Bruton's tyrosine kinase inhibitors

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

 

The present invention relates to the use of new derivatives, which inhibit tyrosinekinase of Bruton (Btk) and are useful for treatment of autoimmune and inflammatory diseases caused by impaired activation of b-cells. Described here is new derivatives of 5-phenyl-1H-pyridine-2-it, 6-phenyl-2H-pyridazin-3-one and 5-phenyl-1H-pyrazin-2-it is useful for the treatment of arthritis.

Protein kinases constitute one of the largest families of enzymes of human and regulate numerous processes the transmission signal by adding phosphate groups to proteins (article Hunter, Cell, 1987, 50,. 823-829). More specifically, tyrosine kinase phosphorylate proteins on the phenol group of tyrosine residues. The family of tyrosine kinase includes members that control cell growth, migration and differentiation. Impaired kinase activity is present in various human diseases, including cancer, autoimmune and inflammatory diseases.

Because protein kinases are key regulators of cellular signal transmission, they provide a target for the modulation of cellular function by using low-molecular-weight kinase inhibitors, and thus provide good targets for drug development. In addition to the treatment of kinase mediated diseases, selective and effective inhibitors of the activity of Keene is s also useful for studying processes of cellular signaling and identification of other cellular therapeutic targets.

There is evidence that b cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. Protein therapeutic drugs, which reduce the number of b cells, such as Rituxan, effective against managed by autoantibodies in inflammatory diseases such as rheumatoid arthritis (article Rastetter and others, Annu Rev Med, 2004, 55, S. 477). Therefore, inhibitors of protein kinases that play a role in b-cell activation may be useful therapeutic tools in relation mediated by b-cell pathologies, such as the production of autoantibodies.

Signal transmission In-cell receptor (BCR) is controlled by a number of b-cell responses, including proliferation and differentiation in Mature producing antibodies cells. BCR is a key regulatory point In cell activity, and disruption of signal transmission may cause malfunction in the regulation of b-cell proliferation and the formation of pathogenic autoantibodies that lead to multiple autoimmune and/or inflammatory diseases. Tyrosinekinase of Bruton (Btk) is a kinase unconnected with the BCR, which is membranoproliferative and is located directly below the BCR. The lack of Btk has been shown to block the transmission of the BCR signal, and therefore, inhibition of Btk mo is lo be a useful therapeutic approach to block diseases, mediated by b-cells.

Btk is a member of the family Boards tyrosinekinase, and, as shown, is a critical regulator of early development of b-cells and the activation and survival of Mature b cells (article Khan and others, Immunity, 1995, 3, S. 283; Ellmeier, etc., J. Exp.Med., 2000, 192, S. 1611). The Btk mutation in humans leads to a state of X-linked agammaglobulinemia (XLA) (reviewed in Rosen and others, New Eng. J. Med., 1995, 333, S. 431 and Lindvall Friday, February etc., Immunol. Rev., 2005, 203, 200 C.). These patients are immunologically "compromised" and show impaired development of b cells, decreased levels of immunoglobulin and peripheral levels In cells, weakened independent of T-cell immune responses, as well as weak mobilization of calcium due to BCR stimulation.

The evidence of the role of Btk in autoimmune and inflammatory diseases are also shown for mice with deficiency of Btk. In preclinical murine models of systemic lupus erythematosus (SLE) mice with deficiency of Btk show a marked improvement in the development of the disease. In addition, mice with deficiency of Btk resistant to induced collagen arthritis (article Jansson and Holmdahl, Clin. Exp.Immunol., 1993, 94, S. 459). Selective inhibitor of Btk showed dose-dependent efficacy in a model of arthritis in mice (article Pan, etc., Chem. Med Chem., 2007, 2, SS. 58-61).

Btk is also expressed by cells other than b cells, which can teaching is painted in diseases. For example, Btk is expressed fat cells and the fat cells in the bone marrow with deficiency of Btk demonstrate weakened caused by antigen degranulation (article Iwaki, etc., J. Biol. Chem., 2005, 280, C. 40261). This indicates that Btk could be useful for the treatment of pathological responses of mast cells, such as allergies and asthma. Also monocytes in patients XLA, are missing the activity of Btk, show reduced production of TNF-alpha after stimulation (article Horwood, etc., J Exp Med, 2003, 197, S. 1603). Consequently, mediated TNF-alpha inflammation can be modulated by low molecular weight inhibitors of Btk. It was also reported that Btk plays a role in apoptosis (article Islam and Smith, Immunol. Rev., 2000, 178, S. 49), and therefore, the Btk inhibitors may be useful for the treatment of certain b-cell lymphomas and leukemias (article Feldhahn and others, J. Exp.Med., 2005, 201, S. 1837).

The present invention relates to compounds of the Btk inhibitors of formula a or formulae I-III, methods of use thereof, as described below.

The present invention relates to a compound of the formula:

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3; where

R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower and kylami, hydroxy groups hydroxynitrile alkilani, lower alkoxygroup, galactography, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2', -NHC(=O)O, -C(R2')2, -C(=NH)NR2', -S(=O)2, -Oh, -C(R2')2C(=O), -C(R2')2C(=O)CONR2', -C(R2')2N(R2')C(=O), - OC(R2')2, -C(R2')2NR2'or-C(=NH), where each R2'independently represents H, lower alkyl or lower halogenated; and

R represents H, or R; where R represents lower alkyl, lower alkoxygroup, amino group, lower alkylamino, lower dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl,alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes, geterotsiklicheskikh, bicyclic cycloalkyl, bicyclic heteroseksualci, spiratically or spiroheterocyclic, each of which is optionally substituted by one or more lower alkilani, lower alkylaminocarbonyl, lower dialkylaminoalkyl, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups, exography, the Guan is kinogruppam, hydroxylaminopurine, carboxypropyl, carbamoyl, carbamates, halogenized alkoxygroup or halogenized alkilani, where two lower alkyl groups may together form a ring;

X represents CH or N;

X'represents CH or N, provided that when X represents N, X'represents CH;

Y1represents H, lower alkyl or lower halogenated;

Y2'and each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n denotes 0, 1 or 2; and

Z* is selected from the group consisting of:

where:

Q represents C(Y3or N;

each Y independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m denotes 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d; the de

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, hydroxynitrile of alkyl, amino, ceanography and lower alkoxygroup;

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl, cyano or lower halogenated;

or its pharmaceutically acceptable salt.

The present invention relates to a compound of the formula I:

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3; where

R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alnilam is, hydroxy groups hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2', -NHC(=O)O, -C(R2')2, -C(=NH)NR2'or-S(=O)2; where each R2'independently represents H or lower alkyl;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, amino group, lower alkylamino, lower dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl,alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes, geterotsiklicheskikh, bicyclic cycloalkyl, bicyclic heteroseksualci, spiratically or spiroheterocyclic, each of which is optionally substituted by one or more lower alkilani, lower alkylaminocarbonyl, lower dialkylaminoalkyl, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups, exography, guanidinopropionic, hydroxylaminopurine, carboxypropyl, carbamoyl, carbamates, halogenized alkoxygroup or halogenized alkilani, where d is e lower alkyl groups may together form a ring;

X represents CH or N;

X'represents CH or N, provided that when X represents N, X'represents CH;

Y1represents H, lower alkyl or lower halogenated;

Y2'and each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1 or 2;

each Y independently represents a halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d; where

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, not necessarily Sames the config one or more substituents, selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl, cyano or lower halogenated;

or its pharmaceutically acceptable salt.

The present invention relates to the compound of formula II:

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3; where

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2', -C(R2')2or-S(=O)2; where each R2'independently represents H or lower alkyl;

R3represents N or R4; where R4before the hat is lower alkyl, the lower alkoxygroup, amino group, lower alkylamino, lower dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl,alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes, geterotsiklicheskikh, bicyclic cycloalkyl, bicyclic heteroseksualci, spiratically or spiroheterocyclic, each of which is optionally substituted by one or more lower alkilani, lower alkylaminocarbonyl, lower dialkylaminoalkyl, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups, exography, guanidinopropionic, hydroxylaminopurine, carboxypropyl, carbamoyl, carbamates, halogenized alkoxygroup or halogenized alkilani, where two lower alkyl groups may together form a ring;

X represents CH or N;

X'represents CH or N, provided that when X represents N, X'represents CH;

Y1represents H, lower alkyl or lower halogenated;

Y2'and each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents, select nimi from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1 or 2;

each Y independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d; where

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents halogen, hydroxyl the PPU, lower alkyl, lower alkoxygroup, lower hydroxyalkyl, cyano or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula II, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula II, X represents CH.

In one embodiment of formula II, Y1represents methyl, Y5is a halogen and X represents CH.

In one embodiment of formula II, Y1represents methyl, Y5represents F, n represents 0, m represents 0, X represents CH.

In one embodiment of formula II, Y1represents methyl, Y5represents F, n represents 0, m represents 0, X represents CH and Y2'represents hydroxymethyl.

In one embodiment of formula II, Y1represents methyl, Y5represents F, n represents 0, m represents 0, X represents CH, Y2'represents a hydroxymethyl and Y4represents tert-butyl or ISO-propyl.

In one embodiment of formula II, Y1represents methyl, Y5represents F, n represents 0, m represents 0, X represents CH, Y2'represents hydroxymethyl, Y4represents tert-butyl or ISO-propyl and R is a-R1-R3 , R1represents pyridyl, R3is an R4and R4represents heterocyclyl, optionally substituted lower alkyl.

In one embodiment of formula II, X'represents CH.

In one embodiment of formula II, X represents N.

In one embodiment of formula II, X'represents N.

In one embodiment of formula II, X represents CH, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula II, X represents CH, X'represents CH, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula II, X represents CH, X'represents CH, Y1represents methyl and Y5is a F.

In one embodiment of formula II, Y5represents F, t represents 0 and m is 0.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, X represents CH, X'represents CH, Y1represents methyl, Y5represents F, n convoy is achet 0 and m is 0.

In one embodiment of formula II, X represents CH, X'represents N, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, X represents N, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, Y2represents hydroxymethyl.

In one embodiment of formula II, Y2'represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula II, Y2'represents a hydroxymethyl and Y5represents a halogen.

In one embodiment of formula II, Y2'represents a hydroxymethyl and Y5is a F.

In one embodiment of formula II, Y2'represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula II, Y2'represents hydroxymethyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, Y2'represents hydroxymethyl, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X 'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, Y4represents tert-butyl.

In one embodiment of formula II, Y4represents tert-butyl or ISO-propyl.

In one embodiment of formula II, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula II, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula II, Y5represents halogen, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula II, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is

In one embodiment of formula II, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula II, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one var is ante formula II, Y4represents ISO-propyl.

In one embodiment of formula II, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, Y5represents halogen, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula II, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment fo the mules II, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula II, Y5represents halogen, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula II, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1- R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula II, Y1represents methyl, X represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y4represents tert-butyl or ISO-propyl, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, not necessarily Sames the config lower alkyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y4represents tert-butyl, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y4represents ISO-propyl, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula II, R is the Wallpaper-R 1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula II, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is methylpiperazine.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is methylpiperazine.

In one embodiment of formula II, R is-R1-R3; R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula II, which represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula II, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is ethylpiperazine.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is ethylpiperazine.

In one embodiment of formula II, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3PR is dstanley a R 4and R4is morpholinyl.

In one embodiment of formula II, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R represents- (CH3)2R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

The present invention relates to the compound of formula III:

where:

Q represents C(Y3or N;

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3; where

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- Oh,- C(=O)O, -C(=O)NR2', -C(R2')2C(R2')2C(=O), -C(R2')2C(=O)NR2'C(R 2')2N(R2')C(=O)- O-C(=NH) or-S(=O)2; where each R2'independently represents H or lower alkyl;

R3represents N or R4where R4represents lower alkyl, lower alkoxygroup, amino group, lower alkylamino, lower dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl,alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes, geterotsiklicheskikh, bicyclic cycloalkyl, bicyclic heteroseksualci, spiratically or spiroheterocyclic, each of which is optionally substituted by one or more lower alkilani, lower alkylaminocarbonyl, lower dialkylaminoalkyl, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups, exography, guanidinopropionic, hydroxylaminopurine, carboxypropyl, carbamoyl, carbamates, halogenized alkoxygroup or halogenized alkilani, where two lower alkyl groups may together form a ring;

X represents CH or N;

X'represents CH or N, provided that when X represents N, X'represents CH;

Y1represents H, and lower the keel or lower halogenated;

Y2'and each Y independently represents a halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1 or 2;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d,

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, hydroxynitrile of alkyl, amino, ceanography and lower alkoxygroup;

Y4dPR is dstanley an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl, cyano or lower halogenated;

or its pharmaceutically acceptable salt.

The present invention relates to the compound of formula III:

where:

Q represents C(Y3or N;

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- Oh,- C(=O)O, -C(=O)NR2', -C(R2')2C(R2')2C(=O), -C(R2')2C(=O)NR2'C(R2')2N(R2')C(=O), -OC(R2')2, -C(-NH), -C(R2')NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents N or R4;

R4represents lower alkyl, n is SCHOU alkoxygroup, the amino group, the lower alkylamino, lower dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes, geterotsiklicheskikh, bicyclic cycloalkyl, bicyclic heteroseksualci,spiratically or spiroheterocyclic, each of which is optionally substituted by one or more lower alkilani, lower alkylaminocarbonyl, lower dialkylaminoalkyl, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups, exography, guanidinopropionic, hydroxylaminopurine, carboxypropyl, carbamoyl, carbamates, halogenized alkoxygroup or halogenized alkilani, where two lower alkyl groups may together form a ring;

X represents CH or N;

X'represents CH or N, provided that when X represents N, X'represents CH;

Y1represents H, lower alkyl or lower halogenated;

Y2'and each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents, selected from the group status is the present of the hydroxy-group, low alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1 or 2;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m denotes 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, hydroxynitrile of alkyl, amino, ceanography and lower alkoxygroup;

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, and lower the keel, the lower alkoxygroup, lower hydroxyalkyl, cyano or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula III, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula III, X represents CH.

In one embodiment of formula III, X'represents CH.

In one embodiment of formula III, X represents CH and X'represents CH.

In one embodiment of formula III, X represents N.

In one embodiment of formula III, X'represents N.

In one embodiment of formula III, Q is a CH.

In one embodiment of formula III, Q is an n

In one embodiment of formula III, X represents CH, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula III, X represents CH, Y1represents methyl, Y5is a halogen, X represents CH and X'represents CH.

In one embodiment of formula III, X represents CH, X'represents CH, Y1represents methyl and Y5represents a halogen.

In one embodiment of formula III, X represents CH, X'represents CH, Y1represents methyl and Y5is a F.

In the bottom version of the formula III, X represents CH, X'represents CH, Q represents CH, Y1represents methyl and Y5is a F.

In one embodiment of formula III, X represents CH, X'represents CH, Q represents N, Y1represents methyl and Y5is a F.

In one embodiment of formula III, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, X represents CH, X'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, X represents CH, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, X represents CH, X'represents CH, Y1represents methyl, Y5represents F, n represents 0, m represents 0 and Y2'represents hydroxymethyl.

In one embodiment of formula III, X represents CH, X'represents N, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula II, X represents N, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y1is own the th methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl.

In one embodiment of formula III, Y2'represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents a hydroxymethyl and Y5represents a halogen.

In one embodiment of formula III, Y2'represents a hydroxymethyl and Y5is a F.

In one embodiment of formula III, Y2'represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl, Y1represents methyl, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5a small town is a place of F, n denotes 0 and m is 0.

In one embodiment of formula III, Q represents CH, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5represents F, n represents 0, m represents 0 and Y is tert-butyl.

In one embodiment of formula III, Q represents CH, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5represents F, n represents 0, m represents 0 and Y is ISO-butyl.

In one embodiment of formula III, Q represents CH, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents N, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, Y2'represents hydroxymethyl, Y1represents methyl, X represents N, X'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents N, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5is own the th F n denotes 0 and m is 0.

In one embodiment of formula III, Q represents N, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5represents F, n represents 0, m represents 0 and Y4represents tert-butyl.

In one embodiment of formula III, Q represents N, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents CH, Y5represents F, n represents 0, m represents 0 and Y4represents an ISO-butyl.

In one embodiment of formula III, Q represents N, Y2'represents hydroxymethyl, Y1represents methyl, X represents CH, X'represents N, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Q represents N, Y2'represents hydroxymethyl, Y1represents methyl, X represents N, X'represents CH, Y5represents F, n is 0 and m is 0.

In one embodiment of formula III, Y4represents tert-butyl.

In one embodiment of formula III, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Y 1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Y5represents halogen, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents the t a N Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents tert-butyl, n hereafter which includes 0 and m is 0.

In one embodiment of formula III, Y4represents ISO-propyl.

In one embodiment of formula III, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Y is a halogen, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1 represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, Q is a N X PR is dstanley a N X'represents CH, Y2'represents hydroxymethyl, Y5represents F, Y1represents methyl, Y4represents ISO-propyl, n is 0 and m is 0.

In one embodiment of formula III, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula III, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula III, Y is a halogen, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula III, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula III, X, not only is et a CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R4represents pyridyl, R is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n convoy is achet 0, m represents 0, R represents a-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y5represents F, Y is hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1before the hat is pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is tert-butyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is oznachaet 0, m represents 0, R represents a-R1-R3, R1represents pyridyl, R3is an R4and R5is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents tert-butyl, Q represents N, X represents CH, X'represents CH, Y2'represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is tert-butyl, Q represents N, X represents CH, X'represents CH, Y5represents F, Y 2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R3is a-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is tert-butyl, Q represents N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is tert-butyl, Q represents N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is ISO-propyl, Q represents CH, X t is made by a SN, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is ISO-propyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y is ISO-propyl, Q represents CH, X represents CH, X'represents N, Y represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4p is ecstasy an ISO-propyl, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optional C is displaced lower alkyl.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is heteroseksualci, optionally substituted lower alkyl.

In one embodiment of formula III, Y4represents a tert-butyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3p is ecstasy a R 4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkyl is nogroup or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4present is employed, a tert-butyl, Q represents N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R2-R3, R1represents pyridyl, R represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y is tert-butyl, Q represents N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents tert-butyl, Q represents N, X represents N, X'represents CH, Y5represents the t a F Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R PR is dstanley a-R 1-R2-R3, R1represents pyridyl, R represents- (CH3)2, R2is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R3represents- (CH3)2That is, R is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3represents the t a R 4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, Y1represents methyl, R represents-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino the group or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower dialkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, Y4represents ISO-propyl, Q is an N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R2-R3, R1represents pyridyl, R2represents- (CH3)2, R3is an R4and R4represents a lower alkylamino, lower alkylamino or heteroseksualci, optionally substituted by one or more lower alkilani.

In one embodiment of formula III, R is Soboh the-R 1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is the th piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4represents piperazinil, substituted lower alkyl.

In one embodiment of formula III, R is-R1-R3, R1the submitted is a pyridyl, R3is an R4and R4is methylpiperazine.

In one embodiment of formula III, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is methylpiperazine.

In one embodiment of formula III, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1- R3; R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3; R1represents pyridyl, R 3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3; R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3; R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3; R1represents pyridyl, R3is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents N, X'pre who is a CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3; R3represents pyridyl, R is an R4and R4is a 4-methylpiperazin-1-yl.

In one embodiment of formula III, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is ethylpiperazine.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, Q represents CH, X represents N, X'the submitted is a CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R 3is an R4and R4is a 4-ethylpiperazin-1-yl.

In one embodiment of formula III, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula III, Q represents CH, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula III, Q represents CH, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R 4and R4is morpholinyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula III, Q is an N, X represents CH, X'represents N, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1-R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

In one embodiment of formula III, Q is an N, X represents N, X'represents CH, Y5represents F, Y2'represents hydroxymethyl, n is 0, m is 0, R is-R1- R3, R1represents pyridyl, R3is an R4and R4is morpholinyl.

