 2-bromopropane.

MS (ESI) m/z 420 (M+H)+

Example 220

(S)-6-[3-(dimethylamino)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Stage 1

(S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-one

156 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol (example 79) was dissolved in 1 ml of dimethylaminoethoxide, to the resulting solution was added 571 μl of triethylamine and cooled to 15°C. To the solution was added 0.5 ml of a suspension of dimethylaminoethoxide,containing 388 mg of the complex of pyridine-sulfur trioxide, and the mixture was stirred at room temperature overnight. To the reaction solution was added ice and a saturated aqueous solution of ameriglide, the resulting mixture is stirred for 15 minutes, diluted with ethyl acetate, the organic layer is successively washed with a saturated aqueous solution of ameriglide and water and dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 50 mg specified in the title compound as a brown amorphous solid substance.

MS (ESI) m/z 380 (M+H)+

Stage 2

()-6-[3-(dimethylamino)azetidin-1-yl]-N 2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

300 mg (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-one is dissolved in 5 ml of 1,2-dichloroethane, to the resulting solution was added 12 ml of a 2M solution of dimethylamine/tetrahydrofuran and 290 μl of acetic acid and the resulting mixture was stirred at room temperature for 30 minutes. Add 340 mg triacetoxyborohydride sodium and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with saturated aqueous sodium bicarbonate solution and saturated salt solution and then dried over sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 187 mg specified in the title compound as a brown powder.

MS (ESI) m/z 409 (M+H)+

[0094]Example 221

(S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as a white powder by the method similar to example 220 using a 2M solution of methylamine/tetrahydrofuran instead of a 2M solution of dimethylamine/tetrahydrofuran.

MS (ESI) m/z 395 (M+H)+

The use of the 222

(S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidine-2,4-diamine

Specified in the title compound obtained as a white powder by the method similar to example 220 using pyrrolidine instead of a 2M solution of dimethylamine/tetrahydrofuran.

MS (ESI) m/z 435 (M+H)+

Example 223

(S)-N2-[1-(4-forfinal)ethyl]-6-(3-morpholinomethyl-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as a white powder by the method similar to example 220 using morpholine instead of a 2M solution of dimethylamine/tetrahydrofuran.

MS (ESI) m/z 451 (M+H)+

Example 224

(S)-N2-[1-(4-forfinal)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 220 using N-methylpiperazine instead of a 2M solution of dimethylamine/tetrahydrofuran.

MS (ESI) m/z 464 (M+H)+

Example 225

(S)-(1-{1-[2-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)piperidine-4-ol

Specified in the title compound obtained as a white powder by the method similar to example 220 using 4-hydroxypiperidine instead of a 2M solution of dimethylamine/then it is carbonated shall return.

MS (ESI) m/z 465 (M+H)+

[0095]Example 226

4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1λ6,4-thiomorpholine-1,1-dione

Stage 1

4-{6-chloro-2-[(1S)-1-(4-forfinal)ethylamino]pyrimidine-4-yl}-1λ6,4-thiomorpholine-1,1-dione

Specified in the title compound obtained as a colorless amorphous solid by the procedure similar to stage 1 of example 1, using thiomorpholine-1,1-dioxide instead of piperazine-2-it.

MS (ESI) m/z 385 (M+H)+

Stage 2

4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1λ6,4-thiomorpholine-1,1-dione

Specified in the title compound obtained as a brown amorphous solid by the method similar to step 2 of example 1, using 4-{6-chloro-2-[(1S)-1-(4-forfinal)ethylamino]pyrimidine-4-yl}-1λ6,4-thiomorpholine-1,1-dione as the starting substance and a mixed solvent of toluene/1,4-dioxane instead of toluene as the reaction solvent.

MS (ESI) m/z 444 (M+H)+

Example 227

(S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)urea

Stage 1

(S)-1-(1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}azetidin-3-yl)urea

105 mg of tert-butyl 3-(carbamoylation)azetidin-1-carboxylate was dissolved in 2 ml of methylene chloride, RA is Toru add 0.5 ml triperoxonane acid and the resulting mixture was stirred at room temperature for 30 minutes. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 3 ml of 1-butanol. 108 mg of (S)-4,6-dichloro-N-[1-(4-forfinal)ethyl]pyrimidine-2-amine and 331 μl of N,N-diisopropylethylamine added to the mixture and the resulting mixture was stirred at 60°C for 20 hours. The reaction solution is cooled in air to room temperature and then diluted with ethyl acetate. The resulting solution was washed successively with water and saturated salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, to obtain 89 mg specified in the title compound as a white powder.

Stage 2

(S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)urea

73 mg (S)-1-(1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}azetidin-3-yl)urea, 25 mg of 2-aminopyrazine, 38 mg of 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl, 29 mg of tert-butoxide sodium and 18 mg of Tris(dibenzylideneacetone)diplodia add in order to 3 ml of degassed mixed solvent, consisting of a mixture of toluene/1,4-dioxane (1/1), and the mixture was stirred at 90°C for 1 hour in argon atmosphere. The reaction solution was diluted with ethyl acetate. The resulting solution was washed successively with a saturated aqueous solution of ameriglide and nasy the military salt solution and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 31 mg specified in the title compound as a brown powder.

MS (ESI) m/z 424 (M+H)+

Example 228

(S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanol

Stage 1

(S)-(1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}azetidin-3-yl)methanol

Specified in the title compound obtained as a white powder by the method similar to stage 1 of example 1, using azetidin-3-ylmethanol instead of piperazine-2-it.

MS (ESI) m/z 323 (M+H)+

Stage 2

(S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanol

Specified in the title compound obtained as a brown amorphous solid by the method similar to step 2 of example 1, using (S)-(1-{6-chloro-2-[1-(4-forfinal)ethylamino]pyrimidine-4-yl}azetidin-3-yl)methanol as a starting substance and 1,4-dioxane instead of toluene as the reaction solvent.

MS (ESI) m/z 396 (M+H)+

Example 229

Tert-butyl (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methylcarbamate

Specified in the title compound obtained as a brown amorphous solids is the method similar to example 1, using tert-butyl, azetidin-3-illecillewaet instead of piperazine-2-it.

MS (ESI) m/z 495 (M+H)+

Example 230

(S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine

80 mg of tert-butyl (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methylcarbamate dissolved in 4 ml of dichloromethane, to the solution was added 0.8 ml triperoxonane acid and the resulting mixed solution was stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel, to obtain 63 mg specified in the title compound as a brown amorphous solid.