The present invention relates to a compound selected from the group consisting of the following compounds:

6-dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-IU the Il-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he;

6-dimethylamino-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-espiridion-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

2-[8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile;

6-dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl} phenyl)-2H-isoquinoline-1-it;

1-(5-{3-[b-(centimetres)-8-fluoro-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]-2-hydroxymethylene}-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-atilmotin;

6-cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

tert-butyl ether 4-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)Pipa is Azin-1-carboxylic acid;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it;

6-cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-3,4-dihydro-2H-isoquinoline-1-it;

6-cyclopropyl-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-espiridion-2-ylamino)-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{3-[5-(1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)the feast of the DIN-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-phthalazine-1-he;

2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionate acid;

6-tert-butyl-2-(3-{5-[5-(1,1-dimethyl-2-morpholine-4-yl-2-oxoethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N,N-dimethylethanamine;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(2,2,2-Cryptor-1-hydroxyethyl)pyridine-2-ylamino]-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-2-[3-(5-{5-[1-(4-chloroethoxy)-2,2,2-triptorelin]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethylene]-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-hydroxymethyluracil-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

2-[3-(5-amino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethylene]-6-tert-butyl-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-methyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-Talas the h-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-(2-ethoxyethyl)isobutyramide;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-methylisoleucine;

6-tert-butyl-2-{3-[5-(5-ethylpyridine-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}nicotinic acid;

2-(3-{5-[5-(1-amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-phthalazine-1-it;

6-tert-butyl-2-{3-[5-(1-ethyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1-isopropyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxyaniline is about)methyl]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl]-2H-phthalazine-1-he;

6-tert-butyl-2-{3-[5-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-[1,6]naphthiridine-2-ylamino)-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylaminomethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-2-{3-[5-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-4-oxopiperidin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it;

6-tert-butyl-2-(3-{5-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

N-[1-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-1-methylethyl]ndimethylacetamide;

6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(6-methyl-56-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he;

6-tert-butyl-2-{3-[5-(1-tert-butyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-espiridion-2-ylamino)-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

8-chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl} phenyl)-2H-isoquinoline-1-it;

8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-it;

8-chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

8-fluoro-6-(1-hydroxy-1-methylethyl)-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6' -ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

8-fluoro-6-(1-hydroxy-1-methylethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-it;

8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-6-(1-methylcyclopropyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-(1-ethyl-1-hydroxypropyl)-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']-bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

2-[8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-1-oxo-1,2-dihydroisoquinoline-6-yl]-2-methylpropionitrile;

6-cyclopropyl-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-8-methoxy-2H-isoquinoline-1-it;

6-cycloprop the l-8-hydroxy-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he;

2-(6-{5-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionate acid;

2-(6-{5-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-methylisoleucine;

2-(6-{5-[3-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N,N-dimethylethanamine;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxyethylamine)methyl]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl]-2H-isoquinoline-1-it;

2-(3-{5-[5-(1-amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-cyclopropyl-8-f the PR-2H-isoquinoline-1-he;

6-cyclopropyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylaminomethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-it;

2-(3-{6-[1-(2,2-defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-6-(1-hydroxy-1-methylethyl)-2H-isoquinoline-1-it;

2-{3-[6-(1-ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-8-fluoro-6-(1-hydroxy-1-methylethyl)-2H-isoquinoline-1-it;

6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-isoquinoline-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-2-(3-{6-[1-(2,2-defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

N-{6-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl}-N-methylguanine; compound with formic acid;

2-(3-{5-[5-(3-aminopyrrolo the DIN-1-ylmethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-he;

6-tert-butyl-2-(3-{5-[(1S,5R)-5-(3,8-diazabicyclo[3,2,1]Oct-3-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-methylaminorex)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

N-{6-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl}-N-methylguanine and

6-tert-butyl-2-(3-{6-[4-(1,4-dimethyl-3-oxopiperidin-2-yl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it.

The present invention relates to a compound selected from the group consisting of the following compounds:

6-dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

6-dimethylamino-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-espiridion-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it;

2-[8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl} phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile;

6-dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it;

1-(5-{3-[6-(centimetres)-8-fluoro-1-oxo-3,4-d the hydro-1H-isoquinoline-2-yl]-2-hydroxymethylene}-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-atilmotin;

6-cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it;

6-tert-butyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it;

6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he

tert-butyl ether 4-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)piperazine-1-carboxylic acid.

The present invention relates to a method of treating inflammatory and/or autoimmune condition comprising the administration to a patient in need this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method of treating arthritis, comprising the administration to a patient in need this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method of treatment of rheumatoid arthritis, including the introduction of a PA is Ianto, needy in this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method of treating asthma, comprising the administration to a patient in need this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method of inhibiting b-cell proliferation comprising administration to a patient in need this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method for inhibiting Btk activity, comprising introducing the compound is an inhibitor of Btk any formula a or formulae I-III, where the compound is an inhibitor of Btk is set IC5050 μm or less in the biochemical analysis on the activity of Btk in vitro.

In one embodiment, the described method connection inhibitor of Btk is set IC50100 nm or less in the biochemical analysis on the activity of Btk in vitro.

In another embodiment, the described method connection inhibitor of Btk is set IC5010 nm or less in the biochemical analysis on the activity of Btk in vitro.

The present invention relates to a method of treating an inflammatory condition comprising co-administration to a patient in need is this, anti-inflammatory compounds in combination with the compound inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to a method of treating arthritis, comprising co-administration to a patient in need this, anti-inflammatory compounds in therapeutically effective amounts in combination with the compound inhibitor of Btk any formula a or formulae I-III.

The present invention relates to a method for the treatment of lymphoma or cells BCR-ABL1 leukemia introduction to a patient in need this connection inhibitor of Btk any formula a or formulae I-III in therapeutically effective amounts.

The present invention relates to pharmaceutical compositions comprising a compound inhibitor of Btk any formula a or formulae I-III in a mixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

The present invention relates to a method for obtaining compounds of formula III, which includes stages:

a) cyclization of a derivative of 2-dimethoxymethyl-6-fermenting acid with hydrazinehydrate; and

b) treatment of the product of stage (a) 2-chloro-6-vorbesuregen and cesium carbonate.

The present invention relates to a method for obtaining compounds of formula III, which includes stages:

a) about what adowanie of arilbred using a combination of Grignard reagent and alkylate at non-cryogenic temperatures to obtain the compounds of formula IV;

b) receiving connection ortholite formula IV where Y is a lower alkyl or cycloalkyl; and

c) carboxylation of the product of stage b) to obtain the compounds of formula V.

The present invention relates to the above method also includes the steps:

d) cyclization of the compounds of formula V with hydrazine to obtain the compounds of formula VI where Y4represents a lower alkyl or cycloalkyl.

The present invention relates to a method for obtaining compounds of formula III, comprising the stage of:

treatment of compounds of formula VI 2-chloro-6-vorbesuregen and metal-carbonate with obtaining the compounds of formula VII.

The present invention relates to the compound of formula VI:

where:

Q represents CH or N;

each Y independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4Aor Y4b; where Y4arepresents a lower alkyl or cycloalkyl, optionally substituted by one or more hydroxy groups, lower and what taxigruppen or halogen; and Y4brepresents an amino group, a lower alkylamino or lower dialkylamino; and

Y represents halogen.

The present invention relates to the above-described compound of formula IV where Y5represents F, Y4represents a lower alkyl or cycloalkyl, and m is 0.

The present invention relates to the above method also comprising the stage of:

recovery of the compounds of formula VII to obtain the compounds of formula VIII.

The present invention relates to a method for obtaining compounds of formula III, which includes stages:

a) heating the compounds of formula IX, where Y is a boronic acid or pinacolborane, at a temperature from about 40°C to 150°C, in the presence of a palladium catalyst, base and phosphine; and

b) treating the product from step a) about 20% aqueous solution of 1,4-dioxane to obtain compounds of formula X.

The present invention relates to the above method, where the phosphine is a DCS3, alkylphosphine connection, animonopolnoe connection, alkyldiphenylamine connection or alldefensive connection.

The present invention relates to the above method, where the base is an inorganic base is a cation, representing potassium carbonate, cesium carbonate, potassium phosphate and potassium acetate, or an amine base, including dicyclohexylamine and triethylamine.

The present invention relates to a method for obtaining compounds of formula XIII, which includes stages:

a) treatment of compounds of formula XI, a compound of formula XII, where Y6and Y8represent halogen;

b) heating the product from step a) at a temperature of from about 25°C to 150°C in the presence of a copper catalyst and a base to obtain the compounds of formula XIII.

The present invention relates to the above method, where the copper catalyst is a copper iodide.

The present invention relates to the above method, where the base is a potassium carbonate, cesium carbonate, potassium phosphate or potassium acetate.

The present invention relates to a method for obtaining compounds of formula III, which includes stages:

a) treatment of compounds of formula I triphosgene with obtaining the compounds of formula II; and

b) cyclization of the product from step a) with a Lewis acid to obtain the compounds of formula III.

The present invention relates to the above method, where the Lewis acid is an aluminum chloride or isopropoxide calcium.

The present image is the buy relates to the compound of formula I':

where:

R represents H, -R1, -R'-R1-R3, -R1-R3or-R2-R3;

R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2', -NHC(=O)O, -C(=NH)NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents H or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, lower alkoxygroup, hydroxynitrile alkilani, hydroxynitrile alkoxygroup, lower alkylsulfonyl, lower alkylsulfonamides, carbamates, carboxypropyl, esters, aminopropane, atilov, Halogens, nitro groups, amino groups,cyano groups, exography or halogenized alkilani;

X represents CH or N;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1, 2 or 3;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y2b, Y4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of schego of alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula I', Y1represents methyl.

In one embodiment of formula I', Y5represents a halogen.

In one embodiment of formula I', X represents CH.

In one embodiment of formula I', Y5is a F.

In one embodiment of formula I', n represents 1 and m represents 0.

In one embodiment of formula I', Y5represents F, n represents 1 and m represents 0.

In one embodiment of formula I', Y3represents H.

In one embodiment of formula I', Y2represents methyl.

In one embodiment of formula I', Y2'represents hydroxymethyl.

In one embodiment of formula I', Y2represents a hydroxyethyl.

In one embodiment of formula I', Y2represents a halogen.

In one embodiment, is ormula I ', Y4represents a

where Y5represents halogen, lower alkyl or lower halogenated.

In one embodiment of formula I'where Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula I'where Y4represents a

where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described compounds, where Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula I'

R1is a-R1-R2-R3;

R2represents phenyl or pyridyl;

R3represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula I'R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R ; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula I'R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula I',

R1is a-R1-R2-R3;

R2represents phenyl or pyridyl;

R3represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

The present invention relates to the compound of formula II':

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, what minagroproma, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents N or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, cyano groups or halogenized alkilani;

X represents CH or N;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1, 2 or 3;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally C is substituted by one or more substituents, selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4bY4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula II', Y1represents methyl.

In one embodiment of formula II', Y5represents a halogen.

In one embodiment of formula II', X p is ecstasy a SN.

In one embodiment, the above-described compounds, Y5is a F.

In one embodiment, the above-described compounds, n is 1 and m is 0.

In one embodiment, the above-described compounds, Y5represents F, n represents 1 and m represents 0.

In one embodiment of formula II', Y is N.

In one embodiment of formula II', Y2represents methyl.

In one embodiment of formula II', Y2represents hydroxymethyl.

In one embodiment of formula II', Y2represents a hydroxyethyl.

In one embodiment of formula II', Y2represents a halogen.

In one embodiment of formula II', Y4represents a

where Y5represents halogen, lower alkyl or lower halogenated.

In one embodiment of formula II', Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated,

In one embodiment of formula II', Y4represents a

where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula II', Y4represents a

DG the Y 5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula II'Y represents

where Y5represents halogen, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula II'Y represents

where Y5and Y6independently represent H, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula II', Y4represents a

where Y5and Y6independently represent H or lower alkyl;

R represents-R1-R2-R3;

R1 represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula II', Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

The present invention relates to the compound of formula III':

where:

Q represents C(Y3or N;

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, zenegra is the groups, exography or halogenized alkilani;

R2represents-C(=O)- Oh,- C(=O)O, -C(=O)NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents N or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups or halogenized alkilani;

X represents CH or N;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n is 0, 1, 2 or 3;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl it is certainly substituted by one or more substituents, selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, hydroxynitrile of alkyl, amino, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula III', Y1represents methyl.

In one embodiment of formula III', X represents CH.

In one embodiment of formula III' , Y5is a F.

In one embodiment of formula III', Y5represents CL.

In one embodiment of formula III', Y5represents Br.

In one embodiment of formula III', Y5represents methyl.

In one embodiment of formula III', Y2'represents hydroxymethyl.

In one embodiment of formula III', n represents 1 and m represents 0.

In one embodiment of formula III', Y5represents F, n represents 1 and m represents 0.

In one embodiment of formula III', Y3represents N.

In one embodiment of formula III', Y2represents methyl.

In one embodiment of formula III', Y2represents hydroxymethyl.

In one embodiment of formula III', Y2represents a hydroxyethyl.

In one embodiment of formula III', Y2represents a halogen.

In one embodiment of formula III', Y4represents a

where Y5represents halogen, lower alkyl or lower halogenated.

In one embodiment of formula III', Y4represents a

where Y5and Y6independently represent H, lower alkyl or halogenated.

In one embodiment of formula III', Y4 represents a

where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula III', Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula III', Y4represents a

where Y5represents halogen, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula III', Y4represents a

where Y5and Y6independently represent H, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted with one or more of the lower alkilani.

In one embodiment of formula III', Y4represents a

where Y5and Y6independently represent H or lower alkyl;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

In one embodiment of formula III'Y represents

where Y5and Y6independently represent H, lower alkyl or lower halogenated;

R represents-R1-R2-R3;

R1represents phenyl or pyridyl;

R2represents-C(=O);

R3is an R4; and

R4represents a morpholine or piperazine, optionally substituted by one or more lower alkilani.

The present invention relates to the compound of formula IV:

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally C is substituted by one or more lower alkilani, hydroxy groups hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2', -NHC (O)O, -C(=NH)NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents N or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, lower alkoxygroup, hydroxynitrile alkilani, hydroxynitrile alkoxygroup, lower alkylsulfonyl, lower alkylsulfonamides, carbamates, carboxypropyl, ester groups, aminopropane, atilov, Halogens, nitro groups, amino groups, cyano groups, exography or halogenized alkilani;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen, oxime, or lower alkyl, where the lower alkyl optionally substituted by one or more will replace the guides and selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n denotes 0, 1, 2 or 3;

each Y independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m is 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents the ha shall ogen, the hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula IV, Y5is a F.

The present invention relates to the compound of formula V':

where:

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- C(=O)O, -C(=O)NR2'or-S(=O)2;

each R2'independently represents H or lower alkyl;

R3represents H or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or heteroseksualci alkyl, each of which is optionally substituted by one or more lower alkilani, hydroxy groups is mi, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, cyano groups or halogenized alkilani;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n denotes 0, 1, 2 or 3;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m denotes 0 or 1;

Y4represents the Y4a, Y4b, Y4cor Y4d;

Y4arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more for what estately, selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula V', Y5is a F.

The present invention relates to the compound of formula VI':

where:

Q represents C(Y3or N;

R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, cyano groups, exography or halogenized alkilani;

R2represents-C(=O)- Oh,- C(=O)O, -C(=O)NR2'or-S(=O)2;

each R2'independently represents FDS is th H or lower alkyl;

R3represents N or R4;

R4represents lower alkyl, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, each of which is optionally substituted by one or more lower alkilani, hydroxy groups, hydroxynitrile alkilani, lower alkoxygroup, Halogens, nitro groups, amino groups, aminopropane, atilov, cyano groups or halogenized alkilani;

Y1represents H, lower alkyl or lower halogenated;

each Y2independently represents halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, low halogenlampe, lower halogenoalkane, carboxypropyl, amino and halogen;

n denotes 0, 1, 2 or 3;

each Y3independently represents H, halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxygroup, amino and halogen;

m denotes 0 or 1;

Y4represents the Y4a, Y4b , Y4cor Y4d;

Y4Arepresents H or halogen;

Y4brepresents lower alkyl, optionally substituted by one or more substituents selected from the group consisting of halogenoalkane, halogen, hydroxy-group, amino group, ceanography and lower alkoxygroup;

Y4crepresents the lowest cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of lower alkyl, lower halogenoalkane, halogen, hydroxy-group, hydroxynitrile of alkyl, amino, ceanography and lower alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkilani, alkoxysilane alkilani or hydroxynitrile alkilani; and

Y5represents a halogen, a hydroxy-group, lower alkyl, lower alkoxygroup, lower hydroxyalkyl or lower halogenated;

or its pharmaceutically acceptable salt.

In one embodiment of formula VI', Y5is a F.

The present invention relates to a method of treating inflammatory and/or autoimmune condition comprising the administration to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

<> The present invention relates to a method of treating arthritis, comprising the administration to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method of treating rheumatoid arthritis, comprising the administration to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method of treating asthma, comprising the administration to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method of inhibiting b-cell proliferation comprising administration to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method for inhibiting Btk activity, comprising introducing the compound is an inhibitor of Btk any one of the above formulas, or their variants, where the compound is an inhibitor of Btk is set IC5050 μm or less in the biochemical analysis on the activity of Btk in vitro.

In one embodiment, is sushestvennee described method, the compound is an inhibitor of Btk is set IC 50100 nm or less in the biochemical analysis on the activity of Btk in vitro.

In one embodiment, the described method connection inhibitor of Btk is set IC5010 nm or less in the biochemical analysis on the activity of Btk in vitro.

The present invention relates to a method of treating an inflammatory condition comprising co-administration to a patient in need, an anti-inflammatory compound in combination with a compound inhibitor of Btk any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method of treating arthritis, comprising co-administration to a patient in need, an anti-inflammatory compound in combination with a compound inhibitor of Btk any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to a method for the treatment of lymphoma or leukemia cells BCR-ABL1 introduction to a patient in need this, the connection of the Btk inhibitor is any one of the above formulas or their variants in therapeutically effective amounts.

The present invention relates to pharmaceutical compositions comprising a compound of the Btk inhibitor of any one of the above formulas, or their variants, in a mixture with at least one headlight is asepticheski acceptable carrier, excipient or diluent.

The present invention relates to derivatives of 5-phenyl-1H-pyridine-2-it, 6-phenyl-2H-pyridazin-3-one and 5-phenyl-1H-pyrazin-2-in accordance with the General formula a or formulae I-III;

The present invention relates to compounds of General formula I'-VI'that include compounds inhibitors of Btk, where the variables Q, R, X, X', Y1, Y2, Y3, Y4, Y5, m and n are such as defined here.

In one embodiment, the present invention describes a compound of General formula I. In one embodiment, the present invention describes a compound of General formula II. In one embodiment, the present invention describes a compound of General formula III. In one embodiment, the present invention describes a compound of General formula I'. In one embodiment, the present invention describes a compound of General formula II'. In one embodiment, the present invention describes a compound of General formula III'. In one embodiment, the present invention describes a compound of General formula IV'. In one embodiment of the present invention, described in connection about the formula V. In one embodiment, the present invention describes a compound of General formula VI'.

The phrase "as defined above" refers to the broadest definition of each group as described here or the broadest claim. In all other variants of implementation, variants and embodiments refer to the substituents that can be present in every embodiment, and which are clearly defined in its broadest definition, see the essence of the invention.

Compounds of General formula a or formulae I-III and I'-VI'inhibit tyrosinekinase of Bruton (Btk). Activation of Btk subsequent kinase leads to activation of phospholipase-γ, which in turn stimulates the release of proinflammatory mediators. Compounds of General formula a or formulae I-III and I'-VI'including side chain 1H-quinoline-4-it, 3,4-dihydro-2H-isoquinoline-1-she 2H-isoquinoline-1-it 5-phenyl-1H-pyridine-2-novyh, 6-phenyl-2H-pyridazin-3-nowych and 5-phenyl-1H-pyrazin-2-nowych ring systems, exhibit unexpectedly high inhibitory activity in comparison with analogues with other side chains. Compounds of General formula a or formulae I-III and I'-VI'useful for the treatment of arthritis and other inflammatory and autoimmune diseases. Compounds of General formula a or f is of rmul I-III and I '-VI'accordingly, useful for treatment of arthritis. Compounds of General formula a or formulae I-III and I'-VI'useful for inhibiting Btk in cells and to modulate b-cell development. The present invention also includes pharmaceutical compositions containing compounds of General formula a or formulae I-III and I'-VI'in a mixture with a pharmaceutically acceptable carrier, excipients or diluents.

Indeterminate form, as used here, refers to one or more values from this group; for example, a connection refers to one or more compounds or at least one connection. As such, the terms indefinite form, "one or more" and "at least one" can be used interchangeably.

The phrase "as defined above" refers to the broadest definition of each group as described here in section of the invention or the broadest claim. In all other embodiments described below implementation, the substituents that can be present in every embodiment, and which are clearly defined in its broadest definition, see the essence of the invention.

As used in the description, in a transitional phrase or in the claims, the terms "include (includes) and "comprising" should be understood as having open values. Thus, the terms should be interpreted synonymous with the phrases "contains at least" or "including at least". When used in the context of the way, the term "comprising" means that the method comprises at least the specified stage, but may include additional stages. When used in the context of compounds or compositions, the term "comprising" means that the compound or composition includes at least these features or components, but may also include additional features or components.

As used here, if the description does not provide otherwise, the word "or" is used in the sense of "inclusion" and/or" not in the sense of "exceptions" either/or".

The term "independently" is used here to indicate that the value is used in any one of the options, regardless of the presence or absence of values having the same or another definition in the same connection. Thus, in the connection in which R" appears twice and is defined as independently carbon atom or nitrogen, both R" may represent a carbon atom, both R" can represent a nitrogen atom, or one of R" may represent a carbon atom, and the other nitrogen atom.

When any value appears more than once in any group or formula depicting and describing compounds described the or claimed in the present invention, its definition in each case depends on its definition in any other case. Also, combinations of substituents and/or values are permissible only if such combinations result in the formation of stable compounds.

The symbols "*" at the end of the link or " •"-" " across links represent the connection point of the functional group or another chemical group to the remainder of the molecule of which it forms a part. So, for example:

The relationship depicted in the cyclic system (opposite the connection to the specified atom), shows that the relationship can be attached to any suitable ring atoms.