MS (ESI) m/z 395 (M+H)+

[0096]Example 231

(S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]econsultant

23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine are dissolved in 2 ml of 1,2-dichloroethane, and the solution is added to 8.1 mg acanaloniidae and 22 μl of N,N-diisopropylethylamine and the resulting mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, and the resulting residue is purified column is a chromatography on silica gel, to obtain 15 mg specified in the title compound as a brown amorphous solid.

MS (ESI) m/z 487 (M+H)+

Example 232

(S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]ndimethylacetamide

23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine are dissolved in 2 ml of 1,2-dichloroethane, to the solution was added 7 μl of acetic anhydride and 11 μl of pyridine and the resulting mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, and the resulting residue is purified column chromatography on silica gel with 20 mg indicated in the title compound as a brown amorphous solid.

MS (ESI) m/z 437 (M+H)+

Example 233

(S)-N2-[1-(4-forfinal)ethyl]-4-[3-morpholinomethyl-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine

Specified in the title compound obtained as brown powder by the procedure analogous to example 38, using the dihydrochloride 4-(azetidin-3-yl)research instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 450 (M+H)+

Example 234

(S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-yl)piperidine-4-ol

Specified in the title compound obtained as measles is newago powder according to the method analogous to example 38, using the dihydrochloride of 1-(3-azetidinol)-4-piperidine instead of (S)-N-(pyrrolidin-3-yl)ndimethylacetamide.

MS (ESI) m/z 464 (M+H)+

Structural formulas of the compounds of examples 1-234 presented in tables 1-12.

Test 1: Test for inhibitory activity against JAK2 and JAK3 tyrosinekinase

1. Preparation of test substance

The test substance dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mm and then diluted DMSO reduced to 100 times the concentrations for measurements(1000, 300, 100, 30, 10, 3, 1, 0,3, 0,1, 0,03, 0,01 µm). Furthermore, solutions, diluted analytical buffer up to 20 times, used as solutions of the test substance. As a negative control used solution in DMSO and diluted to 20 times the analytical buffer. The analytical use buffer 15 mm Tris-Cl (pH 7.5), 0.01 to about/about% Tween-20 and 1 mm dithiothreitol.

2. Measurement of the activity of JAK2 and JAK3 tyrosinekinase

aktivnosti measure using ELISA. The resulting solution of the test substance (10 ál each; n=2) placed in a 96-well plate coated with streptavidin (kits are used Strip Plate 8×12 wells; Perkin Elmer), which is added to 20 ál of substrate solution (625 nm Biotin-labeled peptide substrate, 25 mm ATP, 25 mm MgCl2, 15 mm Tris-Cl (pH 7.5), 0.01 to about/about% Tween-20 and 1 mm dithiothreitol) and stirred. At the end add 20 µl of each of the JAK2 tyrosine kinase (Carnabioscience Co.) (diluted to 0.75 nm analytical buffer) or JAK3 tyrosine kinase (Carnabioscience Co.) (diluted to 0.75 nm analytical buffer), mix and leave to stand at 30°C for 1 hour. The tablet is washed 4 times with wash buffer (50 mm Tris-Cl, pH 7.5, 150 mm NaCl, 0,02 V/V% Tween-20) and then add blocking buffer (0.1% bovine serum albumin) (150 μl each) to lock at 30°C for 30 minutes. The blocking buffer is removed, add 100 ál of horseradish peroxidase antiphosphotyrosine receptor antibodies (BD Bioscience Co.) (diluted 10,000 times with the blocking buffer). Tablet incubated at 30°C for 30 minutes and then washed 4 times with wash buffer add 100 ál of 3,3',5,5'-tetramethylbenzidine (Sigma-Aldrich Co.)for the manifestation of color within 10 minutes. To stop reaction, add 0.1 M sulfuric acid (100 μl). Absorption was measured using a microplate-ri is EP (BIO-RAD; Model 3550) at a wavelength of 450 nm.

3. Analysis of measurement results

The values obtained during the measurement process, using nonlinear regression analysis using the SAS system (SAS Institute Inc.), and evaluate concentration (IC50) test substance at which inhibited 50% of the activity of each of tyrosinekinase. The results obtained are presented in tables 13-18.

Table 13
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity against J tyrosine kinase (IC50nm)
Example 10,9445
Example 20,4943
Example 31,2130
Example 40,5944
Example 50,6262
Example 6the 5.7 500
Example 70,4239
Example 81,182
Example 916360
Example 100,8995
Example 110,8236
Example 120,9279
Example 131,371
Example 141,9120
Example 151,372
Example 168,0630
Example 174,4340
Example 183,0130
Example 192,659
When is EP 20 0,6921
Example 218,7950
Example 221,688
Example 234,2210
Example 241,153
Example 250,97100
Example 260,2728
Example 270,5242
Example 281,2110
Example 292,0160
Example 301,575
Example 310,4126
Example 320,5068
Example 330,40 30
Example 340,5159
Example 352,5440
Example 362,8200
Example 373,2130
Example 382,385
Example 390,9390
Example 403,4310
Example 411,151
Example 421,066
Example 431,2130

Example 84
Table 14
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity is here in relation to J tyrosine kinase (IC 50nm)
Example 442,1140
Example 459,02300
Example 463,793
Example 47121300
Example 486,0140
Example 492,3170
Example 500,8429
Example 513,151
Example 522,0160
Example 535,9390
Example 54221800
Example 552,0190
Example 560,7924
Example 571,382
Example 580,6926
Example 591,760
Example 600,7128
Example 616,0150
Example 622,265
Example 631,036
Example 647,0220
Example 650,278,9
Example 661,837
Example 6711470
Example 681,534
Example 692,683
Example 701, 65
Example 710,7226
Example 720,9631
Example 731,348
Example 74the 3.8230
Example 7512630
Example 762,557
Example 770,7337
Example 781,435
Example 794,3140
Example 801,160
Example 815,6480
Example 821,799
Example 833,758
2,0170
Example 850,5120
Example 862,487

Table 15
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity against J tyrosine kinase (IC50nm)
Example 8714450
Example 8813200
Example 89the 3.8150
Example 906,1380
Example 911,497
Example 929,8460
Example 933,0 220
Example 941,777
Example 952,2110
Example 961,433
Example 9737610
Example 98191300
Example 992,4200
Example 1000,5247
Example 10111600
Example 1022,6140
Example 1034,1310
Example 1041,039
Example 1050,5527
Example 1061,9110
Example 1070,7756
Example 1081,156
Example 1092,4130
Example 1100,6744
Example 1111,6110
Example 1120,6967
Example 113a 4.9200
Example 1144,866
Example 1152,3210
Example 1165,3340
Example 1172,7190
Example 1181,6290
Example 119281600
Example 120 231700
Example 1212,7170
Example 1220,4030
Example 123of 5.4330
Example 1241,366
Example 1251,6130
Example 1268,8630

Table 16
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity against J tyrosine kinase (IC50nm)
Example 1272,9200
Example 1280,6546
Example 1293,4380
Example 1307,7570
Example 1312,8180
Example 1327,8350
Example 1333,0230
Example 1349,2620
Example 1352,6320
Example 1361,1170
Example 1372,2160
Example 1383,4420
Example 1395,0290
Example 1401,461
Example 14114440
Example 1421,266
Note the p 143 142100
Example 1442,1210
Example 1450,3436
Example 1469,51400
Example 1479,2920
Example 14821810
Example 1492,6690
Example 1501,7150
Example 1517,4490
Example 1520,7193
Example 1538,4300
Example 15416340
Example 1552,4390
Example 1566,7/td> 580
Example 1572,0150
Example 1580,6539
Example 1591,0170
Example 1601,0100
Example 16112230
Example 1623,4370
Example 1630,74170
Example 16412470
Example 1653,1360

Example 166
Table 17
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity against J tyrosine kinase (IC50nm)
2,2380
Example 1671,6350
Example 168171300
Example 1693,0500
Example 1701,2180
Example 1711,9570
Example 1720,85150
Example 1731,5200
Example 1740,9947
Example 175a 4.9400
Example 1760,9635
Example 1770,7487
Example 1781,082
Example 179 2,6330
Example 1802,552
Example 1812,256
Example 1826,4440
Example 1831,859
Example 1840,9245
Example 1854,2380
Example 1865,5240
Example 1872,4400
Example 1883,7120
Example 189121500
Example 1901,258
Example 1911,431
Example 1921,9120
Example 1930,8035
Example 1940,7984
Example 1951,250
Example 1960,6435
Example 1971,658
Example 1981,660
Example 1991,664
Example 2000,3926
Example 2010,4135
Example 202the 4.7470
Example 2034,5120
Example 2048,1220

Table 18
The test substanceInhibitory activity against J2 tyrosine kinase (IC50nm)Inhibitory activity against J tyrosine kinase (IC50nm)
Example 2052,8170
Example 20610360
Example 2077,0300
Example 2081,4100
Example 2097,1440
Example 2103,2180
Example 2115,686
Example 21215160
Example 2133,2130
Example 2145,5380
Example 2152,3 210
Example 2161,449
Example 2171,536
Example 2182,285
Example 2192,669
Example 2200,9824
Example 2211,559
Example 2220,7518
Example 2230,6511
Example 2241,116
Example 2250,6913
Example 2261,124
Example 2271,120
Example 2281,119
Example 229a 3.9180
Example 2301,263
Example 2310,5933
Example 2320,5532
Example 2335,8140
Example 234of 5.4170

As described above, the compounds of the present invention or their pharmaceutically acceptable salts exhibit high inhibitory activity against JAK2 tyrosine kinase and low inhibitory activity against JAK3 tyrosine kinase; and therefore, pharmaceutical compositions containing the compounds of the present invention or their pharmaceutically acceptable salts, can be used for prevention or treatment of cancer (for example, cancers of the blood (for example, true polycythemia, essential of thrombocythemia, myeloproliferative neoplasms, such as idiopathic myelofibrosis (chronic myeloid proliferative diseases), syndrome osteomielitis, acute lymphocytic Le is the goat, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma) and solid cancers (such as prostate cancer, breast cancer)), inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis) and angiopathy (for example, pulmonary hypertension, arteriosclerosis, aneurysm, varicose veins). In addition, the compounds of the present invention or their pharmaceutically acceptable salts are excellent from the point of view of the presence of harmful effects because of their inhibitory activity against other collections tyrosinekinase small.

[0116]Test 2: Inhibitory growth activity against JAK2 variant expressing cells

BaF3 cells, which have built-gene JAK2 V617F (BaF3/JAK3 V617F cells), inoculant in 96-well plate (1×103cells/well, and left to stand in CO2the incubator. The next day, the test substance is added to the cells. The test substance diluted DMSO, getting the solutions of concentration 10 mm, 6 mm, 3 mm, 1 mm, 600 μm, 300 μm, 100 μm, 60 μm, 30 μm, or 10 μm. The resulting solution is diluted 100 times with distilled water, getting the solutions of a concentration of 100 μm, 60 μm, 30 μm, 10 μm, 6 μm, 3 μm, 1 μm, 600 nm, 300 nm, or 100 nm. The obtained solutions of the test substance added to the wells to which icesto 10 μl/well. As negative control, 1% DMSO solution is added to the wells in an amount of 10 μl/well. As a result of operations the final concentration of the test substance becomes equal to 10 μm, 6 μm, 3 μm, 1 μm, 600 nm, 300 nm, 100 nm, 60 nm, 30 nm, 10 nm or 0 nm of 0.1% DMSO solution). The solution of test substance added to the wells in three repetitions.

After continuous incubation for 3 days counting viable carried out using the MTT method. MTT method is as follows. First, 10 ml of a solution containing 5 mg/ml MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) is added to each well. The tablet is left to stand in CO2incubator for 4 hours, then to each well was added 100 ml of 0.04 n HCl/2-propanol to stop reaction. The resulting MTT-formazan thoroughly dissolve multichannel pipette and measure the absorption at a wavelength of 595 nm relative absorption at the wavelength of 655 nm (Thermo Co.; Multiskan FC). Nonlinear regression analysis using the SAS system (SAS Institute Inc.) allowed to determine the concentration (IC50) a test substance which inhibits 50% of cell growth. The results obtained are presented in table 19.

[0117]

64
Table 19
The test substance(IC50nm)
Example 183
Example 270
Example 471
Example 790
Example 11100
Example 2055
Example 24100
Example 2789
Example 2894
Example 3060
Example 3187
Example 5053
Example 5681
Example 6080
Example 6593
Example 71100
Example 10560
Example 112
Example 152100
Example 16664
Example 16763
Example 17077
Example 20070
Example 22064
Example 22266
Example 22357
Example 22494
Example 22564
Example 22889
Example 23197
Example 23288

[0118]Example compositions 1

Tablets (for oral administration)

The composition: Each tablet (80 mg) contains:

Connection example 15.0 mg
Corn starch46.6 mg
Crystalline cellulose 24,0 mg
Methylcellulose4.0 mg
Magnesium stearate0.4 mg

The mixed powder in the above ratios pressed into tablets in the usual way, getting a tablet for oral administration.