The term "optional" or "optionally" as used here indicates that the described event or circumstance may occur, but maybe not, and that the description includes the ways in which the event or circumstance encountered, and ways in which they are absent. For example, "optionally substituted" means optionally substituted group can include a hydrogen or Deputy.

The phrase "optional communication" indicates that the bond may be present or may be omitted, and that the description includes single, double or triple bond. If the Deputy designated as "link" or "no", the atoms associated with the deputies, connected directly edstone.

The term "about" is used to denote the approximate area around or near. When the term "about" is used in conjunction with digital range, he modifies this range, expanding the boundaries above and below the specified numerical values. Usually, the term "about" is used to modify the digital values above and below the specified value by 20%.

Some of the compounds of formula a or formulae I-III and I'-VI'can be tautomerism. Tautomeric compounds can exist as two or more vzaimoprevrascheny species. Prototroph the tautomers arise from migration covalently bound hydrogen atom between two atoms. The tautomers usually exist in equilibrium, and attempts to allocate individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The equilibrium position depends on the chemical characteristics of the molecule. For example, for many of aliphatic aldehydes and ketones, such as acetaldehyde, keto form predominates, whereas phenols prevails enol form. Normal prototroph the tautomers include keto/enol (-C(-O)-CH-↔-C (OH)=CH-), amide/kidney acid (-C(=O)-NH-↔-C(-OH)-N-) and amidinov (-C(=NR)-NH-↔-C (other)-N-) tautomers. The last two are particularly suitable for heteroaryl and heterocyclic rings, and us is Aasee the invention includes all tautomeric forms of the compounds.

Used here is the technical and scientific terms have the meanings usually attached to a person skilled in the art to which the present invention unless otherwise stated. Reference is here made to the various methods and materials known to a person skilled in the art. Standard sources, revealing General principles of pharmacology, include the book Goodman and Oilman's, The Pharmacological Basis of Therapeutics, 10th edition, McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to a person skilled in the art can be used to implement the present invention. However, the described preferred materials and methods. Materials, reagents and the like, to which reference is made in the following description and examples, obtained from commercial sources, unless otherwise indicated.

These definitions can join with the formation of chemically relevant combinations, such as "heteroalkyl", "galgenlieder", "arylalkylamines", "alkylaryl", "alkoxyalkyl" and the like. When the term "alkyl" is used as a continuation of another term, as in "phenylalkyl" or "hydroxyalkyl", it denotes an alkyl group, as defined above, substituted by one or two substituents selected from another specified group. So, in the example, "phenylalkyl" denotes an alkyl group containing one or two phenyl substituent, and thus includes benzyl, phenylethyl, and biphenyl. "Acylaminoalkyl" represents an alkyl group containing one or two alkylamidoamines. "Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used here, the term "hydroxyalkyl" as used here denotes the number of heteroalkyl groups, as defined herein. The term -(ar)alkyl denotes unsubstituted alkyl or aracelio group. The term (hetero)aryl or (het)aryl means aryl or heteroaryl group.

The term "spirocyclic", as used here, denotes spirocycles cycloalkyl group, such as, for example, Spiro[3.3]heptane. The term spiroheterocyclic, as used here, denotes spiritlessly heteroseksualci, such as, for example, 2,6-diazaspiro[3.3]heptane.

The term "acyl" as used here refers to a group of the formula-C(=O)R, where R represents hydrogen or lower alkyl as herein defined. The term "alkylaryl" as used here denotes a group of formula C(=O)R, where R is an alkyl as defined here. The term1-6acyl of the means the group-C(=O)R, where R represents hydrogen or C1-5alkyl. The term "arylcarbamoyl" as used here denotes a group of formula C(=O)R, where R is an aryl group; the term "benzoyl" as used here means "arylcarbamoyl" group, where R represents phenyl.

The term "ester" as used here refers to a group of the formula-C(=O)OR where R is a lower alkyl as defined here.

The term "alkyl" as used here denotes unbranched or branched, saturated, monovalent hydrocarbon residue containing 1-10 carbon atoms. The term "lower alkyl" denotes a linear or branched hydrocarbon residue containing 1-6 carbon atoms. "C1-10alkyl" as used here refers to an alkyl comprising from 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including methyl, ethyl, propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl,heptyl and octyl.

When the term "alkyl" is used as a continuation of another term, as in "phenylalkyl" or "hydroxyalkyl", it denotes an alkyl group, as defined above, substituted by one or two substituents selected from another specified group. For example, "phenylalkyl" denotes glad the cal R 'R"- where R'represents a phenyl radical, and R"represents alkalinity radical as defined here, provided that the attachment point phenylalaninol group is Allenova radical. Examples arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly, except that R'represents an aryl radical. The terms "(gets)arylalkyl or(het)aralkyl" are interpreted similarly, except that R'does not necessarily represent aryl or heteroaryl radical.

The terms "halogenated" or "halogenized alkyl" or "lower halogenated" refers to linear or branched hydrocarbon residue containing 1-6 carbon atoms, where one or more carbon atoms substituted by one or more halogen atoms.

The term "alkylene" or "alkylene", as used here, denotes divalently saturated linear hydrocarbon radical containing from 1 to 10 carbon atoms (for example, (CH2)n), or branched saturated divalently hydrocarbon radical containing from 2 to 10 carbon atoms (for example, Snme - or-CH2CH(ISO-Pr)CH2- ) if not stated otherwise. Except for methylene, open the e valence alkalinous group is not attached to the same atom. Examples alkilinity radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylpropyl, 1,1-dimethylethylene, butylene, 2-ethylbutyl.

The term "alkoxygroup" as used here refers to-O-alkyl group, where alkyl is as defined above such as methoxy group, ethoxypropan, n-profilaxia, out-profilaxia, n-butylacrylate, out-butylacrylate, tert-butylacrylate, pentyloxy, hexyloxy, including their isomers. "The lowest alkoxygroup" as used here refers to alkoxygroup with "lower alkyl" group as defined above. "C1-10alkoxy" as used here refers to-O-alkyl, where alkyl represents a C1-10.

The term “DCS3” indicates phosphine, tizamidine three cyclic groups.

The terms "halogenlampe" or "halogenide alkoxygroup" or "inferior halogenlampe" denotes lowest alkoxygroup, where one or more carbon atoms substituted by one or more halogen atoms.

The term "hydroxyalkyl" or "hidrogenesse alkyl" as used here denotes an alkyl radical or a lower alkyl radical as used here, where from one to three hydrogen atoms at different carbon atoms substituted by hydroxyl groups.

The terms "alcalali the Nile" and "arylsulfonyl" as used here denotes a group of formula-S(=O) 2R, where R is an alkyl or aryl respectively and alkyl and aryl are as defined here. The term "heteroalicyclic" as used here refers to a group of the formula-S(=O)2R, where R is a "heteroalkyl" as here defined.

The terms "alkylsulfonamides" and "arylsulfonamides" as used here denotes a group of formula-NR'S(=O)2R, where R is an alkyl or aryl respectively, R'represents hydrogen or C1-3alkyl, and alkyl and aryl are as defined here.

The term "cycloalkyl" as used here denotes a saturated carbocyclic ring containing 3-8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7cycloalkyl" as used here refers to cycloalkyl containing 3-7 carbon atoms in the carbocyclic ring.

The term carboxyethyl, as used here, refers to an alkyl group in which one hydrogen atom substituted on carboxyl, provided that the attachment point heteroalkyl radical is located at the carbon atom. The term "carboxypropyl" or "carboxyl" refers to a group-CO2H.

The term "heteroaryl" or "heteroaromatic" as used here denotes a monocyclic rebelliously radical, containing from 5 to 12 atoms in the cycle containing at least one aromatic ring containing 4 to 8 atoms in the ring, with one or more N, O or S heteroatoms and the remaining atoms in the ring are carbon atoms, provided that interconnection point or heteroaryl radical is an aromatic ring. As known to a person skilled in the art heteroaryl rings have less aromatic character compared to their counterparts containing only carbon atoms. So, for the purposes of the invention, a heteroaryl group must have only some degree of aromatic character. Examples of heteroaryl groups include monocyclic aromatic heterocycles containing 5 or 6 atoms in the cycle and 1-3 heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazol, thiazole, isothiazol, triazoline, thiadiazole and oxadiazole, which optionally can be substituted by one or more, preferably one or two substituents selected from a hydroxy-group, ceanography, alkyl, alkoxygroup, tigroup, low halogenlampe, allylthiourea, halogen, lower halogenoalkane, alkylsulfonyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, and is criminalise and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, allylcarbamate, dialkylamino, arylcarbamoyl, alkylcarboxylic and arylcarboxylic. Examples of bicyclic groups include, but are not limited to, chinoline, ethenolysis, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole and benzisothiazol. Bicyclic group optionally may be substituted at any ring; however, the attachment point is in the ring containing the heteroatom.

The term "heterocyclyl", "heteroseksualci" or "heterocycle", as used here, denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one or two rings, including spirocycles ring system containing three to eight atoms per ring, one or more ring heteroatoms (chosen from N, O or S(O)0-2), and which optionally may be independently substituted by one or more, preferably one or two substituents selected from a hydroxy-group, carbonyl group, ceanography, lower alkyl, lower alkoxygroup, low halogenlampe, allylthiourea, halogen, lower halogenoalkane, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminocarbonyl is a, arylaminomethylene, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, unless otherwise noted. Examples of heterocyclic radicals include, but are not limited to, azetidine, pyrrolidine, hexahydroazepin, oxetanyl, tetrahydrofuranyl, tetrahydrothiophene, oxazolidinyl, diazolidinyl, isoxazolidine, morpholine, piperazinil, piperidinyl, tetrahydropyranyl, thiomorpholine, hinokitiol and imidazolines.

Common abbreviations include: acetyl (AC), azo-bis-isobutyronitrile (AIBN), atmosphere (ATM), 9-borabicyclo[3.3.1]nonan (9-BBN or BBN), tert-butoxycarbonyl (Vos), di-tert-butylperbenzoate or boc-anhydride (RE2Oh), benzyl (EAP), butyl (Bu), registration number in the Chemical Abstracts (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyldiimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), the TRIFLUORIDE diethylaminoethyl (DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (EDC), dichloromethane (DHM), diethylazodicarboxylate (DEAD), di-ISO-propylenecarbonate (DIAD), di-ISO-butylaldehyde (DIBAL or DIBAL-H), di-ISO-propylethylene (DIPEA), N,N-dimethylacetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ,1 'bis-(diphenylphosphino)ethane (dppe), N,N-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), ethyl ester of 2-ethoxy-2H-quinoline-1-carboxylic acid (EEDQ), diethyl ether (Et2O), O-(7-asobancaria-1-yl)-N, N,N'N'-tetramethylurea hexaphosphate acetic acid (HATU), acetic acid (SPLA), 1-N-hydroxybenzotriazole (HOBt), high performance liquid chromatography (HPLC), ISO-propanol (IPA), hexamethyldisilazane lithium (LiHMDS), methanol (Meon), melting point (tPL), MeSO2(mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MSRA), mass spectrum (ms), methyl tert-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N - methylmorpholine (NMM), N-organic (NMP), pyridinium chlorproma (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), ISO-propyl (ISO-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (CT or CT), tert-butyldimethylsilyl or tert-BuMe2Si (TBDMS), triethylamine (tea or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2-(Tf), triperoxonane acid (TFOC), 1,1'bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (the GF), trimethylsilyl or Me3Si (TMS), monohydrate p-toluensulfonate acid (TsOH or nTsOH), 4-Me-C6H4SO2or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA). The usual nomenclature, including consoles normal (n-), from- (m-), secondary (sec-), tertiary (tert-) and neo - have their usual meanings when used with an alkyl group. (book Rigaudy and Klesney, Nomenclature in Organic Chemistry, IUPAC, 1979, Pergamon Press, Oxford).

Examples of representative compounds covered by this invention and the scope of the invention, shown in the following table. These examples and the subsequent methods of obtaining refer to a specialist in the art to more clearly understood and implemented by the present invention. They should not be construed as limiting the scope of invention, but only as illustrating and representing it.

Generally, the nomenclature used in this description, based on the program AUTONOM v,4,0, a computer system Beilstein Institute for the development of IUPAC systematic nomenclature. If there is a difference given the structure and names given to this structure, the structure has more weight. In addition, if the stereochemistry of a structure or part of structure, not shown, for example, using bold or dashed lines, the structure or part of a structure should be interpreted as including the surrounding all their stereoisomers.

In table I are examples pyridinone compounds according to General formula a or formulae I-III.

Table I
No.NomenclatureStructureIC50(μm) HWB CD69
I-16-Dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,043
I-26-Dimethylamino-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-espiridion-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he0,58
I-32-[8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile0,054
I-46-DIMET is a melamine-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he 0,011
I-51-(5-{3-[6-(Centimetres)-8-fluoro-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]-2-hydroxymethylene}-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-atilmotin1,076

No.NomenclatureStructureIC50(μm) HWB CD69
I-66-Cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-he0,004
I-76-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,003
I-86-tert-Butyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymet fenil)-8-fluoro-2H-phthalazine-1-he 0,008
I-96-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,001

No.NomenclatureStructureIC50(μm) HWB CD69
I-10tert-Butyl ether 4-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)piperazine-1-carboxylic acid
I-116-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he0,058
I-126-Cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-3,4-dihydro-2H-isoquinoline-1-he 0,043
I-136-Cyclopropyl-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile4,035

No.NomenclatureStructureIC50(μm) HWB CD69
1-146-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-espiridion-2-ylamino)-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,03
1-156-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,007
1-166-tert-Butyl-8-fluoro-2-{3-[5-(1',2',3',4',5',6'-hexahydro-[3,4 ']bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-2H-phthalazine-1-he0,048
1-176-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,01

No.NomenclatureStructureIC50(μm) HWB CD69
1-186-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,011
1-196-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-phthalazine-1-he0,014
1-20 2-(6-{5-[3-(6-treat-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionate acid0,041
1-216-tert-Butyl-2-(3-{5-[5-(1,1-dimethyl-2-morpholine-4-yl-2-oxoethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he0,011
1-222-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N,N-dimethylethanamine0,014

No.NomenclatureStructureIC50(μm) HWB CD69
I-236-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he 0,392
I-246-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(2,2,2-Cryptor-1-hydroxyethyl)pyridine-2-ylamino]-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he
I-256-tert-Butyl-2-[3-(5-{5-[1-(4-chloroethoxy)-2,2,2-triptorelin]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethylene]-8-fluoro-2H-phthalazine-1-he
I-266-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-hydroxymethyluracil-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,091
I-272-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethylene]-6-tert-butyl-8-fluoro-2H-phthalazine-1-he

No.NomenclatureStructureIC50(μm) HWB CD69
I-286-tert-Butyl-8-fluoro-2-(2-methyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,181
I-292-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-(2-ethoxyethyl)isobutyramide0,03
I-306-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,01
I-316-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he

No.NomenclatureStructure IC50(μm) HWB CD69
I-322-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-methylisoleucine0,034
I-336-tert-Butyl-2-{3-[5-(5-ethylpyridine-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he0,218
I-346-{5-[3-(6-treat-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}nicotinic acid0,258
I-352-(3-{5-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-he0,028
I-366-tert-Butyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-nafta is Azin-1-he 0,059

No.NomenclatureStructureIC50(μm) HWB CD69
I-376-tert-Butyl-2-{3-[5-(1-ethyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he0,219
I-386-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1-isopropyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,067
I-396-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxyethylamine)methyl]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl]-2H-phthalazine-1-he0,008
I-406-tert-Butyl-2-{3-[5-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroximate is phenyl}-8-fluoro-2H-phthalazine-1-he 0,824
I-416-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-[1,6]naphthiridine-2-ylamino)-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he0,033

No.NomenclatureStructureIC50(μm) HWB CD69
I-426-tert-Butyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he0,006
I-436-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylaminomethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he0,015
I-446-tert-Butyl-2-{3-[5-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-who talesin-1-he cash consideration of USD 1,726
I-456-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-4-oxopiperidin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he2,261
I-466-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he4,218

No.NomenclatureStructureIC50(μm) HWB CD69
I-476-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he0,006
I-48N-[1-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-ylamino}pyridine-3-yl)-1-methylethyl]ndimethylacetamide 0,047
I-496-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(6-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-he3,127
I-506-tert-Butyl-2-{3-[5-(1-tert-butyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he0,044
I-516-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,023

No.NomenclatureStructureIC50(μm) HWB CD69
I-526-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-espiridion-2-ylamino)-1,6-digitope the one-3-yl]phenyl}-2H-isoquinoline-1-he 0,057
I-538-Chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,609
I-546-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,014
I-558-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he0,016

No.NomenclatureStructureIC50(μm) HWB CD69
I-568-Chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-about the co-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he 0,392
I-576-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he0,018
I-588-Fluoro-6-(1-hydroxy-1-methylethyl)-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he0,006
I-598-Fluoro-6-(1-hydroxy-1-methylethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,003

No.NomenclatureStructureIC50(μm) HWB CD69
I-608-fluoro-2(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he 0,016
I-618-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he0,051
I-626-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he0,092
I-636-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,016
I-646-(1-Ethyl-1-hydroxypropyl)-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he0,027

No.NomenclatureStructureIC50(μm) HWB CD69
I-652-[8-Fluoro-2-(3-{5-[5-(2-hydroxyethoxy)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-1-oxo-1,2-dihydroisoquinoline-6-yl]-2-methylpropionitrile0,019
I-666-Cyclopropyl-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-8-methoxy-2H-isoquinoline-1-he
I-676-Cyclopropyl-8-hydroxy-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he
I-682-(6-{5-[3-(6-Cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionate acid 0,213

No.NomenclatureStructureIC50(μm) HWB CD69
1-692-(6-{5-[3-(6-Cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N-methylisoleucine0,033
1-702-(6-{5-[3-(6-Cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N,N-dimethylethanamine0,022
1-716-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,039
1-726-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,02

No.NomenclatureStructureIC50(μm) HWB CD69
I-736-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,024
I-746-Cyclopropyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-he0,029
I-756-Cyclopropyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxyethylamine)methyl]pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)phenyl]-2H-isoquinoline-1-he0,037
I-762-(3-{5-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-cyclopropyl-8-ft is R-2H-isoquinoline-1-he 0,04
I-776-Cyclopropyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-isoquinoline-1-he0,02

No.NomenclatureStructureIC50(μm) HWB CD69
I-786-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylaminomethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he0,02
I-796-Cyclopropyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-he0,093
I-802-(3-{6-[1-(2,2-Defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-6-(1-g is droxy-1-methylethyl)-2H-isoquinoline-1-he 0,031
I-812-{3-[6-(1-Ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-8-fluoro-6-(1-hydroxy-1-methylethyl)-2H-isoquinoline-1-he0,013
I-826-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-isoquinoline-1-he0,057

No.NomenclatureStructureIC50(μm) HWB CD69
1-836-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-phthalazine-1-he0,01
1-846-tert-Butyl-2-(3-{6-[1-(2,2-defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)8-fluoro-2H-phthalazine-1-he 0,02
1-85N-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl}-N'-methylguanine
1-862-(3-{5-[5-(3-Aminopyrrolidine-1-ylmethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-he0,101
1-876-tert-butyl-2-(3-{5-[(1S,5R)-5-(3,8-diazabicyclo[3,2,1]Oct-3-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he0,024

No.NomenclatureStructureIC50(μm) HWB CD69
1-886-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-methylaminorex)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}f the Nile)-2H-phthalazine-1-he
1-896-tert-Butyl-2-(3-{6-[4-(1,4-dimethyl-3-oxopiperidin-2-yl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he

Described herein derivative of pyridinone and pyridazinone are kinase inhibitors, in particular inhibitors of Btk. These inhibitors may be useful for treating one or more diseases associated with inhibition of kinases, including diseases associated with inhibition of Btk and/or inhibition of b-cell proliferation in mammals. Not based on any theory, it is assumed that the interaction of the compounds according to the invention with Btk leads to inhibition of Btk activity, and thus to the pharmaceutical utility of these compounds. Accordingly, the present invention includes a method of treating a mammal, such as human, having a disease sensitive to inhibition of Btk activity and/or inhibition of b-cell proliferation comprising administration to a mammal having such a disease an effective amount of at least one given here chemical compounds. Eff the active concentration can be chosen experimentally, for example the assessment of the concentration in the blood connection, or theoretically, the calculation of bioavailability. Other kinases that can be influenced in addition to Btk, include, but are not limited to, other tyrosine kinase and serine/trionychinae.

Kinases play a prominent role in transmitting signals that control fundamental cellular processes such as proliferation, differentiation, and death (apoptosis). Impaired kinase activity is found in a wide range of diseases, including many types of cancer, autoimmune and/or inflammatory diseases and acute inflammatory reactions. Multifaceted role of kinases in key cellular signal transduction pathways provides a good opportunity to identify new drugs that bind to the kinase and the transmission path of the signal.

A variant embodiment includes a method of treating a patient having an autoimmune and/or inflammatory disease, or an acute inflammatory response that is sensitive to inhibition of Btk activity and/or b-cell proliferation.