Example composition 2

Tablets (for oral administration)

The composition: Each tablet (80 mg) contains:

The compound of example 25.0 mg
Corn starch46.6 mg
Crystalline cellulose24,0 mg
Methylcellulose4.0 mg
Magnesium stearate0.4 mg

The mixed powder in the above ratio is pressed into tablets in the usual way, getting a tablet for oral administration.

Industrial applicability

[0119] As described above, the compounds of the present invention or their pharmaceutically acceptable salts exhibit high inhibitory activity against JAK2 tyrosine kinase; therefore, connection nastojasih the invention or their pharmaceutically acceptable salts can be used as a prophylactic or therapeutic drug for cancer (for example, when hematological cancer (e.g., when the true polycythemia, essential of thrombocythemia, myeloproliferative tumors, such as idiopathic myelofibrosis (chronic myeloid proliferative diseases), syndrome of osteomielitis, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, multiple myeloma), in solid cancers (such as prostate cancer, breast cancer)), inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis) and angiopathy (for example, pulmonary hypertension, arteriosclerosis, aneurysm, varicose veins).

1. The connection represented by the following General formula [1] or its pharmaceutically acceptable salt, where the specified connection is defined with the following values (I) or (II)

(I)
X represents CH or N;
R1is a halogen;
R2is:
(1) H,
(2) halogen,
(3) cyano,
(4) a group represented by the following General formula [2]

(where * indicates the position of the linkage; and RC, RDand REare the same or different and each represents (a) H or (b) C1-alkyl, neobyazatel is substituted by hydroxy or C1-alkoxy, or alternatively two of RC, RDand REtaken together with the adjacent C atom, represent a 6-membered N-containing saturated heterocyclic group and the remainder represents H, 6-membered saturated heterocyclic group optionally substituted by alkylsulfonyl),
(5) a group represented by the following General formula [3]

(where * is the value as defined above; and RFand RGare the same or different and each represents (a) H, (b) C1-alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, di-alkylamino saturated 5-6-membered cyclic amino group containing the nitrogen atom as the heteroatom, (C1-alkyl)carbylamine, C1-alkylsulfonyl, aryl selected from phenyl, 5-6-membered heteroaryl containing 1-2 heteroatoms selected from nitrogen atoms, oxygen, or sulfur, optionally substituted C1-alnilam, tetrahydrofuranyl and carbamoyl, (c) (C1-alkyl)carbonyl, (e) carbarnoyl or (f) a 6-membered heteroaryl containing 1-2 nitrogen atom, optionally substituted C1-alnilam, or alternative RFand RGtaken together with the adjacent N atom represent a saturated 4-7 membered cyclic amino group, optionally additionally containing 1-3 atoms(a) nitrogen C the glue or oxygen atom or sulfur, which is optionally substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) C1-alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, C1-alkoxy, amino, (C1-alkoxy)carbylamine, C1-alkylsulfonyl and (Cl-alkyl)carbylamine, (e) C3-cycloalkyl, (g) C1-alkoxy, (h) oxo, (i) group, represented by the following General formula [4]

(where * is the value as defined above; and RHrepresents a C1-alkyl or C6-aryl), (j) a group represented by the following General formula [5]

(where * is the value as defined above; and RIand RJare the same or different and each represents H, C1-alkyl, carbarnoyl, (C1-alkyl)carbonyl or C1-alkylsulfonyl), (k) the group represented by the following General formula [6]

(where * is the value as defined above; and RKrepresents a C1-alkyl, hydroxy, amino, C1-alkylamino, di-alkylamino, (C1-alkoxo-alkyl)amino, C1-alkoxy or 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle selected from nitrogen atoms and oxygen), and (l) a 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle, optionally substituted what hydroxypropoxy; and saturated cyclic amino group which is formed by combining RF, RGand the neighboring N, and may form a Spiro-linkage group represented by the following General formula [7A] and [7B]

(where * is the value as defined above),
(6) a group represented by the following General formula [8]

(where * is the value as defined above; and RLrepresents (a) C1-alkyl, (b) hydroxy, (C) C1-alkoxy, (d) a 5-6-membered saturated cyclic amino group, optionally additionally containing a nitrogen atom in the cycle, optionally substituted C1-alnilam or C1-alkylsulfonyl, or (e) amino, optionally substituted by one or two groups selected from the group consisting of C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl, aralkyl selected from benzyl, halogen-alkyl, dis-alkylamino-alkyl, C1-alkoxo-alkyl and hydroxys-alkyl),
(7) a group represented by the following General formula [9]

(where * is the value as defined above; and RM, RNand ROare the same or different and each represents H, halogen, cyano, C1-alkoxy, carbarnoyl, sulfamoyl, mono-alkylaminocarbonyl or C1-alkylsulfonyl, or alternatively two of RM , RNand ROtaken together, represent methylenedioxy),
(8) -ORP(RPrepresents a C1-alkyl, optionally substituted by a group selected from the group consisting of hydroxy, di-alkylamino, C1-alkoxy and tetrahydrofuranyl, or optional O-containing 6-membered saturated cyclic group, optionally substituted by hydroxy) or
(9) 5-6-membered heteroaryl containing 1-4 nitrogen atom and optionally additionally contain an oxygen atom or sulfur as an additional heteroatom or contains an oxygen atom as heteroatom, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, C1-alkoxy, (C1-alkyl)carbonyl, carbamoyl, C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl, hydroxycarbonyl and C1-alkoxo-alkyl;
R3represents H or hydroxy;
R4represents H or C1-alkyl; and
R5represents H or C1-alkyl;
(II):
X represents-CRA;
RArepresents a group represented by the following General formula [10]

(where * is the value as defined above; and RBrepresents (a) amino, optionally substituted by one or two groups selected from the group consisting of C1-alkyl, C3-cycloalkyl, (Col)C1-alkyl and C1-alkoxo-alkyl, (b) C1-alkoxy, (c) hydroxy, or (d) a 5-6-membered saturated cyclic amino group which may optionally contain heteroatom selected from oxygen atom);
R1is a halogen;
R2represents H;
R3represents H or hydroxy;
R4represents H or C1-alkyl; and
R5represents H or C1-alkyl.

2. The compound or its pharmaceutically acceptable salt p. 1, where the aforementioned compound represented by the General formula [1], defined with the following values [i] or [ii],
[i]
X represents CH or N; and
R2represents a
(1) a group represented by the following General formula [11]:

(where * indicates the position of the linkage; and RF1and RG1are the same or different and each represents (a) H, (b) C1-alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, di-alkylamino, 5-6-membered saturated cyclic amino group containing the nitrogen atom as the heteroatom, (C1-alkyl)carbylamine, C1-alkylsulfonyl, aryl selected from phenyl, 5-6-membered heteroaryl containing 1-2 heteroatoms selected from nitrogen atoms, oxygen, or sulfur, optionally substituted C1-alnilam, tetrahydrofuranyl and carbamoyl, (c) (C1-alkyl)to ronil, (e) carbarnoyl or (f) a 6-membered heteroaryl containing 1-2 nitrogen atom, optionally substituted C1-alnilam, or alternative RF1and RG1taken together with the adjacent N atom represent a 4-7-membered saturated cyclic amino group, optionally additionally containing 1-3 atoms(a) nitrogen cycle or oxygen atom or sulfur, which is optionally substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) C1-alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, C1-alkoxy, amino, (C1-alkoxy)carbylamine, C1-alkylsulfonyl and (C1-alkyl)carbylamine, (e) C3-cycloalkyl, (g) C1-alkoxy, (h) oxo, (i) a group represented by the following General formula [4]

(where * is the value as defined above; and RHrepresents a C1-alkyl or C6-aryl), (j) a group represented by the following General formula [5]

(where * is the value as defined above; and RIand RJare the same or different and each represents H, C1-alkyl, carbarnoyl, (C1-alkyl)carbonyl or C1-alkylsulfonyl), (k) the group represented by the following General formula [6]

(where * is the value as defined above; and RKthe submitted is a C1-alkyl, hydroxy, amino, C1-alkylamino, di-alkylamino, (C1-alkoxo-alkyl)amino, C1-alkoxy or 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle selected from nitrogen atoms and oxygen), and (1) 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle, optionally substituted by hydroxyl,
(2) a group represented by the following General formula [8]

(where * is the value as defined above; and RLrepresents (a) C1-alkyl, (b) hydroxy, (c) C1-alkoxy, (d) a 5-6-membered saturated cyclic amino group, optionally additionally containing a nitrogen atom in the cycle, optionally substituted C1-alnilam or C1-alkylsulfonyl, or (e) amino, optionally substituted by one or two groups selected from the group consisting of C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl, aralkyl selected from benzyl, halogen-alkyl, dis-alkylamino-alkyl, C1-alkoxo-alkyl and hydroxys-alkyl),
(3) a group represented by the following General formula [9]

(where * is the value as defined above; and RM, RNand ROare the same or different and each represents H, halogen, cyano, C1-alkoxy, carbarnoyl, sulfamoyl, mono-alkylaminocarbonyl or C1-alkylsulfonyl, or alternative the two of R M, RNand ROtaken together, represent methylenedioxy),
(4) -ORP1(where RP1represents a C1-alkyl, optionally substituted by a group selected from the group consisting of hydroxy, di-alkylamino, C1-alkoxy and tetrahydrofuranyl) or
(5) 5-6-membered heteroaryl containing 1-4 nitrogen atom and optionally additionally contain an oxygen atom or sulfur as an additional heteroatom or contains an oxygen atom as heteroatom, optionally substituted by one or two groups selected from the group consisting of cyano, halogen, hydroxy, C1-alkoxy, (C1-alkyl)carbonyl, carbamoyl, C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C3-alkyl, hydroxycarbonyl and C1-alkoxo-alkyl;
[ii]
X represents-CRA;
RArepresents a group represented by the following General formula [10]

(where * is the value as defined above; and RBrepresents (a) amino, optionally substituted by one or two groups selected from the group consisting of C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl and C1-alkoxo-alkyl, (b) C1-alkoxy, (c) hydroxy, or (d) a 5-6-membered saturated cyclic amino group which may optionally contain heteroatom selected from oxygen atom); and
R2represents H

3. The compound or its pharmaceutically acceptable salt p. 1, where
X represents CH;
R2represents a
(1) a group represented by the following General formula [11]

(where * indicates the position of the linkage; and RF1and RG1are the same or different and each represents (a) H, (b) C1-alkyl, optionally substituted by one or two groups selected from the group consisting of hydroxy, amino, di-alkylamino, 5-6-membered saturated cyclic amino group containing the nitrogen atom as the heteroatom, (C1-alkyl)carbylamine, C1-alkylsulfonyl, aryl selected from phenyl, 5-6-membered heteroaryl containing 1-2 heteroatoms selected from nitrogen atoms, oxygen, or sulfur, optionally substituted C1-alnilam, tetrahydrofuranyl and carbamoyl, (c) (C1-alkyl)carbonyl, (e) carbarnoyl or (f) a 6-membered heteroaryl containing 1-2 nitrogen atom, optionally substituted C1-alnilam, or alternative RF1and RG1taken together with the adjacent N atom represent a 4-7-membered saturated cyclic amino group, optionally additionally containing an atom (a) nitrogen cycle or oxygen atom or sulfur, which is optionally substituted by one or two groups selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) C1-alkyl, not battelino substituted by one or two groups selected from the group consisting of hydroxy, C1-alkoxy, amino, (C1-alkoxy)carbylamine, (C1-alkyl)sulfonylamino and (C1-alkyl)carbylamine, (e) C3-cycloalkyl, (g) C1-alkoxy, (h) oxo, (i) a group represented by the following General formula [4]

(where * is the value as defined above; and RHrepresents a C1-alkyl or C6-aryl), (j) a group represented by the following General formula [5]

(where * is the value as defined above; and RIand RJare the same or different and each represents H, C1-alkyl, carbarnoyl, (C1-alkyl)alkylsulphonyl or C1-alkylsulfonyl), (k) the group represented by the following General formula [6]

(where * is the value as defined above; and RKrepresents a C1-alkyl, hydroxy, amino, C1-alkylamino, di-alkylamino, (C1-alkoxo-alkyl)amino, C1-alkoxy, alkylsulfonyl or 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle selected from nitrogen atoms and oxygen), and (l) a 5-6-membered saturated cyclic amino group containing 1-2 heteroatoms in the cycle, optionally substituted by hydroxyl,
(2) a group represented by the following General formula [8]