Autoimmune and/or inflammatory disease, which can be affected by the compounds and compositions according to the invention, include, but are not limited to: psoriasis, Allergy, Crohn's disease, irritable bowel syndrome, sjögren's disease, tissue graft rejection and hypertree ottor the giving of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitides), autoimmune hemolytic and thrombocytopenic States, the syndrome? (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic idiopathic thrombocytopenic purple (ITP), Addison disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock and asthenic bulbar paralysis.

Included methods of treatment in which at least one described here is the chemical compound is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAID, non-specific inhibitors of the enzyme SOH-2 cyclo-oxygenase, gold compounds, corticosteroids, methotrexate, antagonists of the receptor of tumor necrosis factor (TNF), immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, the combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, Ketoprofen, sodium nabumetone, sulfasalazin, tolmetin sodium and hydroxychloroquine. Examples of NSAID also on the less specific inhibitors SOH-2, such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the implementation of the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid, or aspirin, sodium salicylate and choline and magnesium salicylates.

Anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid can be cortisone, dexamethasone, methylprednisolone, prednisolone, phosphate prednisolone sodium, or prednisone.

In additional embodiments, the implementation of the anti-inflammatory agent is a compound of gold, such as nutritional gold or auranofin.

The present invention also includes embodiments of which the anti-inflammatory agent is a metabolic inhibitor such as an inhibitor digidrofolatreduktazy, such as methotrexate, or inhibitor dihydroorotatdehydrogenase, such as Leflunomide.

Other embodiments of the invention include combinations in which at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as etanercept, or infliximab, which is an anti-TNF-alpha monoclonal antibody.

Other variationbetween the invention relates to combinations, in which at least one active agent is a compound of the immunosuppressant, such as connection-immunosuppressant selected from methotrexate, Leflunomide, cyclosporine, tacrolimus, azathioprine and mycophenolate mofetil.

In-cell and b-cell precursors expressing the CPD, are involved in the pathology of b-cell malignancies, including, but not limited to, b-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma, lymphoma, hairy cells, multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia.

It was shown that CPD is an inhibitor of the death of Fas/APO-1 (CD-95), including signaling complex (DISC) in-generic lymphoid cells. Survival cell leukemia/lymphoma can be kept in balance between opposing proapoptotic the action of caspase-activated DISC, and the subsequent anti-apoptotic regulatory mechanism, including TCE and/or its substrates (article Vassilev, etc., J. Biol. Chem., 1998, 274, her. 1646-1656).

Also found that the CPD inhibitors useful as homocysteine agents, and thus, useful in combination with other chemotherapeutic drugs, in particular drugs that induce apoptosis. Examples of other hamot rapeutically drugs which can be used in combination with homocysteinemia the CPD inhibitors include inhibitors of topoisomerase I (camptothecin or topotecan), topoisomerase II inhibitors (e.g., daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulidentata agents (e.g. Taxol and vinblastine) and biological agents (e.g. antibodies such as aHTH-CD20 antibody, IDEC 8, immunotoxins, and cytokines).

The Btk activity is also associated with certain leukemias expressing the fused bcr-abl gene, resulting in the translocation of parts of chromosomes 9 and 22. This violation is usually observed in chronic myelogenous leukemia. Btk mainly fosfauriliruetsa kinase bcr-abl, which initiates downstream survival signals that disrupt apoptosis in cells bcr-abl. (article Feldhahn and others, J. Exp. Med., 2005, 201(11), it. 1837-1852).

Compounds of the present invention can be introduced into a wide range of dosage forms and carriers for oral administration. Oral administration may be in tablet form, oblachennyh tablets, dragées, hard and soft gelatine capsules, solutions, emulsions, syrups or suspensions. Compounds of the present invention is effective in the introduction of other techniques, including continuous (intravenous drip) local parenteral, intramuscular, inside the military, subcutaneous, transdermal (which may include the agent to improve penetration), buccal, nasal, inhalation and suppozitornyj introduction, among other techniques. The preferred method of administration is generally oral, using normal daily dosage, which can be selected in accordance with the degree of disease and the response of the patient to the active ingredient.

The compound or compounds of the present invention and their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers or diluents, can be introduced in the form of pharmaceutical compositions and unit dosages. Pharmaceutical compositions and forms for a single administration may include conventional ingredients in conventional proportions, with or without additional active compounds or substances, and unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended used daily dosage. The pharmaceutical compositions can be used in the form of solids, such as tablets or filled capsules, semi-solid substances, powders, formulations of extended release or liquids such as solutions, suspensions, emulsions, elixirs, or filled cap the uly for oral administration; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. The usual composition may contain from about 5% to about 95% active compound or compounds (weight). The term "composition" or "dosage form" includes solid and liquid formulations of active compounds, and the specialist in the art it is clear that the active ingredient can exist in various combinations depending on the target organ or tissue and the desired dose and pharmacokinetic parameters.

The term "excipient" as used here refers to the connection that is used to obtain a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use, as well as for pharmaceutical applications for humans. Compounds of the present invention can be administered separately, but usually introduced in a mixture with one or more suitable pharmaceutical excipients, diluents or carriers selected depending on the selected route of administration and standard pharmaceutical practice.

"Pharmaceutically acceptable" indicates that it is useful to obtain a pharmaceutical composition, which is Oba is but safe, non-toxic and biologically and otherwise appropriate, and includes those that are acceptable for veterinary use, as well as for pharmaceutical application for a person.

Form "pharmaceutically acceptable salt" of the active ingredient may initially give the desired pharmacokinetic properties of the active ingredient, which are not available for mesolevel forms, and often can positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound refers to salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid additive salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy shall entail)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4 - chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, laurenzana acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or (2) salts formed in the presence of an acidic proton in the initial compound, the substitution on the metal ion, for example, alkali metal ion, alkali earth metal ion or an aluminum ion; or coordination compounds with organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

Solid form compositions include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring, solubilization, lubricants, suspendida agents, binders, preservatives, agents razryhlitel the th for tablets or encapsulating material. In powders, the carrier is typically a finely powdered solid substance which is a mixture with finely ground active ingredient. In tablets, the active component is typically a mixture with a carrier having the necessary binding capacity in suitable proportions, and having the desired shape and size. Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. Solid forms of compositions may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersing additives, thickeners, solubilizing agents and the like.

Liquid formulations suitable for oral administration include liquid composition, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. They include solid forms of compositions, which should be turned into liquid form of the composition immediately before use. Emulsions can be obtained in the form of solutions, for example, in solution in aqueous propylene glycol, or may contain emulsifying agents such as lecithin, monooleate sorbitol or acacia. Aqueous solutions of m which may be obtained by dissolving the active component in water and adding suitable colorants, perfumes, stabilizers and thickening agents. Aqueous suspensions can be obtained by dispersing finely ground active component in water with viscous material such as natural or synthetic resin, gum, methylcellulose, sodium carboxymethyl cellulose and other well-known suspendresume agents.

Compounds of the present invention can be prepared in a form for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be present in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in containers with multiple doses with the addition of preservative. Songs can have such forms as suspensions, solutions or emulsions in oily or aqueous media, for example, a solution in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or additives include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (for example, etiloleat), and can contain a compound agents, such as preservatives, moisturizing, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of powder is CA, received aseptic allocation of sterile solid or by lyophilization from solution, for preparation before use with a suitable vehicle, e.g. sterile, pyrogen-free water.

Compounds of the present invention can be prepared in a form for topical application to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams, for example, can be obtained with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be obtained with a water or oil based, and usually also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickening agents, or coloring agents. Formulations suitable for topical introduction into the oral cavity include cakes, including active agents in the aromatic base, usually sucrose and acacia or tragakant; lozenges comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes for the mouth including the active ingredient in a suitable liquid carrier.

Compounds of the present invention can be formulated for administration as suppositories. First melt the low-melting wax such as a mixture of glycerides of fatty to the slot or cocoa butter, and the active component is dispersed homogeneous, for example, by stirring. The molten homogeneous mixture is then poured in the usual dimensional shapes, leave to cool and harden.

Compounds of the present invention can be formulated for vaginal administration. Suitable pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers which are known from the prior art.

Compounds of the present invention can be formulated for nasal administration. Solutions or suspensions used directly in the nasal cavity by conventional means, for example, by using drops, pipette or spray. The compounds may be obtained in the form of a unit dose or in multiple doses. In the latter case, drops or pipette, this can be done by the introduction of the patient, if appropriate, pre-measured volume of a solution or suspension. In the case of spray that can be done, for example, by means of measuring the spray pump spray.

Compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract, and includes intranasal introduction. The connection usually has a small particle size, for example, about five (5) microns or less. This particle size can be processible, known from the prior art, for example, micronization. The active ingredient is injected into the vessel under pressure with a suitable gas propellant such as a chlorofluorocarbon (CFC), for example, DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosol usually may also contain a surfactant such as lecithin. The dosage of drug can be monitored by measuring valve. Alternatively, the active ingredients can be administered in the form of a dry powder, for example, a powder mix of the compound in a suitable basis for powder, such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidine (PVP). Powder carrier can form a gel in the nasal cavity. The powder composition may be in unit dosage form, for example, capsules or cartridges, for example, gelatin or blister packs from which the powder may be administered using an inhaler.

Optionally, the compositions can be obtained with enteric coatings, suitable for introduction prolonged or controlled release of the active ingredient. For example, the compounds of the present invention can be introduced into the device for transdermal or subcutaneous the delivery of a drug. These delivery systems are preferred when it is necessary for a prolonged release of the connection, and when the patient's perception of treatment is critical. Connection systems transdermal delivery is often attached by adhesive to the skin of solid media. An interesting connection can also be combined with power penetration, such as azone (1-dodecylsulfate-2-one). Delivery system with prolonged release of injected subcutaneously into the subcutaneous layer surgically or by injection. Subcutaneous implants encapsulate the connection lipitorhistory membrane, such as silicone rubber or bioreserves polymer, for example, polylactic acid.

Suitable compounds along with pharmaceutical carriers, diluents and excipients are described in the book Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th-oe edition, Easton, Pennsylvania. Specialist in the art can modify the compositions according to the description for various formulations for a particular route of administration, without making the compositions of the present invention is unstable or not reducing their therapeutic activity.

Modification of this connection to give it greater solubility in water or other media, for example, can easily be done minor modifications (about adowanie salt, etherification and so on) that are known to the person skilled in the art. Also a specialist in this area of technology known modifications of routes of administration and dosage of a particular compound to control the pharmacokinetics of these compounds to enhance a favorable impact on patients.

The term "therapeutically effective amount" as used here refers to the amount necessary to reduce the symptoms of the disease in the patient. The dose is adjusted according to the individual requirements in each particular case. Included the dosage, which varies widely depending on numerous factors such as the severity of curable diseases, the age and General health of the patient, other medications that treated the patient, the method and form of administration and the preferences and experience of the attending physician. For oral administration suitable daily dosage of from about 0.01 to about 1000 mg/kg body weight per day for monotherapy and/or combination therapy. The preferred daily dosage is from about 0.1 to about 500 mg/kg body weight, more preferred from 0.1 to about 100 mg/kg of body weight, and most preferably from 1.0 to about 10 mg/kg of body weight per day. Thus, for administration to a patient weighing 70 kg, the dosage may costal is to be from about 7 mg to 0.7 g per day. The daily dosage may be administered in one dose or multiple doses, usually from 1 to 5 doses per day. It is usually begin with small doses that are less than the optimum dose of the compound. Then, the dosage increase by small increments until the optimum effect of the specific patient. Specialist in the art of treating diseases described here are capable without additional experiments and, based on their own knowledge, experience and description of the invention, to evaluate therapeutically effective amount of the compounds of the present invention for the disease and the patient.

The pharmaceutical preparations are preferably in unit dosage forms. In such form the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules and powders in containers or ampoules. Also, the unit dosage form can be a capsule, tablet, sachet or cake separately, or it can represent a suitable number of any of these forms in Packed form.

Examples

Example 1. 4-Bromo-2-fluoro-6-methylbenzamide

4-Br the m-2-fluoro-6-methylbenzoic acid (200 g) was dissolved in 1 l of THF and treated portions carbonyl diimidazol (180 g, 1.3 equiv.). The reaction mixture was stirred at room temperature for about 3 hours, and then was suppressed by addition of an aqueous ammonium hydroxide solution (400 ml). The resulting reaction mixture was stirred over night at room temperature and then concentrated under reduced pressure to a volume of about 0.5 L. the resulting suspension was diluted by adding 1 l of water. The precipitated product was isolated by filtration, washed with water (3×300 ml), dried in vacuum at a temperature of about 60°C To produce 174 g (87% isolated yield) of product.

Example 2. 4-Cyclopropyl-2-fluoro-6-methylbenzamide

A mixture of 4-bromo-2-fluoro-6-methylbenzamide (10 g), cyclopropylboronic acid (4,87 g, 1.25 equiv.), tricyclohexylphosphine (725 mg, is 0.06 equiv.), the chloroform adduct of Tris(dibenzylideneacetone)diplegia(0) (446 mg, 0.01 equiv.) and potassium carbonate (17.9 g, 3 equiv.) in toluene (100 ml) and water (10 ml) was stirred at boiling under reflux in an inert (nitrogen) atmosphere for about 24 hours, the Reaction mixture is then cooled to a temperature of about 60°C and was treated with 10% aqueous ammonium hydroxide solution (60 ml) and then ethyl acetate (60 ml). The layers were separated, the organic phase is washed with saturated sodium chloride solution and was filtered to remove undissolved material. The extract was concentrated under reduced pressure d is about 30 ml to obtain a suspension. It was diluted with heptane (80 ml) and ethyl acetate (20 ml), and then boiled under reflux to dissolve all solids. The resulting solution was slowly cooled to CT for crystallization of the product. The precipitated product was isolated by filtration, washed with a mixture of ethyl acetate-heptane (1:1) (60 ml), was dried in a vacuum at a temperature of about 60°C To produce 6.85 g (82,3% isolated yield) of product.

Example 3. 6-Cyclopropyl-8-forsakenly-1(2H)-he

To a solution of 4-cyclopropyl-2-fluoro-6-methylbenzamide (37,2 g at 0.19 mol) in 2-methyltetrahydrofuran (MeTHF; 223 ml) was added 1,1-dimethoxy-N,N-dimethylethanamine (29,8 g of 0.25 mole). The mixture was heated at 60°C for 2 hours, then about 100 ml MeTHF drove in vacuo to remove methanol. The reaction mixture was heated again to 55°C. and was added dropwise tert-piperonyl potassium, 1 M solution in THF (289 ml of 0.29 mol). After 1 h stirring at 60°C. the reaction mixture was left to cool to CT and was poured into the model HC1, 1 M solution (289 ml of 0.29 mol), and then THF/MeTHF drove at 60°C for crystallization. In the process of distillation was slowly added IPA (223 ml). After you remove most of THF/MeTHF, the solution was cooled to room temperature. The target product was led from a mixture of IPA/water, collected by filtration and washed with water and cold IPA. The filter residue was dried in vacuum at 50°C for 30, g specified in the connection header (77% isolated yield) as a white solid. MS (ESI) 204 (M+N)+.

Example 4. 2-Chloro-6-(6-cyclopropyl-8-fluoro-1-oxoethyl-2(1H)-yl)benzaldehyde

Method a: To a reactor volume of 1 l was loaded 6-cyclopropyl-8-forsakenly-1(2H)-he (65 g of 0.32 mol), 2-bromo-6-chlorobenzaldehyde (84,2 g of 0.38 mol), copper iodide(1) (12.2 g, 64,0 mmole) and potassium carbonate (88,4 g of 0.64 mol). The reactor was evacuated and filled with nitrogen. The sequence was repeated three times. Then added DMF (650 ml) and the resulting mixture was heated at 120°C for 20 hours the Reaction mixture was cooled to a temperature of about 70°C., and was added THF (975 ml). Then the mixture was left to cool to room temperature, then was filtered through a layer of celite. The filtrate was concentrated in vacuum for distillation THF. Crystallization was carried out using a mixture DMFILE/N2On (10/5/2) at a temperature of about 60°C, and the material was kept during the night during slow cooling. The target product was collected by filtration and washed with IPA/H2O. the Residue on the filter was dried in vacuum at 70°C overnight with the receipt of 65.4 g specified in the title compound (60% isolated yield) as a yellow solid. MS (ESI) 341, 343 (M+N)+.

Method: In a round bottom flask of 100 ml was loaded 6-cyclopropyl-8-forsakenly-1(2H)-he (2 g, 9,84 mmole) and HMDS (14,0 ml) and the suspension was added TFOC (of 22.4 mg, 15,2 μl, 0.2 mmole). The floor is built the mixture was heated at 122°C for 5 h, then the excess HMDS drove on a rotary evaporator. To the obtained residue was added 2-chloro-6-forbindelse (1.64 g, 10.3 mmole), potassium carbonate (1,36 g, 9,84 mmole), ethoxytrimethylsilane (3,49 g of 29.5 mmole) and DMF (20,0 ml) and the reaction mixture was heated at 80°C With stirring for 5 hours the Solution was left to cool to CT, and to the solution was added 6 ml IPA and 14 ml of water for crystallization of the product. After stirring for 4 h at room temperature, the crystalline product was collected by filtration and washed with a mixture of IPA/H2O. the Residue on the filter was dried in a vacuum oven at 50°C overnight to obtain 1.97 g specified in the title compound (59% isolated yield) as a yellow solid. MS (ESI) 341, 343 (M+N)+.

Example 5. 2-(3-Chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-forsakenly-1(2H)-he

2-Chloro-6-(6-cyclopropyl-8-fluoro-1-oxoethyl-2(1H)-yl)benzaldehyde (64,6 g at 0.19 mol) was dissolved in DHM (650 ml), and then to the solution was added IPA (325 ml). At 4°C to the reaction mixture portions was added NaBH4 (7,15 g at 0.19 mol), then the resulting solution was stirred for 1 h the Reaction extinguished with water (170 ml), then the mixture was filtered through a layer of celite. Layer DHM was collected by phase separation, and DHM drove, and was also added IPA. The target product was recrystallized from IPA, collected by filtration is washed with cold IPA. The filter residue was dried in vacuum at 70°C To produce 56,3 g specified in the connection header (86,6% isolated yield) as a white solid. MS (ESI) 343, 345 (M+N)+.

Example 6. 6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H°-isoquinoline-1-he

In the reactor of 2 l) was added 2-(3-chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-forsakenly-1(2H)-he (62,5 g of 0.18 mol), 1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (108 g, and 0.25 mole), DCS3(3.2 g, 11.5 mmole), Pd(OAc)2(1.27 g, 5.7 mmole) and K2CO3(54.6 g, of 0.38 mole) in order. The reactor was evacuated and filled with nitrogen. The sequence was repeated three times. Then to the reaction mixture was added 20% aqueous solution of 1,4-dioxane (1 l). The resulting mixture was heated at 88 With soft boiled and stirred for 1 h in nitrogen atmosphere. To the reaction solution was added an additional 7 g of 1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-it to the end of the reaction. After 2 h the temperature of the bath was cooled to 70°C., and the reaction mixture was slowly added to 600 ml of water, maintaining the temperature above 70°C. the Material began to precipitate, and the suspension of ohlord is whether to 5 C. The solid material was collected by filtration, and washed Meon (300 ml). The crude solid was dissolved in DHM (1.3 l) and again in the Meon (150 ml). To the solution was added trithiocyanuric acid chinatravel salt (100 g) in water (390 ml), then the resulting mixture was stirred intensively at room temperature for 2 h and was filtered through a layer of celite. Layer DHM was collected by separation of the phases, and after drying, activated carbon (22 g) obtained mixture was stirred additionally for 2 h at RT, then was filtered through a layer of celite. The filtrate was heated for distillation DHM in nitrogen atmosphere, and to replace DHM was added ethanol. Target product began to crystallize from ethanol using the seed, and the crystalline material was collected by filtration after cooling to 5°C and washed with cold EtOH. The filter residue was dried in a vacuum oven at 70°C To produce 91,7 g specified in the title compound (83% isolated yield) in the form of a whitish solid. MS (ESI) 607 (M+N)+1H NMR (300 MHz, DMSO-d6) δ ppm 0,82-of 0.91 (m, 2H) 1,04-to 1.14 (m, 2H) 2,01 and 2.13 (m, 1H) 2,20 (s, 3H) 2,38 is 2.46 (m, 4H) 2,97-to 3.09 (m, 4H) to 3.58 (s, 3H) 4,15 is 4.36 (m, 2H) 4,77 (t, 4,34 Hz, 1H) 6,59 (dd, J-7,55, 1.89 Hz, 1H) 6,99 (dd, J=13,60 and 1.51 Hz, 1H) 7,21 (d, J=9,06 Hz, 1H) 7,26 (d, J=1,51 Hz, 1H) 7,28-7.38 (m, 4H) 7,39-7,46 (m, 1H) of 7.48-7,56 (m, 1H) a 7.85 (d, J=3,02 Hz, 1H) of 8.37 (s, 1H) to 8.57 (d, J=2,27 Hz, 1H).

Example 7. 3-tert-Butyl-5-forbindelse

Bromo-3-tert-butyl-5-torbenson (323,2 g of 1.4 mol) was dissolved in THF (3.3 l) and cooled to -10°C. was Added PrMgCl (2M solution in THF, 0.5 equiv., 350 ml) for 20 min, then HBuLi (2.5 M solution in hexane, 1.0 equiv., 560 ml) for two hours. Was added DMF (4 equiv., 450 ml) for one hour, then was stirred for 45 minutes and extinguished 3M Hcl (1000 ml). The layers were separated, and the aqueous fraction was diluted with water (1 l) and extracted with ethyl acetate (1 liter). The organic fractions were combined and washed with water (2×2 l). The organic fraction was concentrated to obtain an orange oil (252 g, Quant.), used directly in the next reaction.

Example 8. 1-tert-Butyl-3-dimethoxymethyl-5-torbenson

3-tert-Butyl-5-forbindelse (252 g of 1.4 mol) was dissolved in methanol (4 vol., 1000 ml) and triethylorthoformate (1, 252 ml). Added toluensulfonate acid (3,4 weight. %, 6 g) in one portion and the resulting solution was stirred at RT for 1 hour. Was added triethylamine (0.12 to about., 30 ml) and the reaction mixture was concentrated to obtain oil, and then re-suspended in ethyl acetate (3 l) and NaHCO3(aq. the feast upon., 1 l) and water (1 l) under vigorous stirring. The organic phase is washed with additional water (1 l), well filtered, and then concentrated to obtain an orange oil (311,2 g, 98.5 per cent) used orestano in the following reaction.

Example 9. 4-tert-Butyl-2-dimethoxymethyl-6-Formentera acid

1-tert-Butyl-3-dimethoxymethyl-5-torbenson (333 g of 1.47 mol) was dissolved in THF (10 vol., 3,3 l) and cooled to -70°C. was added dropwise uli (1.4 M in cyclohexane, 1.0 equiv., 1000 ml) for 1.5 hours. The solution was stirred at -70°C for one hour and then the reaction mixture was added gas CO2through sintered glass gatorshield tube, supporting intensive mixing. The reaction mixture was left to be heated with vigorous stirring at the desired ventilation to release excess CO2from the solution. When the internal temperature reached +10°C, the reaction extinguished with water (3 l), then conc. HCl (1,15 equiv., 140 ml). The aqueous fraction was extracted with ethyl acetate (1l) and the combined organic fractions were combined and washed with water (2×1 l) and then concentrated by solvent substitution heptane. Thin crystals were filtered off, washed with heptane, and then dried at RT under vacuum in N3 with getting to 220.3 g (55.3%).

Example 10. 6-tert-Butyl-8-fluoro-2H-phthalazine-1-he

4-tert-Butyl-2-dimethoxymethyl-6-fermenting acid (to 220.3 g, 0,815 mol) was dissolved in ethanol (2 vol., 440 ml) and acetic acid (0,5, 110 ml). Added hydrazinehydrate (1.5 equiv., 61 ml) and the solution p is remedial at 80°C for 6 hours. The mixture was cooled to CT during the night, then in an ice bath, and then was filtered and washed with cold ethanol. Fine white crystals were dried at 100°C in a vacuum oven at N3, obtaining 154,7 g (86%) of 6-tert-butyl-8-fluoro-2H-phthalazine-1-it.

Example 11. 2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-chlorobenzaldehyde

In a round bottom flask with a volume of 3 l was added 6-tert-butyl-8-fluoro-2H-phthalazine-1-he (132,3 g to 0.6 mole), 2-chloro-6-forbindelse (104,8 g of 0.66 mol) and cesium carbonate (117,4 g of 0.36 mol). The flask was evacuated and filled with nitrogen three times. Then the reaction flask was added ethoxytrimethylsilane (142 g of 1.2 mol) and DMF (1.6 l), and the resulting mixture was heated to 60°C. After 4 h stirring, the solution was left to cool to room temperature, and the reaction was suppressed by adding dropwise to 800 ml of N2O. Target product began to precipitate from a mixture of DMF and water. The solid substance was collected by filtration after cooling to 5°C, and washed with a mixture of DMF/water (2/1, 750 ml, pre-cooled to 6°C) and H2O (400 ml). The filter residue was dried in a vacuum oven at 65°C overnight with getting 147 g specified in the connection header (68,2% isolated yield) as a yellow solid. MS (ESI) 358, 360 (M+H)+.

Example 12. 6-tert-Butyl-2-(3-chloro-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he

2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-chlorobenzaldehyde (125 g of 0.35 mol) was dissolved in DHM (1 l) with stirring at RT, and then to the solution was added 0.5 l of IPA. The resulting solution was cooled to 4°C, and portions were added NaBH4(5.9 g, of 0.16 mol). After 30 min of stirring the reaction was suppressed by the addition of H2O (200 ml). The organic layer was collected by separation of the phases, and DHM drove away from the solution by the addition of IPA (1.6 l) at a temperature of about 80°C. the desired product began to crystallize from the IPA at a temperature of about 30°With adding seed, then to the solution was added dropwise water (750 ml). The resulting solution was cooled to 5°C. and was filtered to collect crystals. The filter residue was washed with a mixture of IPA/water (2/1, 450 ml, pre-cooled to 5°C) and dried in a vacuum oven at 65 C overnight with getting 82.3 g specified in the connection header (65,5% isolated yield) as a white solid. MS (ESI) 360, 362 (M+N)+.

Example 13

The mixture of the source of bromide (200 g), penatration (161 g), Pd(OAc)2 (2.38 g), X-Phos (EUR 7.57 g), COAs (242 g) and dioxane (1200 ml) was stirred and degirolami three times. The mixture was heated at 100°C for 2 hours, then cooled to 65°C. the Suspension was filtered through a layer of celite (100 g). The residue was washed with 800 ml of dioxane. The filtrate is kept in vacuum is about 800 ml. The residue was heated to 65°C. was Slowly added heptane (1200 ml) for 1 h, the Suspension was cooled to CT, and then cooled in an ice bath for 4 hours. The product was isolated by filtration and washed with a mixed solution of heptane (500 ml) and dioxane (250 ml), which was pre-cooled to 5°C. the Residue was dried over night at 70°C in a vacuum furnace. The product, 1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he, was obtained as brown solid (178 g, 79% yield).

Example 14. 6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he

In the reactor of 2 liters was added 6-tert-butyl-2-(3-chloro-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he (64 g, 0,18 mol), 1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (90,5 g of 0.21 mol), DCS3(3.0 g, 10.7 mmole), Pd(dba)2 (3.1 g, 5.4 mmole) and K2CO3(49 g of 0.36 mole) in order. The reactor was evacuated and filled with nitrogen. This sequence was repeated three times. Then to the reaction mixture was added 20% aqueous solution of 1,4-dioxane. The resulting mixture was heated at 88°C at a soft boil under reflux and was stirred for 1.5 h under nitrogen atmosphere. After 2 h the temperature is ur bath was lowered to 80°C, to the reaction mixture was slowly added 1,3 l IPA maintaining the temperature above 70°C. the Material has started to appear, and the suspension was cooled to CT under stirring. The solid material was collected by filtration and washed with IPA, water, and then IPA. The crude solid was again dissolved in DHM (780 ml) and Meon (100 ml). To the solution was added chinatravel salt trithiocyanuric acid, 15% aqueous solution (490 ml), then the resulting mixture was stirred intensively at room temperature for 2 hours After adding to the solution of activated carbon (9.7 g) and diatomaceous earth (9.7 g), the mixture was stirred additionally for 2 h at RT, then was filtered through a short layer of diatomaceous earth. DHM layer was collected by phase separation, and the aqueous layer was extracted with additional DHM (490 ml). The combined organic substance was diluted Hcl, 1.0 M solution (780 ml), then DHM was removed on a rotary evaporator under vacuum. In the process of evaporation to the mixture was added IPA to remove THM. The aqueous acid solution was treated dropwise at room temperature NH4OH, 30% solution, to obtain material. Target product began to crystallize from a mixture of IPA/water, and the crystalline material was collected by filtration, washed with water and IPA. The filter residue was dried in a vacuum oven at 60 to receive the 92,4 g specified in the connection header (83,5% isolated yield) as a yellow solid. MS (ESI) 624 (M+N)+.1H NMR (400 MHz, DMSO-d6) δ ppm to 1.38 (s, 9H) of 2.20 (s, 3H) 2,39 is 2.46 (m, 4H) 2,99-of 3.07 (m, 4H) to 3.58 (s, 3H) 4,30-4,39 (m, 2H) 4,58 (t, J=5,31 Hz, 1H) 7,21 (d, J=a 9.09 Hz, 1H) 7,29 (d, J=2,53 Hz, 1H) 7,35 (dd, J=a 9.09, 3,03 Hz, 1 H) 7,37-the 7.43 (m, 2H) 7,49 (d, J=7,58 Hz, 1H) 7,74 (dd, J=13,14, 2,02 Hz, 1H) 7,87 (dd, J=4,04, 2,53 Hz, 2H) at 8.36 (s, 1H) and 8.50 (d, J=2,53 Hz, 1H) 8,53 (d, J=3.5 Hz. 1H).

Example 15

The mixture of the source of bromide (39,8 g), penatration (30,7 g), Pd(OAc)2 (0,46 g), X-Phos (1,46 g), KOAc (46,0 g) and dioxane (240 ml) was stirred and degirolami three times. The mixture was heated at 100°C for 2 hours, then cooled to 65°C. the Suspension was filtered through a layer of celite (27 g). The residue was washed with 240 ml of dioxane. The filtrate is kept in a vacuum to 160 ml the Residue was heated to 65°C. was Slowly added heptane (240 ml) for 1 hours

The suspension was cooled to CT, and then cooled in an ice bath for 4 hours. The product was isolated by filtration and washed with a mixed solution of heptane (100 ml) and dioxane (50 ml), which was pre-cooled to 5°C. the Residue was dried over night at 70°C in a vacuum furnace. The product was obtained as light brown solid (37.5 g, 84% yield).

Example 16. 6-tert-Butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-5-(5-(morpholine-4-carbonyl)pyridine-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl)phenyl)phthalazine-1(2H)-he

In flask 2 ml) was added 1-methyl-3-(5-(morpholine-4-carbon is l)pyridine-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-he (171 mg, to 0.39 mmole), 6-tert-butyl-2-(3-chloro-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he (100 mg, of 0.28 mmole), potassium carbonate (76,6 mg, 0.55 mmole), tricyclohexylphosphine (4,7 mg, 16.6 mmol) and Pd(dba)2 (4,78 mg, 8,31 of µmol). The flask was evacuated and filled with nitrogen. The sequence was repeated three times. Then to the reaction mixture pipette was added 20% aqueous solution of 1,4-dioxane (1.5 ml). The resulting mixture was heated at 96°C, With a soft boil under reflux and was stirred for 5 hours After cooling down to CT to the reaction mixture were added DHM (1 ml) and chinatravel salt trithiocyanuric acid, 15% aqueous solution (1 ml), then the resulting solution was stirred at 40°C for 4 h, and optionally within 4 h after adding 20 mg of activated charcoal, then filtered through a layer of celite and washed DHM. DHM layer was collected by phase separation, and the aqueous layer was extracted with additional DHM. The combined organic substances were diluted with IPA, and DHM completely drove away. The target product was recrystallized from IPA, collected by filtration and washed with IPA. The filter residue was dried in a vacuum oven at 50°C To produce 120 mg specified in the title compound (68% isolated yield) as a yellow solid. MS (ESI) 640 (M+N)+.

Example 17

Stage 1

To a solution of 5-bromo-1-methyl-3-(5-(morphol is n-4-carbonyl)pyridine-2-ylamino)pyridine-2(1H)-it (22 g, to 55.9 mmole, equiv.: to 1.00) in THF (300 ml) was added the equivalent of 60% sodium hydride (1.1 equiv. Was stirred at RT for 10 min after the addition, and then was heated to an internal temperature of 70°C and was stirred for 12 hours. The next day the reaction was completed according to TLC (95/5 V/Meon). Was carefully added water, then EtOAc (300 ml each) and was divided. Washed the organic phase with saturated sodium chloride solution, dried with sodium sulfate, filtered, and concentrated to a dark oil. Purified accelerated chromatography (methylene chloride : ethyl acetate) to give 24.5 g of the product as a yellow-brown solid. MS ES M+1=493, 495.

Stage 2

To a suspension of reagent Schwartz, the hydrochloride of bis(cyclopentadienyl)zirconium (4.42 g, 17.1 mmole, equiv.: 1,3) in THF (100 ml) at RT, was added tert-butyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl(5-(morpholine-4-carbonyl)pyridine-2-yl)carbamate (6.5 g, 13.2 mmole, equiv.: to 1.00) in THF solution (200 ml) in one portion. The suspension gradually became a yellow solution. Conducted TLC after 10 min (95:5 MS:Meon) showed the presence of starting material and a new product. After 40 min, nothing has changed. The reaction mixture was poured into 100 g SiOH (Merck 60) and was stirred for 10 minutes, then filtered and concentrated. Implemented accelerated chromatography (MC:EtOAc 90:10 to 20:80) to e the investments of the target product as a colorless solid. 2,45, MSESM+1 =408,410.

Stage 3

To a solution of tert-butyl methyl ether (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-(5-formylpyridine-2-yl)carbamino acid (1.0 g, of 2.45 mmole) in DHM (49 ml) was added 1-methylpiperazine (491 mg, 4.9 mmole), triacetoxyborohydride sodium (1.3 g, 6.12 mmole) and acetic acid (294 mg, 4.9 mmole). The reaction mixture was heated to 40°C (thermometer Celsius) and stirred over night. The reaction mixture was diluted DHM, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 20% methanol in DHM to obtain 1.08 g (89,5%) tert-butyl ether (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]carbamino acid.

Stage 4

tert-Butyl ester (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]carbamino acid (1.08 g, 2,19 mmole), 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (1.19 g, is 2.41 mmole), X-Phos (105 mg, 0.2 mmole), bis(dibenzylideneacetone)palladium (63 mg, 0.1 mmole) and trikaliotis (931 mg, 4,39 mmole) was added into the flask to microwave radiation with a volume of 20 ml. Flask was closed and cleaned up. Was added water (3.5 ml) and n-butanol (14,0 ml) pipette and the flask was filled with nitrogen. The reaction mixture is agrawala to 115°C (thermometer Celsius) for 2.5 hours Range LCMS of the crude reaction mixture showed the expected fully protected product plus having lost one or both of the protective groups. The reaction mixture was filtered through celite and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 15% methanol in DHM. The fraction containing the target product with and without both VOS and acetate protective group together. The approximate yield of 2-(5-{tert-butoxycarbonyl-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid was 87%.

Stage 5

2-(5-{tert-Butoxycarbonyl-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ether acetic acid (1.5 g, of 1.92 mmole) was dissolved in 19 ml of dioxane. Dissolved monohydrate of lithium hydroxide (404 mg, 9,62 mmole) in 19 ml of water was added dropwise. The reaction mixture was heated at 50°C (thermometer Celsius) for 2 hours, the Reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was dissolved in 1,1,1,3,3,3-hexaplar-2-propanol (20 ml) and heated in a microwave reactor at 140°C. (degrees) for 30 minutes, the Reaction mixture koncentrirane and, and the residue was purified accelerated by chromatography using a gradient from 0% to 15% methanol in DHM. The residue was diluted DHM and concentrated again. Added isopropylacetate, and the mixture was heated in a water bath to obtain a solution. The solution was cooled to CT and left at RT overnight. The obtained solid was filtered and dried to obtain 185 mg of 6-tert-butyl - 8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it. The second batch of crystals led to obtain 88 mg of the product with a total yield 273 mg (22.3 per cent). MS: (M+H)+=638; tPL=235,0-238,0°C.1H NMR (400 MHz, DMSO-(d6) δ ppm 1.39 in (s, 9H) a 2.12 (s, 3 H) 2,19-to 2.41 (m, 8H) of 3.60 (s, 3H) 4,32-and 4.40 (m, 2H) 4,58-4,63 (m, 1H) 4,60-br4.61 (m, 1H) to 7.25 (d, J=8,59 Hz, 1H) 7,34-7,44 (m, 3H) 7,52 (s, 2H) 7,52-rate of 7.54 (m, 1H) 7,74 (dd, J=13,14, of 1.52 Hz, 1H) 7,87 (d, J=1,52 Hz, 1H) 8,04 (d, J=2,02 Hz, 1H).

Example 18

Stage 1

5-Bromo-2-nitropyridine (7.0 g, 35 mmol), (1-methoxy-2-methylpropyloxy)trimethylsilane (12.0 g, 69 mmol), bis(dibenzylideneacetone)palladium (1.0 g, 1.75 mmole) and zinc fluoride (1.8 g, of 17.5 mmole) was added in a round bottom flask and saturated with nitrogen. A pipette was added tert-butylphosphine (3.5 ml 1.0 M solution in toluene) and 140 ml of DMF. The reaction mixture was heated at 80°C (thermometer Celsius) during the night. The reaction mixture was diluted with ethyl acetate, was added water, and the layers based on separate treatment of the I. The organic layer was washed with water and saturated sodium chloride solution, dried and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 15% ethyl acetate in hexane to obtain 1.88 g (24%) of methyl ester of 2-methyl-2-(6-nitropyridine-3-yl)propionic acid.

Stage 2

Methyl ester of 2-methyl-2-(6-nitropyridine-3-yl)propionic acid (1.88 g, 8.4 mmole) was dissolved in THF and was added 200 mg of 10% palladium on coal. The reaction mixture was treated with hydrogen under a pressure of 50 psi for 5 h NMR showed that the recovery was incomplete. Was added palladium on coal, and the reaction mixture was treated with hydrogen again at 50 psi for several hours. The reaction mixture was filtered through celite and concentrated to obtain 1.5 g (92%) of methyl ester of 2-(6-aminopyridine-3-yl)-2-methylpropionic acid, which was used without further purification.

Stage 3

Methyl ester of 2-(6-aminopyridine-3-yl)-2-methylpropionic acid (1.5 g, 7.7 mmole), 3,5-dibromo-1-methyl-1H-pyridine-2-he (2,05 g, 7.7 mmole), cesium carbonate (7,53 g, 23.1 mmole), bis(dibenzylideneacetone)palladium (353 mg, 0,385 mmole), and Xanthos (446 mg, 0.77 mmole) was added in a round bottom flask, and the flask was filled with nitrogen. Added degassed dioxane (50 ml) pipette. The reaction mixture was heated at 100°C. A thermometer is this) during the night. The reaction mixture was filtered through celite and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 50% ethyl acetate in hexane to obtain 1.8 g (62%) of methyl ester of 2-[6-(5 - bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl]-2-methylpropionic acid.

Stage 4

Methyl ester 2-[6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl]-2-methylpropionic acid (1.8 g, 4.75 mmole), bis(pinacolato)diboron (3.0 g, 11.9 mmole), bis(dibenzylideneacetone)palladium (137 mg, 0.24 mmole), X-Phos (227 mg, value (0.475) mmole) and potassium acetate (1.4 g, 14,25 mmole) was added in a round bottom flask, and the flask was filled with argon. Added degassed dioxane (25 ml) and the reaction mixture was heated at 100°C (thermometer Celsius) in an argon atmosphere for 2.5 hours the Crude reaction mixture was filtered through celite, washed with dioxane and a small amount of DHM, and concentrated. The residue was treated with diethyl ether, filtered and dried to obtain 1,14 g (56%) of methyl ester of 2-methyl-2-{6-[1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydropyridines-3-ylamino]pyridine-3-yl}propionic acid which was used without further purification.

Stage 5

Methyl ester of 2-methyl-2- {6-[1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydropyridines-3-ylamino]pyridine-3-yl}propionic what Islami (417 mg, to 0.98 mmole), 2-bromo-b-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzaldehyde (327 mg, 0,81 mmole) and Pd(dppf)Cl2-DHM (34 mg, 0,041 mmole) was added to the vessel to microwave radiation with a volume of 20 ml Vessel was closed and filled with nitrogen. A pipette was added cesium carbonate (792 mg, 2,43 mmole), dissolved in 1 ml of water and dioxane (8 ml). The vessel was filled twice with nitrogen. The reaction mixture was heated at 100°C (thermometer Celsius) for 1 h, the Reaction mixture was cooled to CT. Added ethyl acetate and water and the layers were separated. The organic layer was washed with water, dried and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 7% methanol in 50/50 mixture of ethyl acetate and hexane to obtain 450 mg (89%) of methyl ester 2-(6-{5-[3-(b-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-formylphenyl]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid.

Stage 6

Methyl ester 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-formylphenyl]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid (450 mg, 0.72 mmole) was dissolved in 20 ml of a mixture 1:1 DHM and methanol. Was added sodium borohydride (68 mg, 1.8 mmole) and the reaction mixture was stirred at RT for 30 min the Reaction was suppressed saturated aqueous ammonium chloride. Added ethyl acetate, and the layers were separated. The organic layer is washed and saturated aqueous sodium bicarbonate, was dried and concentrated. The residue was purified accelerated by chromatography using a gradient from 0% to 7% methanol in 50/50 mixture of ethyl acetate and hexane to obtain 390 mg (87%) methyl ester 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid.