(where * is the value as defined above; and RLthe stand is made by a (a) C1-alkyl, (b) hydroxy, (C) C1-alkoxy, (d) a 5-6-membered saturated cyclic amino group, optionally additionally containing a nitrogen atom in the cycle, optionally substituted C1-alnilam or C1-alkylsulfonyl, or (e) amino, optionally substituted by one or two groups selected from the group consisting of C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl, aralkyl selected from benzyl, halogen-alkyl, di-alkylamino-alkyl, C1-alkoxo-alkyl and hydroxys-alkyl),
(3) a group represented by the following General formula [9]

(where * is the value as defined above; and RM, RNand ROare the same or different and each represents H, halogen, cyano, C1-alkoxy, carbarnoyl, sulfamoyl, mono-alkylaminocarbonyl or C1-alkylsulfonyl, or alternatively two of RM, RNand ROtaken together, represent methylenedioxy),
(4) -ORP1(where RP1represents a C1-alkyl, optionally substituted by a group selected from the group consisting of hydroxy, di-alkylamino, C1-alkoxy and tetrahydrofuranyl) or
(5) 5-6-membered heteroaryl containing 1-4 nitrogen atom and optionally additionally contain an oxygen atom or sulfur as an additional heteroatom or contains an oxygen atom as a heteroatom, neobyazatelnostyu one or two groups selected from the group consisting of cyano, halogen, hydroxy, C1-alkoxy, (C1-alkyl)carbonyl, carbamoyl, C1-alkyl, C3-cycloalkyl, (C3-cycloalkyl)C1-alkyl, hydroxycarbonyl and C1-alkoxo-alkyl.

4. The compound or its pharmaceutically acceptable salt p. 1, where the specified connection is selected from the group consisting of the following compounds (1)-(219):
(1) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-it,
(2) N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidine-4-yl]pyrrolidin-3-yl}acetamide", she
(3) (S)-6-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(4) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(5) (S)-N2'-[1-(4-forfinal)ethyl]-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine,
(6) (S)-N2'-[1-(4-forfinal)ethyl]-6-methoxy-N6'(pyrazin-2-yl)-3,4'-bipyridine-2',6'-diamine,
(7) (S)-2'-[1-(4-forfinal)ethylamino]-6'-(pyrazin-2-ylamino)-3,4'-bipyridine-6-ol,
(8) (S)-N2-[1-(4-forfinal)ethyl]-4-(oxazol-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(9) (S)-6-chloro-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(10) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(11) (S)-N2-[1-(4-forfinal) ethyl]-N4-(p is the Razin-2-yl)-6-(1H-pyrazole-4-yl)pyrimidine-2,4-diamine,
(12) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yloxy}ethanol,
(13) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,
(14) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,
(15) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,
(16) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-it,
(17) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2,6-dione,
(18) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}tetrahydropyrimidin-2(1H)-it,
(19) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,
(20) (S)-N2-[1-(4-forfinal)ethyl]-6-morpholino-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(21) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}imidazolidin-2-it,
(22) (S)-N2-[1-(4-forfinal)ethyl]-6-(oxazol-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(23) (S)-N2-[1-(4-forfinal)ethyl]-6-(6-methoxypyridine-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(24) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrazole-3-yl)pyrimidine-2,4-diamine,
(25) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyridine-2-ol,
(26) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-ylamino)pyrimidine-4-yl}pyridine-2-ol,
(27) N-((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)acetamide", she
(28) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-4-yl)pyridine-2,6-diamine,
(29) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1H-pyrazole-3-yl)pyridine-2,6-diamine,
(30) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylsulphonyl)phenyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(31) (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)phenyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(32) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-isopropyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(33) N-{(S)-1-[2-{[(S)-1-(4-forfinal)ethyl]amino}-6-(pyrazin-2-ylamino)pyridine-4-yl]pyrrolidin-3-yl}acetamide", she
(34) (S)-N2-[1-(4-forfinal)ethyl]-4-morpholino-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(35) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-thiomorpholine-2,6-diamine,
(36) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propan-1-ol,
(37) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)acetamide", she
(38) (S)-6-(azetidin-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(39) (S)-6-(3-torasemide-1-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(40) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-he is,
(41) (S)-4-(1-ethyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(42) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-5-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(43) (S)-4-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(44) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,
(45) 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-ol,
(46) (S)-N2-[1-(4-forfinal)ethyl]-N4-(5-methylthiazole-2-yl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue,
(47) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4,5'-bipyrimidin-2,6-diamine,
(48) (S)-N2-[1-(4-forfinal)ethyl]-6-(2-methoxythiazole-5-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(49) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,
(50) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides,
(51) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxamide,
(52) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}picolinamides,
(53) 4-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-2-carboxamide,
(54) 6-(3-aminopyrrolidine-1-yl)-N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrim the Dean-2,4-diamine,
(55) N-(1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3-yl)methanesulfonamide,
(56) (S)-2-({2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}(2-hydroxyethyl)amino)ethane-1-ol,
(57) (S)-N4-[2-(dimethylamino)ethyl]-N2-[1-(4-forfinal)ethyl] N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue,
(58) 1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-carboxamide,
(59) (S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-carboxamide,
(60) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(methylsulphonyl) piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(61) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4-diamine,
(62) (R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-hydroxypyrrolidine-2-it,
(63) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[(tetrahydrofuran-2-yl)methyl]pyrimidine-2,4,6-analogue,
(64) ((S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol,
(65) ((R)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-2-yl)methanol,
(66) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-ol,
(67) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol,
(68) 1-{2-[(S)-1-(4-forfinal)this is laminitis]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-3-ol,
(69) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinanilide,
(70) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4-diamine,
(71) (S)-N4-(2-amino-ethyl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue,
(72) (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)methanesulfonamide,
(73) (S)-N-(2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ethyl)acetamide", she
(74) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}ndimethylacetamide,
(75) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide,
(76) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzonitrile,
(77) (S)-N2-[1-(4-forfinal)ethyl]-6-(furan-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(78) ethyl (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperidine-4-carboxylate,
(79) (S)-5-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}nicotinamide,
(80) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}piperazine-4-carboxylic acid,
(81) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-2-phenylethanol,
(82) (S)-2-{2-[(S)-1- (4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-phenylpropane-1-ol,
(83) (R)-2-{2-[(S)-1-(4-forfinal)atilim is but]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-4-methylpentan-1-ol,
(84) (S)-6-[2-(dimethylamino)ethoxy]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(85) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1H-pyrazole-4-carboxylic acid,
(86) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}benzamide,
(87) (S)-6-(benzo[d]-1,3-dioxol-5-yl)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(88) (S)-N2-[1-(4-forfinal)ethyl]-6-(2-herperidin-4-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(89) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4-diamine,
(90) (S)-2-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}ethanol,
(91) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4,6-analogue,
(92) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide,
(93) (S)-3-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}isonicotinamide,
(94) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-methylbutane-1-ol,
(95) (S)-N2-[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulphonyl) piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(96) (1S,2S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yloxy}cyclohexanol,
(97) (S)-N2-[1-(4-forfinal)ethyl]-N4-[(5-methyl shall irisin-2-yl)methyl]-N 6(pyrazin-2-yl)pyrimidine-2,4,6-analogue,
(98) (S)-N2-[1-(4-forfinal)ethyl]-N4-(furan-2-ylmethyl)-N6(pyrazin-2-yl)pyrimidine-2,4,6-analogue,
(99) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-[1-(pyridine-3-yl)ethyl]pyrimidine-2,4,6-analogue,
(100) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-4-(hydroxymethyl)piperidine-4-ol,
(101) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-2-ylmethyl)pyrimidine-2,4,6-analogue,
(102) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-3-ylmethyl)pyrimidine-2,4,6-analogue,
(103) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-N6-(pyridine-4-ylmethyl)pyrimidine-2,4,6-analogue,
(104) (S)-2-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-ylamino}-3-hydroxypropylamino,
(105) (3S,4S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}pyrrolidin-3,4-diol,
(106) N2-[(S)-1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyrimidine-2,4-diamine,
(107) (S)-8-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1,3-dioxo-8 azaspiro[4.5]decane-2-it,
(108) (S)-N2-[1-(4-forfinal)ethyl]-6-[4-(phenylsulfonyl)piperazine-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(109) (S)-4-{2-[1- (4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzamide,
(110) (S)-N2-[1-(4-forfinal) the Tyl]-N 6(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6-diamine,
(111) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(112) (S)-N2-[1-(4-forfinal)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(113) (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methoxyphenyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(114) (S)-4-(4-forfinal)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(115) (S)-N2-[1-(4-forfinal)ethyl]-4-methyl-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(116) (S)-N2-[1-(4-forfinal)ethyl]-4-(furan-3-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(117) (S)-N2-[1-(4-forfinal)ethyl]-4-[4-(methylsulphonyl)piperazine-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(118) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-4-(hydroxymethyl)piperidine-4-ol,
(119) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}benzosulfimide,
(120) (S)-N2-[1-(4-forfinal)ethyl]-4-methoxy-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(121) 4-{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1λ6,4-thiomorpholine-1,1-dione,
(122) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}piperidine-4-ol,
(123) (S)-1-(4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-1,4-diazepan-1-yl)ethanone,
(124) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyrimidine-2-yl)pyridine-2,4,6-analogue,
(125) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-N4-(pyridin-2-yl)pyridine-2,4,6-analogue,
(126) N2-[(S)-1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(1,4-dioxa-8 azaspiro[4.5]Decan-8-yl)pyridine-2,6-diamine,
(127) methyl(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinate,
(128) (S)-4-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylbenzenesulfonamide,
(129) (S)-N2-[1-(4-forfinal)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(130) (S)-N2-[1-(4-forfinal)ethyl]-N4N6di(pyrazin-2-yl)pyridine-2,4,6-analogue,
(131) (S)-N2-[1-(4-forfinal)ethyl]-N2-methyl-(1-methyl-1H-pyrazole-4-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(132) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}methanol,
(133) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid,
(134) (S)-N2-[1-(4-forfinal)ethyl]-4-(2-methoxyethoxy)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(135) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile,
(136) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(137) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(138) (S)-N2-[1-(4-forfinal)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(139) (S)-N2-[1-(4-forfinal)ethyl]-4-(1,2, 4-oxadiazol-3-yl)-Nsup> 6(pyrazin-2-yl)pyridine-2,6-diamine,
(140) methyl(S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinate,
(141) (S)-2-[1-(4-forfinal)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,
(142) (S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(143) (S)-N-tert-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(144) (S)-N-ethyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(145) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}[4-(methanesulfonyl)piperazine-1-yl]methanone,
(146) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(pyrrolidin-1-yl)methanone,
(147) (S)-2-[1-(4-forfinal)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,
(148) (S)-1-{2-[(S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-2-carboxamide,
(149) (S)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)-4-(tetrahydro-2H-Piran-4-yloxy)pyridine-2,6-diamine,
(150) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,
(151) (S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,
(152) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(morpholino)methanone,
(153) (S)-N-benzyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(154) (S)-N-cyclopropyl-2-[1-(4-forfinal)ethylamino]-6-(feast of the zine-2-ylamino)isonicotinamide,
(155) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}(4-methylpiperazin-1-yl)methanone,
(156) (S)-2-[1-(4-forfinal)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(157) (S)-2-[1-(4-forfinal)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,
(158) (S)-N-butyl-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(159) (S)-2-[1-(4-forfinal)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,
(160) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2-triptorelin)isonicotinamide,
(161) (S)-N-(2-ethoxyethyl)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(162) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-methylisatin-3-carboxamide,
(163) (S)-N2-[1-(4-forfinal)ethyl]-4-(methoxymethyl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(164) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N,N-dimethylamide-3-carboxamide,
(165) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanesulfonamide,
(166) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carbonitrile,
(167) 2-(4-forfinal)-2-[4-(1-methyl-1H-pyrazole-4-yl)-6-(pyrazin-2-ylamino)pyridine-2-ylamino]ethanol,
(168) (S)-N-ethyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,
(169) (S)-N,N-diethyl-1-{2-[1-(4-forfinal)this is laminitis]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,
(170) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}ethanone,
(171) (S)-N2-[1-(4-forfinal)ethyl]-6-(3-methoxyisatin-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(172) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-methylaziridine-3-ol,
(173) (S)-2-[1-(4-forfinal)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,
(174) (S)-2-[1-(4-forfinal) ethylamino]-N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,
(175) (S)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(176) (S)-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-3-yl}(morpholino)methanone,
(177) (S)-N-(cyclopropylmethyl)-2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(178) (S)-N-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)acanaloniidae,
(179) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-Isopropylamine-3-carboxamide,
(180) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(pyrrolidin-1-yl)methanone,
(181) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-methoxyethyl)azetidin-3-carboxamide,
(182) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(piperidine-1-yl)methanone,
(183) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)(morpholino)methanone,
(184) (S)-N-(Cyclops who drank)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,
(185) (S)-N-(cyclopropylmethyl)-1-{2-[1-(4-forfinal)ethylamino]-6- (pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-carboxamide,
(186) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-N-(2-hydroxyethyl)azetidin-3-carboxamide,
(187) (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-ol,
(188) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-3-Isopropylamine-3-ol,
(189) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol,
(190) (S)-3-cyclopropyl-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-ol,
(191) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-Isopropylamine-3-ol,
(192) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}-3-methylaziridine-3-ol,
(193) (S)-4-(3,3-diversecity-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(194) (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}acetamide", she
(195) (S)-1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}urea
(196) (S)-4-(3-cyclopropyl-3-methoxyisatin-1-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(197) (S)-N2-[1-(4-forfinal)ethyl]-4-(3-isopropyl-3-methoxyisatin-1-yl)-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(198) (S)-N2-[1-(4-forfinal)ethyl]-4-(3-methoxy-3-methylase the DIN-1-yl)-N 6(pyrazin-2-yl)pyridine-2,6-diamine,
(199) (S)-N2-[1-(4-forfinal)ethyl]-4-(1-methyl-1H-pyrazole-4-yl)-N6-(5-methylpyrazine-2-yl)pyridine-2,6-diamine,
(200) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methanesulfonyl)piperidine-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(201) (S)-N-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}propionamide,
(202) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(203) (S)-4-(1-cyclopropyl-1H-pyrazole-4-yl)-N2-[1-(4-forfinal)ethyl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(204) (S)-N2-[1-(4-forfinal)ethyl]-4-[1-(methoxymethyl)-1H-pyrazole-4-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine,
(205) (S)-6-[3-(dimethylamino)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(206) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(207) (S)-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidine-2,4-diamine,
(208) (S)-N2-[1-(4-forfinal)ethyl]-6-(3-morpholinomethyl-1-yl)-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(209) (S)-N2-[1-(4-forfinal)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(210) (S)-(1-{1-[2-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)piperidine-4-ol,
(211) -{2-[(1S)-1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}-1λ 6, 4-thiomorpholine-1,1-dione,
(212) (S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)urea,
(213) (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methanol,
(214) tert-butyl (S)-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methylcarbamate,
(215) (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-forfinal)ethyl]-N4(pyrazin-2-yl)pyrimidine-2,4-diamine,
(216) (S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]acanaloniidae,
(217) (S)-N-[(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-yl}azetidin-3-yl)methyl]acetamide", she
(218) (S)-N2-[1-(4-forfinal)ethyl]-4-[3-morpholinomethyl-1-yl]-N6(pyrazin-2-yl)pyridine-2,6-diamine and
(219) (S)-1-(1-{2-[1-(4-forfinal)ethylamino]-6-(pyrazin-2-ylamino)pyridine-4-yl}azetidin-3-yl)piperidine-4-ol.