Stage 7

Methyl ester 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid (390 mg, of 0.62 mmole) was dissolved in dioxane (5 ml). Was added dropwise Monohydric of lithium hydroxide (78 mg, of 1.86 mmole) dissolved in 5 ml of water. The reaction mixture was heated at 50°C (thermometer Celsius) for three hours. The reaction mixture was concentrated, added ethyl acetate, and the layers were separated. The aqueous layer was acidified using 1 M Hcl. Added ethyl acetate, and the layers were separated. The organic layer was dried and concentrated. To the residue was added isopropylacetate, and the mixture was heated to obtain a solution, which was cooled to CT and kept at RT for several hours. The amorphous solid was filtered and dried to obtain 325 mg(86%) 2-(6-{5-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid. A portion of this material is PE is crystallizable from acetonitrile to obtain crystalline solid. MS: (M+H)+=612; tPL=218,0-220,0°C.1H NMR (300 MHz, DMSO-d6) δ ppm to 1.38 (s, 9H) of 1.46 (s, 6N) 3,17 (d, J=4,91 Hz, 1H) of 3.60 (s, 3H) 4,27 was 4.42 (m, 2H) 4,57-of 4.66 (m, 1H) 7,26 (d, J=8,69 Hz, 1H) 7,33 was 7.45 (m, 3H) rate of 7.54 (s, 2H) of 7.75 (d, J=13,22 Hz, 1H) 7,87 (s, 1H) 8,18 (d, J=2,27 Hz, 1H) 8,51 (d, J=2,64 Hz, 1H) at 8.60 (s, 1H) 8,65 (d, J=1.89 Hz, 1H) to 12.35 (br. s, 1H).

Example 19

2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-2-methylpropionic acid (50 mg, 0.08 mmole), morpholine (11 mg, 0.12 mmole), EDC (23 mg, 0.12 mmole) and DMAP (15 mg, 0.12 mmole) was dissolved in 1 ml DHM and stirred at RT under nitrogen atmosphere over night. Added ethyl acetate and a saturated aqueous solution of ammonium chloride, and the layers were separated. The organic layer was washed with diluted solution of ammonium chloride, then with saturated aqueous sodium bicarbonate solution, dried and concentrated. The crude product was purified accelerated by chromatography using a gradient from 0% to 10% methanol in DHM to obtain 40 mg (74%) of 6-tert-butyl-2-(3-{5-[5-(1,1-dimethyl-2-morpholine-4-yl-2-oxoethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it. MS: (M+N)+681.1H NMR (300 MHz, [chloroform-d) δ ppm was 1.43 (s, 9H) 1,53 (s, 6N) to 3.45 (br. s, 7H) 3,71 (s, 3H) 3,76 (br. s, 1H) to 4.41 (br. s, 2H) 6,85 (d, J=8,69 Hz, 1H) 7,31-the 7.43 (m, 3H) of 7.48-to 7.61 (m, 4H) of 7.96 (s, 1H) 8,15 (s, 1H) 8,30 (s, 1H) 8,69 (s, 1H).

Example 20

2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-the CSR-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}pyridine-3-yl)-N,N-dimethylethanamine. Received as described for compound I-21. MS: (M+H)+=639.1H NMR(300 MHz, DMSO-d6) δ ppm to 1.38 (s, 9H) of 1.41 (s, 6N) of 3.60 (s, 3H) 4,30-4,39 (m, 2H) 4,57 with 4.65 (m, 1H) 7,25 was 7.45 (m, 5H) 7,50 (d, J=at 7.55 Hz, 1H) 7,69-7,79 (m, 1H) 7,87 (d, J=1,51 Hz, 1H) of 8.06 (d, J=2,27 Hz, 1H) 8,51 (d, J=2,64 Hz, 1H) 8,64 (s, 1H) 8.66 (d, J=2,64 Hz, 1H).

Example 21

2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino} pyridine-3-yl)-N-(2-ethoxyethyl)isobutyramide. Received as described for compound I-21.MS:(M+H)+=683.1H NMR (300 MHz, DMSO-d6) δ ppm of 1.01 (t, J=6,99 Hz, 3H) to 1.38 (s, 9H) of 1.41 (s, 6N) a 3.15 (m, 2H) 3,59 (s, 3H) or 4.31-and 4.40 (m, 2H) 4,54 with 4.65 (m, 1H) 7,24 (d, J=8,69 Hz, 1 H) 7,29-7,56 (m, 6N) 7,70-7,79 (m, 1H) 7,84-7,89 (m, 1H) to 8.14 (s, 1H) 8,51 (d, J=2,64 Hz, 1H) 8,55 at 8.60 (m, 1H) 8,65 (d, J=2,27 Hz, 1H).

Example 22

6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it. In a round bottom flask of 250 ml was added 6-bromopyridin-3-ol (4,69 g 26,95 mmole) and tert-butyl methyl ether 3-iodisation-1-carboxylic acid (7,63 g 26,95 mmole) and Cs2CO3(of 12.26 g, 37,73 mmole) in DMF (10 ml) under stirring in argon atmosphere. The reaction mixture was heated at 90°C during the night. The reaction mixture was then poured into water (200 ml). The crude product was extracted with EtOAc (3X 50 ml). The organic extract was concentrated and purified accelerated chromatography using 10% EtOc in hexane to obtain the product 2,62 g (30% yield) of tert-butyl methyl ether 3-(6-bromopyridin-3-yloxy)azetidin-1-carboxylic acid as a light brown solid.

Example 23

To a solution of tert-butyl methyl ether 3-(6-bromopyridin-3-yloxy)azetidin-1-carboxylic acid (1.08 g, or 3.28 mmole) in DHM (30 ml), was added TFOC (10 ml). Leave the mixture was mixed at RT for 2 hours LCMS and TLC showed completion of reaction. Evaporated whole solvent and excess TFUCK. The remainder of the brown solid salt of 5-(azetidin-3-yloxy)-2-bromopyridine with triperoxonane acid (1.06 g, 95% yield) was used directly in the next stage.

Example 24

In the salt solution of 5-(azetidin-3-yloxy)-2-bromopyridine with triperoxonane acid (0.5 g, of 1.46 mmole) in dichloromethane (20 ml) was added an aqueous solution of formaldehyde (37%, of 0.58 ml, 7,29 mmole). Then carefully added Na(OAc)3BH (0,774 g, 3.65 mmole). The reaction mixture was stirred at RT in an argon atmosphere for 45 minutes the Reaction extinguished with water (30 ml) and then was extracted with dichloromethane (3×20 ml). The combined organic phases were washed intensively with a saturated solution of sodium chloride and water. Evaporation of the solvent resulted in the receipt of 2-bromo-5-(1-methylisatin-3 - yloxy)pyridine (0,37 g, yield 98%) which was pure enough for the next stage.

Example 25

To a solution of 2-bromo-5-(1-methylisatin-3-yloxy)pyridine (0,327 g of 1.32 mmole) and 3-amino-5-bromo-1-methyl-1H-p is ridin-2-it (0,321 g, was 1.58 mmole) in dioxane (5.5 ml) was added Cs2CO3(to 0.645 g, 1.98 mmole), Xanthos (0,153 g, 0,264 mmole) and the reaction mixture was passed argon for 15 minutes At the end was added Pd (OAc)2(0.03 g, 0,132 mmole). The reaction mixture was heated at 100°C in argon atmosphere for 3 hours TLC showed the disappearance of 2-bromo-5-(1-methylisatin-3-yloxy)pyridine. The reaction mixture was treated with water (30 ml) and was extracted with dichloromethane (3×20 ml). The organic phase was concentrated and applied on a column of silica gel for separation. Using 3-5% Meon in DHM received 5-bromo-1-methyl-3-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-1H-pyridine-2-it is in the form of a green solid (200 mg, 40% yield).

Example 26

Into the reaction flask for microwave radiation was added 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-chlorbenzoyl ether acetic acid (329 mg, 0,818 mmole), respiration (416 mg, 1,637 mmole), COAs (241 mg, 2,454 mmole) and X-phos (39 mg, 0,0818 mmole) and dioxane (4 ml). Missed argon for 15 min, and then added Pd(dba)2 (24 mg, 0,0409 mmole). The flask was sealed and heated at 60°C for 18 hours the Reaction mixture was then diluted with EtOAc (5 ml) and washed with NaHCO3(concentrated solution) (1X10 ml) and water (10 ml). The organic phase is then concentrated and purified on a column of silica gel using 25% EtOAc in Hex with recip is of 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid as a yellow oil (330 mg, 81%).

Example 27

Into the reaction flask for microwave radiation was added 5-bromo-1-methyl-3-[5-(1-methylisatin-3-yloxy)pyridine-2-ylamino]-1H-pyridine-2-he (74 mg, 0,2024 mmole) and 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid (100 mg, 0,2024 mmole) with K3RHO4(86 mg, 0,4048 mg), X-phos (9.6 mg, 0,02024 mmole) in n-butanol (2.5 ml) and water (0.5 ml). Missed argon for 15 min, and then added Pd(dba)2 (6 mg, 0,01012 mmole). The flask was closed and the reaction mixture was heated to 100°C. the Reaction mixture was stirred at this temperature for 2 hours LCMS showed completion of the condensation reaction, and it's a mixture of the final product and its acetate. The red reaction mixture was diluted Meon (5 ml). Solution was added LiOH monohydrate (84 mg, 10 equiv.) in 1 ml of water, and leaving the reaction mixture was mixed at RT for 3 hours LCMS showed conducting hydrolysis of the acetate. Meon then removed on a rotary evaporator. The residue was then diluted with water (10 ml) and was extracted with dichloromethane (3×10 ml). The combined organic phases were concentrated and purified on a column of silica gel using 5-10% Meon mixture in 1/1 EtOAc/hexane to obtain 80 mg of the product. Recrystallized from tOr obtaining 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methylisatin-3-yl) - Rev. XI)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it is in the form of light brown crystals, 60 mg tPL: >300°C. MS (E-spray): 611 (M+1); H NMR (l3, 400 MHz): δ 1,4 (s, S, tert-Bu), and 2.4 (s, 3H, N-CH2), 3,1 (m, 2H, CH2), and 3.8 (m. 2H, CH3), and 3.7 (s, 3H, N-CH3), and 4.4 (b, 2H, CH2), 4,7 (t, 1H, CH), 6,8 (d,1H), and 7.1 (dd, 1H), 7,35 (m, 2H), 7,55 (m, 4H), of 7.75 (d, 1H), 7,8 (br, 1H, NH), and 8.3 (d, 1H),8.55(d, 1H).

Example 28

Scheme I

This example illustrates the synthesis of 6-tert-butyl-2-{3-[5-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it.

Stage 1. Obtaining 1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-(2-hydroxyethyl)thiourea

To a solution of 5-bromo-3-amino-1-methyl-2-pyridone (500 mg, 2,46 mmole) in chloroform (12 ml) was added a saturated aqueous solution of sodium bicarbonate (12 ml). To intensively stirred mixture was added dropwise thiophosgene (0.2 ml, 2.7 mmole). The mixture was stirred for 1 hour, and then transferred into a separating funnel. The chloroform phase was collected and the aqueous phase was again extracted with methylene chloride (10 ml). The organic phases were combined in a round bottom flask with a volume of 100 ml To quickly stir the solution slowly dropwise added ethanolamine (0.16 ml, 2.7 mmole). The material was stirred for 1.5 hours, and the precipitated product collected by filtration. The solid was dried in a vacuum oven, obtaining the target product as a bright white-yellow solid (515 mg). (M-is) -=304 / 306 m/e.

Stage 2. Getting 5-bromo-3-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-1H-pyridine-2-it

To a solution of 1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-(2-hydroxyethyl)thiourea (306 mg, 1 mmol) in tetrahydrofuran (8 ml) was added 2N aqueous solution of sodium hydroxide (1.25 ml, 2.5 mmole). Under vigorous stirring was added dropwise a solution of para-toluensulfonate (210 mg, 1.1 mmole) in tetrahydrofuran (4 ml) for 2 minutes. The material was stirred for 1 hour, and then the solvent and volatile impurities were removed on a rotary evaporator. The residue was transferred into ethyl acetate (25 ml) and water (15 ml), and stirred in a separating funnel. The organic phase was collected, and the aqueous phase was again extracted with ethyl acetate (2×20 ml). The organic phases were combined, dried with magnesium sulfate, was filtered and removed. The crude product was purified preparative TLC was suirable 7% methanol in methylene chloride to obtain the desired product as a light green-gray solid (243 mg). (M+N)+=272/274 m/e.

Stage 3. Getting 6-tert-butyl-2-{3-[5-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it

A mixture of 5-bromo-3-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-1H-pyridine-2-she (111 mg, 0,41 mmole), 2-(6-tert-butyl-8-fluoro-1-oxo-1H-CFT is Latin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid (201 mg, 0,41 mmole), X-Phos (15 mg, 0,033 mmole) and trisnantoro potassium phosphate (174 mg, of 0.82 mmole) was transferred into a mixture of n-butanol/water (4:1, 8,1 ml) and was evacuated degassing. Added bis(dibenzylideneacetone)palladium(0) (10 mg, 0.02 mmole) and the mixture was evacuated degassing, and then was heated to 100°C in argon atmosphere. After 3 hours, the material was cooled to room temperature. The material was transferred to a dichloromethane (40 ml) and water (40 ml), and shaken in a separating funnel. The dichloromethane phase was collected and washed with a saturated solution of sodium chloride (40 ml). The aqueous phase was again extracted with methylene chloride (2 X 30 ml) and the organic phases were combined, dried with magnesium sulfate, was filtered and removed. The remaining n-butanol was removed on the pump/rotary evaporator. Chromatography (preparative TLC [3 plates], 11% methanol/dichloromethane - methanol containing 5% triethylamine) resulted in the receipt of semifinished product. The material was chromatographically second time (preparative TLC [2 plates] using 12% methanol/dichloromethane-methanol containing 5% triethylamine), which resulted in the receipt specified in the connection header in the form of a whitish crystalline solid (25 mg). (M+N)+=518 m/e;1H NMR (300 MHz, DMSO-d6) δ ppm to 1.38 (s, 9 H) to 3.56 (s, 3 H) 3,69-a 3.83 (m, 2 H) of 4.25 (t, J=8.5 Hz, 2H) 4,29 is 4.36 (m, 2H) 4,65 (m, 1H) 7,35-rate of 7.54 (m, 5H) 7,74 (dd, J=13.3-inch, 1.7 Hz, 1H) 7,87 (d. J=1.7 Hz, 1H) 8,49 (d, J=2.6 Hz, 1H).

When the EP 29

Stage 1

tert-Butyl ester (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-(5-formylpyridine-2-yl)carbamino acid (500 mg, 1,22 mmole), ethanamine (6,12 ml of 2.0 M solution in THF), triacetoxyborohydride sodium (649 mg, a 3.06 mmole) and acetic acid (147 mg, of 2.45 mmole) was added into the flask to microwave radiation with a volume of 20 ml Vessel was closed and heated in a sand bath at 40°C (thermometer Celsius) throughout the night. Analysis of TLC and LCMS showed incomplete termination of the reaction. Was added 6 ml of ethanamine into the flask, and the reaction mixture was heated again at 40°C (thermometer Celsius) during the night. The reaction mixture was diluted DHM and washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified accelerated chromatography using 10% methanol in DHM to obtain 340 mg (63.5 per cent) of tert-butyl methyl ether (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-(5-ethylaminomethyl-2-yl)carbamino acid.

Stage 2

2-{5-[tert-Butoxycarbonyl-(5-ethylaminomethyl-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid was obtained by the procedure described for obtaining compounds 1-15, except what tert-butyl ester (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-(5-ethylaminomethyl-2-yl)carbamino to the slots used instead of tert-butyl methyl ether (5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]carbamino acid. The product was purified accelerated by chromatography using a gradient from 0% to 20% methanol in DHM to obtain 220 mg (about 78%) of target compound with and without the VOS and acetate protective groups.

Stage 3

6-tert-Butyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1 is received, using the procedure described for obtaining compounds 1-15, except that the starting material was 2-{5-[tert-butoxycarbonyl-(5-ethylaminomethyl-2-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid instead of 2-(5-{tert-butoxycarbonyl-[5-(4-methylpiperazin-1-ylmethyl)pyridine-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid. The same methods purification and crystallization was used to obtain 27 mg (15.3%) and end connections. MS: (M+H)+=583; tPL=265,0-268,0°C.1H NMR (400 MHz, DMSO-d6) δ ppm of 1.01 (t, J=7,07 Hz, 3H) 1,35-of 1.41 (m, 9H) 3,54-3,63 (m, 5H) 4,37 (br. s., 2H) 4,55 with 4.64 (m, 1H) 7,24 (d, J=8,59 Hz, 1H) of 7.36 (d, J=2,53 Hz, 1H) 7,38-7,44 (m, 2H) 7,50 (d, J=7,58 Hz, 1H) 7,52-7,58 (m, 1H) 7,70-to 7.77 (m, 1H) 7,87 (d, J=2,02 Hz, 1H) 8,10 (d, J=2,02 Hz, 1H) 8,51 (d, J=2,53 Hz, 1H) 8,54 (s, 1H) 8,63 (d, J=2,53 Hz, 1H).

Example 30. 6-tert-Butyl-2-{3-[5-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-Talas the n-1-it

Stage 1

Obtaining 1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-(3-hydroxypropyl)thiourea

The receipt of this material was carried out similarly to the method of example 28, step 1, but substituting 3-amino-1-propanol on ethanolamine.

Stage 2

Getting 5-bromo-3-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-1H-pyridine-2-it

The receipt of this material was carried out similarly to the method of example 28,step 2.

Stage 3

Getting 6-tert-butyl-2-{3-[5-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-it

Example 31

A mixture of 5-bromo-3-(5,6-dihydro-4H-1,3-oxazin-2-ylamino)-1-methylpyridin-2(1H)-she (180 mg, 0,63 mmole), 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid (300 mg, and 0.61 mmole), X-Phos (24 mg, 0.05 mmole) and trisnantoro potassium phosphate (260 mg, 1,22 mmole) was transferred into a mixture of n-butanol/water (4:1, 8,1 ml) and was degirolami in vacuum. Added bis(dibenzylideneacetone)palladium(0) (15 mg, 0.026 mmole) and the mixture was degirolami in vacuum, and then heated to 100°C in argon atmosphere. After 50 minutes, the material was cooled to room temperature. The mixture was transferred to a rotary evaporator/pump, and dissolve Itel removed. The material was transferred into ethyl acetate (40 ml) and water (40 ml), and shaken in a separating funnel. The organic phase was collected, and the aqueous phase was again extracted with ethyl acetate (2×30 ml). The organic phases were combined, dried with magnesium sulfate, was filtered and removed. Chromatography (preparative TLC: 38 cm × 20 cm large plate - inflicted 20 cm basis and spend up to about 30 cm in height [3 plates], elwira 12% methanol/dichloromethane - methanol contained 5% triethylamine]) to give 55 mg of the semifinished product. The material was treated with hot dichloromethane in hexane to obtain specified in the connection header in the form of a whitish crystalline solid (44 mg). (M+N)+=532 m/e;1H NMR (300 MHz, chloroform-d) δ ppm was 1.43 (s, 9H) 1,86-of 1.94 (m, 2H) 3,44 (t, 7-5,8 Hz, 2H) 3,66 (s, 3H) 3.75 to 3,86 (m, 1H) 4.26 deaths (t, J=5.5 Hz, 2H) 4,32-4,39 (m, 2H) 7,33 (dd, J=6,04, 3,40 Hz, 1H) 7,37 (d, 7=of 2.27 Hz, 1H) of 7.48-7,52 (m, 2H) 7,51-7,53 (m, 1H) of 7.55 (s, 1H) of 8.27 (d, J=2.6 Hz, 1H) 8,32 (d, J=2.3 Hz, 1H).

Example 32

To a solution of 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{ 1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it (35303-138) (240 mg, 385 mcmole, equiv.: 1,00) was added m-SRV (83 mg, at ~77% to about 1 mmole, 1.0 equiv). The reaction mixture was stirred over night at RT. The mixture was diluted with methylene chloride and washed with 1.0 N NaOH solution. The organic phase was washed with a saturated solution of sodium chloride,dried with sodium sulfate, was filtered and concentrated to obtain a solid substance, mixed with a certain quantity of dark-green material. Was dissolved in minimum amount of methanol, diluted with methylene chloride and applied to the column. The accelerated cleanup chromatography (pure methylene chloride to 90:10:0.1 methylene chloride:methanol:ammonium hydroxide) yielded 85 mg of the pure product after removal of the solvent. LCMS M+1=643).

Example 33

This example illustrates the synthesis of(+/-)-6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it".

Stage 1.

Getting(+/-)-1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-yl)-3-(3-hydroxy-1-methylpropyl)thiourea

The receipt of this material was carried out similarly to the method of example 28, step 1, but substituting (+/-)-3-aminobutane-1-ol on ethanolamine.

Stage 2

Receive (+/-)-5-bromo-1-methyl-3-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1H-pyridine-2-it

The receipt of this material was carried out similarly to the method of example 28,step 2.

Stage 3

Receive (+/-)-6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-phthalazine-1-it

Por the measures 34

The receipt of this material was carried out similarly to the method of example 29, step 3. (M+N)+=546 m/e;1H NMR (400 MHz, chloroform-d) δ ppm to 1.21 (d, J=6.6 Hz, 3H) of 1.42 (s, 9H) 1,53-to 1.67 (m, 1H) 1,89-to 1.98 (m, 1H) 3,51-3,59 (m, 1H) 3,65 (s, 3H) 4,15-to 4.23 (m, 1H) 4.26 deaths-4,32 (m, 1H) to 4.38 (br s, 2H) 7,32-7,51 (m, 1H) 7,44 (d, J=2,53 Hz, 1H) of 7.48-7,53 (m, 3H) at 7.55 (s, 1H) 7,56-of 7.70 (m, 1H) 8,28 (d, J=2,02 Hz, 1H) to 8.40 (d, J=2,02 Hz, 1H).