5. Pharmaceutical composition having the properties of an inhibitor of the activity of the JAK2 tyrosine kinase, containing a therapeutically effective amount of the compound or its pharmaceutically acceptable salt according to any one of paragraphs.1-4 as an active ingredient.

6. The pharmaceutical composition under item 5, where the specified composition suitable for the prevention or treatment of cancer, inflammatory disorders, angiopathy.

7. The pharmaceutical composition according to p. 6, where cancer is the Wallpaper hematological cancer or a solid form of cancer.

8. The pharmaceutical composition according to p. 7, where the hematological cancer is myeloproliferative neoplasm, myelodysplastic syndromes, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia or multiple myeloma.

9. The pharmaceutical composition according to p. 8, where myeloproliferative neoplasm is an absolute polycythemia.

10. The pharmaceutical composition according to p. 8, where myeloproliferative neoplasm is an essential trombozitemia.

11. The pharmaceutical composition according to p. 8, where myeloproliferative neoplasm is an idiopathic myelofibrosis.

12. The pharmaceutical composition according to p. 7, where the solid form of cancer is a prostate cancer or breast cancer.

13. The pharmaceutical composition according to p. 6, where inflammatory infringement is rheumatoid arthritis, inflammatory bowel disease, osteoporosis or multiple sclerosis.

14. The pharmaceutical composition according to p. 6, where the disorder is a pulmonary hypertension, arteriosclerosis, aneurysm, or varicose veins.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of general formula (I): wherein m and n independently represent 0 or 1; G and E represent oxygen, R1 and R2 together with a carbon atom whereto attached form a heterocycle including one or two heteroatoms specified in oxygen, sulphur, -S(O)-, -S(O)2-, -N=, -N(R5)-; one or more carbon atoms in the above heterocycle are optionally substituted by one or more identical or different substitutes specified among the substitutes R4; R3 represents alkoxy or halogenoxy; R4 represents hydrogen, alkyl or halogen; R5 represents hydrogen, alkyl carbonyl, alkoxy carbonyl or alkyl sulphonyl; X represents a bond, -CH2- or -NH-; A represents phenyl, pyridyl, pyrazynyl or quinolyl optionally substituted by one or more identical or different substitutes specified among the substitutes R4; or pharmaceutically acceptable salts, hydrates, N-oxides or salvates thereof.

EFFECT: invention also refers to the pharmaceutical composition of the above compounds as the phosphodiesterase PDE4 inhibitor for treating, eg skin diseases.

19 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

Ppar modulators // 2449999

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to new 1,3-dioxane derivatives of formula: wherein A, W, Ar, Ra and Rb have the values specified in the description, or to their pharmaceutical salts.

EFFECT: applying the modulators in treating a disease or a condition associated with PPAR modulation, such as diabetes, cancer, inflammation, neurodegenerative disorders and infections, and also development of based pharmaceutical compositions.

23 cl, 28 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: chemistry.

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

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine; pharmacology.

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

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

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

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

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

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

41 cl, 535 ex

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

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, characterised by X-ray powder diffraction at reflected angles of 2θ: 14.902, 18.123, 18.87, 20.204, 20.883, 21.79, 24.186, 26.947. The invention relates to a fungicidal composition containing a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, in an effective amount and at least one additional component selected from a group consisting of a surfactant and a liquid carrier. The invention relates to a method of controlling plant diseases caused by fungal plant pathogens, which includes applying a fungicidally effective amount of said polymorph on a plant or part thereof or seeds. The invention also relates to methods of obtaining said crystalline polymorph.

EFFECT: crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, having a higher melting point and which is less soluble.

12 cl, 13 tbl, 2 dwg, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

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