Example 35

In a flame-dried resealable reaction flask in an argon atmosphere was added 2-(6-chloropyridin-3-yl)propan-2-ol (750 mg, 4,375 mmole), 2-(dicyclohexylphosphino)biphenyl (307 mg, 0,875 mmole), and then was added LiN(TMS)2(1M in THF, 13.5 ml, 13.5 mmole). The flask was closed and heated at 90°C for 18 hours. The dark reaction mixture was then diluted with EtOAc (10 ml). Was added HCl (2M) (10 drops) with stirring. The reaction mixture was then concentrated and applied to a separation column, ISCO, and suirable 5% Meon/(1/1 EtOAC/hexane) to give 2-(6-aminopyridine-3-yl)propan-2-ol as a solid (635 mg, yield 95%).

Example 36

In a flame-dried reaction flask was dissolved 2-(6-aminopyridine-3-yl)propan-2-ol (530 mg, 3,484 mmole) in anhydrous dioxane (13 ml). Then was added 3,5-dibromo-1-methyl-1H-pyridine-2-he (1,022 g, a 3.83 mmole), Cs2CO3(3.4 g, 10,45 mmole) and Xanthos (0.2 g, 0,3482 mmole).

Missed argon for 15 is in then added Pd(OAc)2(39 mg, 0,1742 mmole). The flask was sealed and heated to 120°C. the Reaction mixture is maintained at this temperature for 6 hours the Reaction mixture was then diluted with EtOAc (10 ml) and was filtered through celite. The filter residue washed with EtOAc (3×10 ml). The combined filtrates were concentrated and purified by dividing ISCO column using 5-10% Meon mixture in 1/1 EtOAC/hexane to obtain 5-bromo-3-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-1H-pyridine-2-she (710 mg, yield 60%) as a green solid.

Example 37

Into the reaction flask for microwave radiation was added 5-bromo-3-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-1 H-pyridin-2-he (68,4 mg, 0,2024 mmole) and boronat (100 mg, 0,2024 mmole) together with K2RHO4(86 mg, 0,4048 mg), Xphos (9.6 mg, 0,02024 mmole) in n-butanol (2.5 ml) and water (0.5 ml). Missed argon for 15 min, and then added Pd(dba)2(6 mg, 0,01012 mmole). The flask was closed and the reaction mixture was heated to 100°C. the Reaction mixture is maintained at this temperature for 2 hours LCMS showed completion of the condensation reaction, and received a mixture of the final product and its acetate. The red reaction mixture was diluted Meon (5 ml). Solution was added LiOH monohydrate (84 mg, 10 equiv.) in 1 ml of water, and the reaction mixture was stirred at RT for 3 hours LCMS showed the end of the s hydrolysis of the acetate. Meon then removed on a rotary evaporator. The residue was then diluted with water (10 ml) and was extracted with dichloromethane (3×10 ml). The combined organic phases were concentrated and purified on a column of silica gel using 5-10% Meon mixture in 1/1 EtOAc/hexane to obtain 60 mg of the product. Recrystallization from Egothor and hexane to obtain 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-it is in the form of a light brown crystal resulted in the receipt of 40 mg tPL: 200,0-205, 0°C. MS (E-spray): 584 (M+1);1H NMR (l3, 400 MHz): δ of 1.4 (s, 9H, tert-Bu) of 1.55 (s, 6H, 2Me), and 3.7 (s, 3H, N-CH2), and 4.4 (d, 2H, O-CH2), 6,8 (d, 1H), 7,35 (dd, 1H), and 7.4 (d, 1H), 7.5 to about 7.6 (m, 4H), 7,9 (br, 1H, NH), and 8.3 (d, 1H), 8,35 (dd, 1H), and 8.7 (d, 1H).

Example 38. Ethyl ester of 2-(3-bromophenyl)-3-(3-tert-butylbenzylamine)acrylic acid

Benzyl ether (3-bromophenyl)acetic acid (1 g, 4,12 mmole) was dissolved in ethyl formate (8 ml, 99 mmol). Was added sodium hydride (60%, 660 mg of 16.5 mmole). After stirring overnight the product extinguished 2 M aq. a solution of Hcl. The product was separated between ethyl acetate and water. An ethyl acetate layer was washed with water, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum.

This material (0.65 g) and 3-tert-butylaniline (0,37 ml, 2,48 mmole) was stirred in 1 ml of ethanol for 18 hours. The mixture was concentrated in vacuum and purified accelerated chromatography (gradient elution from 5 to 20% ethyl acetate/hexane) to give the ethyl ester of 2-(3-bromophenyl)-3-(3-tert-butylbenzylamine)acrylic acid (0.5 mg). MS (ESI) 402 (M+H) .

Example 39. 3-(3-Bromophenyl)-7-tert-butyl-1H-quinoline-4-one

To the ethyl ether of 2-(3-bromophenyl)-3-(3-tert-butylbenzylamine)acrylic acid (151 mg, 0,388 mmole) was added 10 g of polyphosphoric acid. The resulting mixture was heated at 140°C for 90 minutes. Added 80 ml of water. The mixture was stirred for 40 minutes. The precipitate was filtered off, washed with water and dried in air for 3 days with 3-(3-bromophenyl)-7-tert-butyl-1H-quinoline-4-it (123 mg, 0,345 mmole). MS (ESI) 356 (M+N)+.

Example 40. 7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]that dioxaborolan-2-yl)phenyl]-1H-quinoline-4-one

3-(3-Bromophenyl)-7-tert-butyl-1H-quinoline-4-one (119 mg, 0,334 mmole), bis(pinacolato)diboron (102 mg, 0,401 mmole) and potassium acetate (98 mg, 1.0 mmol) were placed in a sealable vessel with 2 ml of DMSO. Through a mixture missed argon for 1 minute. Was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (8.0 mg, 0,0098 mmole). After the mixture was let in argon for one minute, and the lid tightly closed. The resulting mixture was heated at 80°C for 18 h the V to the separation of the ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 7-tert-butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-1H-quinoline-4-it (77 mg, 0,19 mmole). MS (ESI) 404,1 (M+N)+.

Example 41. Obtain compound II-1: 7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1H-quinoline-4-one

A solution of 5-bromo-1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-it (19 mg, 0,050 mmole), 7-tert-butyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-1H-quinoline-4-it (20 mg, 0.05 mmole), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0,0052 mmole) and sodium carbonate (16 mg, 0.15 mmole) in 2 ml of 1,2-dimethoxyethane and 1 ml of water was subjected to microwave radiation at 170°C for 12.5 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 7-tert-butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1H-quinoline-4-it (5,7 mg, 0,0085 mmole). MS (ESI) 590,1 (M+N)+.

Prima is 42. Ethyl ester of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid

Benzyl ester of (3-bromo-2-were)acetic acid (421 mg, 1,32 mmole) was dissolved in ethyl formate (2.5 ml, 31 mmol). Was added sodium hydride (95%, 67 mg, 2.6 mmole). After stirring for 30 minutes, the mixture was suppressed 1M aq. a solution of Hcl. The product was separated between ethyl acetate and water. An ethyl acetate layer was washed with water, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum.

Part of this material and N,N-xylene-1,3-diamine (96 mg, 0.70 to mmole) was stirred in 1 ml of ethanol for 18 hours. The mixture was concentrated in vacuum and purified accelerated chromatography (gradient elution from 5 to 20% ethyl acetate/hexane) to give the ethyl ester of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid (164 mg, 0,407 mmole). MS (ESI) 405,0 (M+N)+.

Example 43. 3-(3-Bromo-2-were)-7-dimethylamino-1H-quinoline-4-one

To the ethyl ether of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid (100 mg, 0,248 mmole) was added 4 g of polyphosphoric acid. The mixture was stirred at 140°C for 10 minutes. Added 50 ml of water, and the mixture was stirred. The precipitate was filtered and washed with water. The filtrate was extracted with what astora 10% methanol/dichloromethane. The organic layer was dried with anhydrous magnesium sulfate and concentrated in vacuum. The resulting residue was combined with the precipitate and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 3-(3-bromo-2-were)-7-dimethylamino-1H-quinoline-4-it (22 mg, 0,062 mmole). MS (ESI) 357,0 (M+N)+.

Example 44. 1-Methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)-1H-pyridine-2-he

5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-he (1,00 g, to 2.55 mmole), bis(pinacolato)diboron (1,94 g of 7.64 mmole), potassium acetate (750 mg, of 7.64 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (121 mg, 0,254 mmole) and bis(dibenzylidineacetone)palladium(0) (73 mg, of 0.13 mmole) was dissolved in 15 ml of degassed 1,4-dioxane. The upper space of the vessel was evacuated and filled with argon 5 times. The mixture was heated at 110°C for 3 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 8% methanol/dichloromethane) to give 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-it (0,798 g, is 1.81 mmole). MS (ESI) 441,2 (M+H)+.

Example 45. Getting connection 11-2: 7-Dimethylamino-3-('2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1H-quinoline-4-one

To methyl 3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (27 mg, 0,062 mmole), 3-(3-bromo-2-were)-7-dimethylamino-1H-quinoline-4-ONU (22 mg, 0,062 mmole), potassium phosphate (26 mg, 0.12 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (1.7 mg, 0,0036 mmole) and bis(dibenzylideneacetone)palladium(0) (1.0 mg, 0,0018 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 1 hour. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 7-dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1H-quinoline-4-it (14 mg, 0,024 mmole). MS (ESI) to $ 591.1 (M+N)+.

Example 46. 6-Fluoro-3,4-dihydro-2H-isoquinoline-1-he

To a solution of triphosgene of 0.85 g, 2.9 mmole) in DHM (10 ml) was added a solution of 3-fortunetelling (1 g, 7.2 mmole) in DHM (5 ml) and then dropwise obavljale of tea (1.4 g, 14.4 mmole) at room temperature. The resulting solution was stirred for 2 h, then was filtered through a layer of celite and washed DHM. The filtrate is then added to the suspension ll3(3.8 g, of 28.8 mmole) in DHM (25 ml) at 0°C. the resulting solution was left to warm to CT and was stirred for 16. The reaction extinguished with water (15 ml) and then 10% Hcl (5 ml). The organic layer was collected by separation of the phases, and the aqueous layer was extracted with DHM. Merged layers DHM washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried MgSO4concentrated in vacuo and purified accelerated by chromatography (50% ethyl acetate/hexane) to give 6-fluoro-3,4-dihydro-2H-isoquinoline-1-she (0.75 g, 63% yield). MS (ESI) 166,1 (M+N)+.

Example 47. 6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he

6-Fluoro-3,4-dihydro-2H-isoquinoline-1-he (1.56 g, 9,45 mmole) were placed in a sealable vessel with 25 ml of 33% dimethylamine in ethanol. The mixture was heated at 150°C for 7 hours. The resulting solution was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated by chromatography (elution with ethyl acetate) to give 6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-it (787 mg, 4,14 mmole). MS (ESI) 191,1 (M+N)+ .

Example 48. 2-(3-Bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he

6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (762 mg, 4,01 mmole), copper iodide (153 mg, 0,802 mmole) and potassium carbonate (554 mg, 4,01 mmole) were placed in a sealable vessel. Added 6 ml of DMSO and 1,3-dibromobenzene with (1.89 g, 8,01 mmole). Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (153 mg, 0,802 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with dichloromethane and filtered through a layer of celite. The filtrate was divided between dichloromethane and 5% aq. the ammonium hydroxide solution. The dichloromethane layer was dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 100% ethyl acetate/hexane) to give 2-(3-bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-it (939 mg, of 2.72 mmole). MS (ESI) 345,0 (M+N)+.

Example 49. 6-Dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3,4-dihydro-2H-isoquinoline-1-he

2-(3-Bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (163 mg, 0,472 mmole), bis(pinacolato)diboron (144 mg, 0,567 mmole) and potassium acetate (138 mg, of 1.42 mmole) were placed in a sealable vessel with 2 ml of DMSO. Through a mixture missed argon for 1 minute. obavljale [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (12 mg, 0.015 mmole). Argon continued to pass through the mixture for one minute, and the lid tightly closed. The mixture was heated at 80°C for 18 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (30% ethyl acetate/hexane) to give 6-dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3,4-dihydro-2H-isoquinoline-1-she (137 mg, 0,349 mmole). MS (ESI) 393,2 (M+N)+.

Example 50. Obtaining the compounds I-1*: 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-he (67 mg, 0.17-mmole), 6-dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3,4-dihydro-2H-isoquinoline-1-he (67 mg, 0.17-mmole), tetrakis(triphenylphosphine)palladium(0) (20 mg, of 0.017 mmole) and sodium carbonate (54 mg, of 0.51 mmole) in 2 ml of 1,2-dimethoxyethane and 1 ml of water was heated at 170°C for 12.5 minutes in the microwave. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatographie the (gradient elution from 2 to 5% methanol/dichloromethane) to give 6-dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (40 mg, 0,069 mmole). MS (ESI) 579,2 (M+N)+.

Example 51. 6-Fluoro-2H-isoquinoline-1-he

6-Fluoro-3,4-dihydro-2H-isoquinoline-1-he (149 mg, of 0.903 mmole) was dissolved in 3 ml of 1,4-dioxane. After the solution was passed argon for 1 minute, and was added 2,3-dichloro-5,6-dicyano-n-benzoquinone (205 mg, of 0.903 mmole). The mixture was heated at 100°C for 24 hours. The mixture was separated between ethyl acetate and 1M aq. the sodium hydroxide solution. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated by chromatography (50% ethyl acetate/hexane) to give 6-fluoro-2H-isoquinoline-1-she (54 mg, of 0.33 mmole). MS (ESI) 164,1 (M+N)+.

Example 52. 6-Dimethylamino-2H-isoquinoline-1-he

6-Fluoro-2H-isoquinoline-1-he (54 mg, of 0.33 mmole) were placed in a sealable vessel with 5 ml of 33% dimethylamine in ethanol. The mixture was heated at 150°C for 3.5 hours. The mixture was concentrated in vacuum and purified accelerated chromatography (gradient elution from 50 to 100% ethyl acetate/hexane) to give 6-dimethylamino-2H-isoquinoline-1-it (39 mg, of 0.21 mmole). MS (ESI) 189,1 (M+N)+.

Example 53. 2-(3-Bromophenyl)-6-dimethylamino-2H-isoquinoline-1-he

6-Dimethylamino-2H-isoquinoline-1-he (39 mg, of 0.21 mmole), copper iodide (8.0 mg, 0,041 mmole) and potassium carbonate (29 mg, 0.1 mmole) was placed in a sealable vessel. Was added 3 ml of DMSO and 1,3-dibromobenzyl (98 mg, at 0.42 mmole). Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 5 hours. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (25% ethyl acetate/hexane) to give 2-(3-bromophenyl)-6-dimethylamino-2H-isoquinoline-1-she (45 mg, of 0.13 mmole). MS (ESI) 345,0 (M+N)+.

Example 54. Obtain compound III-1: 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (58 mg, of 0.13 mmole), 2-(3-bromophenyl)-6-dimethylamino-2H-isoquinoline-1-ONU (45 mg, of 0.13 mmole), potassium phosphate (56 mg, 0.26 per mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (3.7 mg, 0,0078 mmole) and bis(dibenzylideneacetone)palladium(0) (2.2 mg, 0,0038 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 2 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of chloride n is sodium, was dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 6-dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-she (45 mg, 0,078 mmole). MS (ESI) 577,1 (M+H)+.

Example 55. 1,3-Dibromo-2-bromeilles

2,6-Dibromsalan (2.50 g, 10.0 mmol) was dissolved in 20 ml of carbon tetrachloride. Was added N-bromosuccinimide (of 1.87 g, 10.5 mmole), followed by benzoyl peroxide (73 mg, 0.30 mmole). The resulting mixture was heated at the boil under reflux for 90 minutes. Added 50 ml of petroleum ether. The mixture was filtered and concentrated in vacuum to obtain 1,3-dibromo-2-bromoethylene (3,52 g, 10.7 mmole).1H NMR (300 MHz, CDCl3) δ a 4.83 (s, 3H), 7,02 (t, J=8 Hz, 1H) and at 7.55 (d, J=8 Hz, 2H).

Example 56. 2,6-Dibromopropyl ether acetic acid

To 1,3-dibromo-2-bromeilles (3,35 g, 10.2 mmole) was added potassium acetate (4,00 g and 40.8 mmole) and 25 ml of N,N-dimethylformamide. The mixture was heated at 70°C for 20 minutes. The resulting mixture was divided between water and ethyl acetate. An ethyl acetate layer was washed with water, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient suirou is of from 0 to 5% ethyl acetate-hexane) to give 2,6-dibromobenzyl ether acetic acid (1.92 g, 6,23 mmole).1H NMR (300 MHz, CDCl3) δ a 2.12 (s, 3H), 5,42 (s, 2H), was 7.08 (t, J=8gts, 1H) and 7,58 (d, J=8 Hz, 2H).

Example 57. 2-Bromo-6-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)benzyl ester of acetic acid

6-Dimethylamino-2H-isoquinoline-1-he (50 mg, of 0.27 mmole), 2,6-dibromopropyl ether acetic acid (164 mg, 532 mmole), copper iodide (10 mg, 0,053 mmole) and potassium carbonate (37 mg, of 0.27 mmole) were placed in a sealable vessel. Was added 3 ml of DMSO. Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 5 hours. The mixture was separated between ethyl acetate and water.

The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 30 to 40% ethyl acetate/hexane) to give 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)benzyl ester of acetic acid (48 mg, 0.12 mmole). MS (ESI) 417,0 (M+H)+.

Example 58. 2-(6-Dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzyl ether acetic acid

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (43 mg, 0,097 mmole), 2-bromo-6-(6-dimethylamino-1-oxo-1H-from inolin-2-yl)benzyl ether acetic acid (40 mg, 0,097 mmole), potassium phosphate (41 mg, 0,19 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (2.7 mg, 0,0057 mmole) and bis(dibenzylideneacetone)palladium(0) (1.6 mg, 0,0028 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 2-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6 - dihydropyridines-3-yl}benzyl ether acetic acid (33 mg, 0,051 mmole). MS (ESI) 649,2 (M+N)+.

Example 59. Obtain compound III-3: 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he

To 2-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzyl ether acetic acid (29 mg, of 0.045 mmole) in 2 ml of tetrahydrofuran, 1 ml methanol and 1 ml of water was added 1M aq. a solution of lithium hydroxide (0,13 ml of 0.13 mmole). After stirring within 18 hours, the mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 6-dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it (20 mg, 0,033 mmole). MS (ESI) 607,2 (M+N)+.

Example 60. 2-('3-Bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-he

6-Dimethylamino-2H-isoquinoline-1-he (50 mg, of 0.27 mmole), copper iodide (10 mg, 0,053 mmole) and potassium carbonate (37 mg, of 0.27 mmole) were placed in a sealable vessel. Was added 3 ml of DMSO and 2,6-dibromsalan (133 mg, 0,532 mmole). Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 5 hours. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (30% ethyl acetate/hexane) to give 2-(3-bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-it (43 mg, 0.12 mmole). MS (ESI) 357 (M+N)+.

Example 61. Obtain compound III-2: 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (69 mg, 0.16 mmole), 2-(3-bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-ONU (36 mg, 0.10 mmole), potassium phosphate (43 mg, of 0.20 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (2,9 mg, 0,0061 mmole) and bis(dibenzylideneacetone)palladium(0) (1.7 mg, 0,0030 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 10% methanol/dichloromethane) to obtain the b-dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-she (46 mg, 0,078 mmole). MS (ESI) to $ 591.1 (M+N)+.

Example 62. 2-(3-Bromo-2-were)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he

6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (150 mg, 0,789 mmole), copper iodide (30 mg, 0.16 mmole) and potassium carbonate (109 mg, 0,789 mmole) were placed in a sealable vessel. Was added 3 ml of DMSO and 2,6-dibromochloro (395 mg, was 1.58 mmole). Through a mixture missed argon during the course is 2 minutes and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (30 mg, 0.16 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with dichloromethane and filtered through a layer of celite. The filtrate was divided between dichloromethane and 5% aq. the ammonium hydroxide solution. The dichloromethane layer was washed with a saturated solution of sodium chloride. The combined aqueous layers were washed with dichloromethane. The combined dichloromethane layers were dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 2-(3-bromo-2-were)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-she (181 mg, 0,504 mmole). MS (ESI) 361,1 (M+N)+.

Example 63. Receiving compound I-3*: 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (77 mg, of 0.18 mmole), 2-(3-bromo-2-were)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-ONU (63 mg, of 0.18 mmole), potassium phosphate (74 mg, 0.35 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (5.0 mg, 0,010 mmole) and bis(dibenzylideneacetone)palladium(0) (3.0 mg, 0,0052 mmole) was added 4 ml of Tegaserod is authorized a mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 6-dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (33 mg, 0,056 mmole). MS (ESI) 593,3 (M+N)+.

Example 64. 2-Bromo-6-(6-dimethylamino-1-oxo-3.4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid

6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (150 mg, 0,789 mmole), 2,6-dibromopropyl ether acetic acid (487 mg, was 1.58 mmole), copper iodide (30 mg, 0.16 mmole) and potassium carbonate (109 mg, 0,789 mmole) were placed in a sealable vessel. Was added 3 ml of DMSO. Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (30 mg, 0.16 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with dichloromethane and filtered through a layer of celite. The filtrate was divided between dichloromethane and 5% aq. the ammonium hydroxide solution. The dichloromethane layer was dried without the one magnesium sulfate, concentrated in vacuo and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (93 mg, 0.22 mmole). MS(ESI)417,1 (M+H)+.

Example 65. Getting connection 1-2*: 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3.4-dihydro-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (60 mg, of 0.14 mmole), 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ether acetic acid (46 mg, of 0.11 mmole), the potassium phosphate (47 mg, 0.22 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (3.1 mg, 0,0065 mmole) and bis(dibenzylideneacetone)palladium(0) (1.9 mg, 0033 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon to 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 2 ml of tetrahydrofuran, 1 ml methanol and 1 ml of water. Added 1M aq. a solution of lithium hydroxide (0,33 is l, of 0.33 mmole). After stirring for 18 hours the mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 6-dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (36 mg, 0,059 mmole). MS (ESI) 609,1 (M+N)+.

Example 66. 2-Bromo-6-(6-methylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid

To a solution of 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (224 mg, 0,482 mmole) in 5 ml of 1,4-dioxane was added 2,3-dichloro-5,6-dicyano-n-benzoquinone (109 mg, 0.48 mmole). After stirring for 4 hours the mixture was separated between ethyl acetate and 1M aq. NaOH solution. The organic layer was washed with water, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 40 to 50% ethyl acetate/hexane) to give 2-bromo-6-(6-methylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (93 mg, 0,23 mmole). MS (ESI) 404,8 (M+H) +.

Example 67. 2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-methylamino-3.4-dihydro-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (96 mg, 0.22 mmole), 2-bromo-6-(6-methylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ether acetic acid (88 mg, 0.22 mmole), the potassium phosphate (46 mg, 0.22 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (6.2 mg, of 0.013 mmole) and bis(dibenzylideneacetone)palladium(0) (3.7 mg, 0064 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 2 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 2 ml of tetrahydrofuran, 1 ml methanol and 1 ml of water. Added 1M aq. a solution of lithium hydroxide (to 0.65 ml, 0.65 mmole). After stirring for 18 hours the mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dig orotan) to obtain 2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-methylamino-3,4-dihydro-2H-isoquinoline-1-it (43 mg, 0,072 mmole). MS (ESI) 595 (M+N)+.

Example 68. 2-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl')benzyl ester of acetic acid

To 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ether acetic acid (422 mg, 1,01 mmole), bis(pinacolato)diboron (308 mg, 1,21 mmole) and potassium acetate (298 mg, 3,03 mmole) in a closed flask were added 5 ml of dimethylsulfoxide. Through this mixture missed argon for 3 minutes. Was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (25 mg, 0,030 mmole). Argon continued to pass through the mixture for one minute, and the lid tightly closed. The mixture was heated at 80°C for 18 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 30 to 50% ethyl acetate/hexane) to give 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid (251 mg, 0,541 mmole). MS (ESI) 487,2 (M+Na)+.

Example 69. 6-Dimethylamino-2-{2-hydroxymethyl-3-{1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he

5-Bromo-1-methyl-3-(1-methyl-1H-pyrazole-3-ylamino)-1H-pyridine-2-he (35 mg, of 0.13 mmole), 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (58 mg, of 0.13 mmole), tetrakis(triphenylphosphine)palladium(0) (14 mg, a 0.012 mmole) and sodium carbonate (40 mg, or 0.38 mmole) was dissolved in 2 ml of 1,2-dimethoxyethane and 1 ml of water. The mixture was subjected to microwave radiation at 120°C for 30 minutes. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 3 ml of tetrahydrofuran, 1.5 ml of methanol and 1.5 ml of water. Added 1M aq. solution of lithium hydroxide (0,38 ml of 0.38 mmole). The mixture was stirred for 3 hours. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 6-dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-it (39 mg, 0,078 mmole). MS (ESI) 499,2 (M+N)+.

Example 70. 1-Methyl-4-(6-nitropyridine-3-yl)piperazine

To 5-bromo-2-nitropyridine (2.00 g, 9.5 mmole) in 10 ml of dimethyl sulfoxide was added potassium carbonate (2,72 g, 19.7 mmole), 1-methylpiperazine (1,64 ml of 14.8 mmole) and tetrabutylammonium iodide (36 mg, 0,097 mmole) and heated at 120°C for 18 hours. The mixture was acidified with 1M aq. solution of Hcl, and was divided between dichloromethane and water. The aqueous layer was podslushivaet 2M aq. a solution of sodium carbonate and was extracted with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, concentrated in vacuo and treated with water to obtain 1-methyl-4-(6-nitropyridine-3-yl)piperazine (1,82 g, 8,19 mmole). MS (ESI) 223,1 (M+N)+.

Example 71. 5-(4-Methylpiperazin-1-yl)pyridin-2-ylamine

1-Methyl-4-(6-nitropyridine-3-yl)piperazine (1,748 g 7,865 mmole) was stirred in 30 ml of methanol with 175 mg of 10% palladium on coal in an atmosphere of hydrogen for 5 hours. The mixture was filtered and concentrated in vacuo to obtain 5-(4-methylpiperazin-1-yl)pyridine-2-ylamine (of 1.485 g, 7,724 mmole). MS (ESI) 193,1 (M+N)+.

Example 72. 5-Bromo-1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-1H-pyridine-2-he

To 5-(4-methylpiperazin-1-yl)pyridine-2-ylamine (1.06 g, of 5.53 mmole), 3,5-dibromo-1-methyl-1H-pyridine-2-ONU (1,23 g, br4.61 mmole), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400 mg, 0,691 mmole) and cesium carbonate (4,50 g of 13.8 mmole) was added 45 ml of 1,4-dioxane and Tris(dibenzylideneacetone)dipalladium(0) (422 mg, 0,461 mmole). The mixture was heated in an oil bath at 120°C is 6 hours in an argon atmosphere. The mixture was separated between ethyl acetate and dilute aqueous sodium bicarbonate solution. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 5-bromo-1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-1H-pyridine-2-she (484 mg, of 1.28 mmole). MS (ESI) 380,0 (M+N)+.

Example 73. 5-Bromo-1-methyl-3-(5-morpholine-4-espiridion-2-ylamino)-1H-pyridine-2-he

This compound was obtained analogously to 5-bromo-1-methyl-3-[5-(4-methylpiperazin-1-yl)pyridine-2-ylamino]-1H-pyridine-2-ONU. MS (ESI) 365,0 (M+N)+.

Example 74. 6-(Ethylmethylamino)-3,4-dihydro-2H-isoquinoline-1-he

6-Fluoro-3,4-dihydro-2H-isoquinoline-1-he (2.00 g, 12,1 mmole) were placed in a sealable flask with N-ethylmethylamine (4,0 ml, 47 mmol). The mixture was heated at 150°C for 24 hours. The mixture was concentrated in vacuum and purified accelerated by chromatography (elution with ethyl acetate) to give 6-(ethylmethylamino)-3,4-dihydro-2H-isoquinoline-1-she (2.10 g, 10.3 mmole). MS (ESI) 205,1 (M+N)+.

Example 75. 2-Bromo-6-[6-(ethylmethylamino)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]benzyl ester of acetic acid

6-(Ethylmethylamino)-3,4-dihydro-2H-isoquinoline-1-he (2,07 g, 10.1 mmole), 2,6-dibromopropyl ether acetic acid (6.25 g, a 20.3 mmole), copper iodide (386 mg, 2,03 mmole) and potassium carbonate (1,40, 10.1 mmole) were placed in a closed flask. Added 30 ml of DMSO. Through a mixture missed argon for 3 minutes, and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (386 mg, 2,03 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with 300 ml of ethyl acetate and 300 ml of water. The mixture was stirred for 20 minutes, was filtered through a layer of celite. The layers were separated. An ethyl acetate layer was dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 2-bromo-6-[6-(ethylmethylamino)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]benzyl ester of acetic acid (1,21 g of 2.81 mmole). MS (ESI) 433,0 (M+N)9+.

Example 76. 5-Bromo-1-methyl-3-(1-methyl-1H-pyrazole-3-ylamino)-1H-pyridine-2-he

3,5-Dibromo-1-methyl-1H-pyridine-2-he (469 mg, of 1.76 mmole), 1-methyl-1H-pyrazole-3-ylamine (205 mg, 2,11 mmole), Tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0,087 mmole), 2,2'-bis(diphenylphosphino-1,1'-binaphthalene (82 mg, of 0.13 mmole) and cesium carbonate (801 mg, 2,46 mmole) were placed in a sealable flask with 10 ml of toluene. The mixture was heated at 130°C for 18 hours. The resulting mixture was poured into 50 ml of water. The mixture was extracted with ethyl acetate. telecity layer was washed with a saturated solution of sodium chloride, was dried with anhydrous magnesium sulfate, was filtered, concentrated in vacuo and purified accelerated chromatography (elwira ethyl acetate/hexane) to obtain 5-bromo-1-methyl-3-(1-methyl-1H-pyrazole-3-ylamino)-1H-pyridine-2-she (271 mg, 0,957 mmole). MS (ESI) 284,9 (M+N)+.

Example 77. 2-(6-Dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester of acetic acid

To 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)benzyl ether acetic acid (420 mg, 1,01 mmole), bis(pinacolato)diboron (308 mg, 1,21 mmole) and potassium acetate (298 mg, 3,03 mmole) in a closed flask were added 5 ml of dimethylsulfoxide. Argon was passed through the mixture for 3 minutes. Was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (25 mg, 0,030 mmole). Argon continued to pass through the mixture for one minute, and the lid tightly closed. The mixture was heated at 80°C for 18 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 2-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ester acetic acid is acid (183 mg, 0,396 mmole). MS (ESI) 463,1 (M+N)+.

Example 78. 6-Dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-he

5-Bromo-1-methyl-3-(1-methyl-1H-pyrazole-3-ylamino)-1H-pyridine-2-he (47 mg, 0.17-mmole), 2-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (77 mg, 0.17-mmole), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmole) and sodium carbonate (53 mg, of 0.50 mmole) was dissolved in 2 ml of 1,2-dimethoxyethane and 1 ml of water. The mixture was subjected to microwave radiation at 120°C for 30 minutes. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 3 ml of tetrahydrofuran, 1.5 ml of methanol and 1.5 ml of water. Added 1M aq. solution of lithium hydroxide (0.5 ml, 0.5 mmole). The mixture was stirred for 3 hours. The mixture was separated between ethyl acetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (elution with 5% methanol/dichloromethane) to give 6-dimethylamino-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1 H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-eskinol the n-1-it (37 mg, of 0.075 mmole). MS (ESI) 497,1 (M+N)+.

Example 79. 1-{5-[3-(6-Dimethylamino-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-yl}-3-atilmotin

1-ethyl-3-[1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydropyridines-3-yl]urea (50 mg, 0.16 mmole), 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)benzyl ether acetic acid (65 mg, 0.16 mmole), potassium phosphate (66 mg, 0.31 in mmole), 2-(dicyclohexylphosphino-2',4',6'-three-ISO-propyl-1,1'-biphenyl (4.4 mg, 0,0092 mmole) and bis(dibenzylideneacetone)palladium(0) (2.6 mg, 0,0045 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 2 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 2 ml of tetrahydrofuran, 1 ml methanol and 1 ml of water. Added 1M aq. a solution of lithium hydroxide (0,47 ml of 0.47 mmole). After stirring for 3 hours the mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) received the eat 1-{5-[3-(6-dimethylamino-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-yl}-3-utilmately (33 mg, 0,068 mmole). MS (ESI) 488,1(M+H)+.

Example 80. 5-Bromo-1-methyl-3-(5-morpholine-4-iletileri-2-ylamino)-1H-pyridine-2-he

5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-he (2.3 g, 5.9 mmole) was dissolved in 30 ml of tetrahydrofuran. Added borane-tertrahydrofuran ring complex (2.5 g, 29 mmol). After stirring for 18 hours the mixture was concentrated in vacuum. Added ethanol. The mixture was boiled under reflux for one hour. The mixture was concentrated in vacuum and purified accelerated chromatography to obtain 5-bromo-1-methyl-3-(5-morpholine-4-iletileri-2-ylamino)-1H-pyridine-2-she (500 mg, 1.32 to mmole). MS (ESI) 381,0 (M+N)+.

Example 81. (6-Chloropyridin-3-yl)-(4-methylpiperazin-1-yl)methanon

To a solution of 6-chloronicotinic acid (3.00 g, 19.0 mmol) in 30 ml of dimethylformamide was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (10,9 g of 20.9 mmole), 1-methylpiperazine (2.30 g, 22,1 mmole) and triethylamine (2,18 g, 21.5 mmole). After stirring for 18 hours the mixture was separated between ethyl acetate and water. An ethyl acetate layer was dried with anhydrous sodium sulfate, concentrated in vacuum and purified accelerated by chromatography (elution with 3% methanol/dichloromethane) to give (6-chloropyridin-3-yl)-(4-methylpiperazin-1-yl)methanone (2.50 g, was 9.33 mmole).

the example 82. 5-Bromo-1-methyl-3-[5-(4-methylpiperazin-1-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-he

To a solution of (6-chloropyridin-3-yl)-(4-methylpiperazin-1-yl)methanone (2.00 g, 7,46 mmole) in 10 ml of dimethylformamide was added 3-amino-5-bromo-1-methyl-1H-pyridine-2-he (1,80 g of 8.95 mmole) and sodium hydride (537 mg, 22.4 mmole). After stirring for 18 hours the mixture is extinguished by water. The mixture was extracted with ethyl acetate. An ethyl acetate layer was dried with anhydrous sodium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution 0 to 5% methanol/dichloromethane) to give 5-bromo-1-methyl-3-[5-(4-methylpiperazin-1-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-she (900 mg, of 1.94 mmole). MS (ESI) 406,0 (M+N)+.

Example 83. Ethyl ester of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid

Benzyl ester of (3-bromo-2-were)acetic acid (421 mg, 1,32 mmole) was dissolved in ethyl formate (2.5 ml, 31 mmol). Was added sodium hydride (95%, 67 mg, 2.6 mmole). After stirring for 30 minutes, the mixture was suppressed 1M aq. a solution of Hcl. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with water, washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum.

Part of this material and N,N-xylene-1,3-diamine (96 mg, 0.70 and IMO the I) was stirred in 1 ml of ethanol for 18 hours. The mixture was concentrated in vacuum and purified accelerated chromatography (gradient elution from 5 to 20% ethyl acetate/hexane) to give the ethyl ester of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid (164 mg, 0,407 mmole). MS (ESI) 405,0 (M+N)+.

Example 84. 3-(3-Bromo-2-were)-7-dimethylamino-1H-quinoline-4-one

To the ethyl ether of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)acrylic acid (100 mg, 0,248 mmole) was added 4 g of polyphosphoric acid. The mixture was stirred at 140°C for 10 minutes. Added 50 ml of water, and the mixture was stirred. The precipitate was filtered and washed with water. The filtrate was extracted with a solution of 10% methanol/dichloromethane. The organic layer was dried with anhydrous magnesium sulfate and concentrated in vacuum. The resulting residue was combined with the precipitate and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 3-(3-bromo-2-were)-7-dimethylamino-1H-quinoline-4-it (22 mg, 0,062 mmole). MS (ESI) 357,0 (M+N)+.

Example 85. 7-Dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl} phenyl)-1H-quinoline-4-one

To methyl 3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (27 mg, 0,062 mmole), 3-(3-bromo-2-METI is phenyl)-7-dimethylamino-1H-quinoline-4-ONU (22 mg, 0,062 mmole), potassium phosphate (26 mg, 0.12 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (1.7 mg, 0,0036 mmole) and bis(dibenzylideneacetone)palladium(0) (1.0 mg, 0,0018 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 1 hour. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo and was purified preparative TLC (5% methanol/dichloromethane) to give 7-dimethylamino-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-1H-quinoline-4-it (14 mg, 0,024 mmole). MS (ESI) to $ 591.1 (M+N)+.

Example 86. 2-(3-Bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he

6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (762 mg, 4,01 mmole), copper iodide (153 mg, 0,802 mmole) and potassium carbonate (554 mg, 4,01 mmole) were placed in a closed flask. Added 6 ml of DMSO and 1,3-dibromobenzyl (1.89 g, 8,01 mmole). Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (153 mg, 0,802 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with dichloromethane and filtered through a layer of celite. Filtration is at separated between dichloromethane and 5% aq. the ammonium hydroxide solution. The dichloromethane layer was dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 100% ethyl acetate/hexane) to give 2-(3-bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-it (939 mg, of 2.72 mmole). MS (ESI) 345,0 (M+N)+.

Example 87. 6-Dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3.4-dihydro-2H-isoquinoline-1-he

2-(3-Bromophenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (163 mg, 0,472 mmole), bis(pinacolato)diboron (144 mg, 0,567 mmole) and potassium acetate (138 mg, of 1.42 mmole) were placed in a sealable flask containing 2 ml of DMSO. Through a mixture missed argon for 1 minute. Was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (12 mg, 0.015 mmole). Argon continued to pass through the mixture for one minute, and the lid tightly closed. The mixture was heated at 80°C for 18 hours. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (30% ethyl acetate/hexane) to give 6-dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3,4-dihydro-2H-isoquinoline-1-she (137 mg, 0,349 mmole). MS (ESI) 393,2 (M+N)+.

Example 88 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-1H-pyridine-2-he (67 mg, 0.17-mmole), 6-dimethylamino-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3,4-dihydro-2H-isoquinoline-1-he (67 mg, 0.17-mmole), tetrakis(triphenylphosphine)palladium(0) (20 mg, of 0.017 mmole) and sodium carbonate (54 mg, of 0.51 mmole) in 2 ml of 1,2-dimethoxyethane and 1 ml of water was heated at 170°C for 12.5 minutes in the microwave. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 6-dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6 - dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (40 mg, 0,069 mmole). MS (ESI) 579,2 (M+H)+.

Example 89. 2-(3-Bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-he

6-Dimethylamino-2H-isoquinoline-1-he (50 mg, of 0.27 mmole), copper iodide (10 mg, 0,053 mmole) and potassium carbonate (37 mg, of 0.27 mmole) were placed in a closed flask. Was added 3 ml of DMSO and 2,6-dibromsalan (133 mg, 0,532 mmole). Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 5 hours. The resulting mixture was divided between ethylacetate and water. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuo, and purified accelerated chromatography (30% ethyl acetate/hexane) to give 2-(3-bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-it (43 mg, 0.12 mmole). MS (ESI) 357 (M+N)+.

Example 90. 6-Dimethylamino-2-(2-methyl-3-{ 1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (69 mg, 0.16 mmole), 2-(3-bromo-2-were)-6-dimethylamino-2H-isoquinoline-1-ONU (36 mg, 0.10 mmole), potassium phosphate (43 mg, of 0.20 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (2,9 mg, 0,0061 mmole) and bis(dibenzylideneacetone)palladium(0) (1.7 mg, 0,0030 mmole) was added to 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 10% methanol/dichloromethane) to give 6-dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl) is iridin-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-she (46 mg, 0,078 mmole). MS (ESI) to $ 591.1 (M+H)+.

Example 91. 2-Bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid

6-Dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (150 mg, 0,789 mmole), 2,6-dibromopropyl ether acetic acid (487 mg, was 1.58 mmole), copper iodide (30 mg, 0.16 mmole) and potassium carbonate (109 mg, 0,789 mmole) were placed in a closed vessel. Was added 3 ml of DMSO. Through a mixture missed argon for 2 minutes, and the lid tightly closed. The mixture was heated at 150°C for 24 hours. Added copper iodide (30 mg, 0.16 mmole) and the mixture was heated at 150°C for 24 hours. The mixture was diluted with dichloromethane and filtered through a layer of celite. The filtrate was divided between dichloromethane and 5% water. the ammonium hydroxide solution. The dichloromethane layer was dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 25 to 50% ethyl acetate/hexane) to give 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (93 mg, 0.22 mmole). MS (ESI) 417,1 (M+N)+.

Example 92. 6-Dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1.6-dihydropyridines-3-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-he

To 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetrame the Il-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-ONU (60 mg, of 0.14 mmole), 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ether acetic acid (46 mg, of 0.11 mmole), potassium phosphate (47 mg, 0.22 mmole), 2-(dicyclohexylphosphino)-2',4',6'-three-ISO-propyl-1,1'-biphenyl (3.1 mg, 0,0065 mmole) and bis(dibenzylideneacetone)palladium(0) (1.9 mg, 0033 mmole) added 4 ml of degassed mixture of 1:3 water/n-butanol. The upper space of the vessel was evacuated and filled with argon 4 times. The mixture was heated at 100°C for 110 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated in vacuum. The mixture was dissolved in 2 ml of tetrahydrofuran, 1 ml methanol and 1 ml of water. Added 1M aq. a solution of lithium hydroxide (0.33 ml, of 0.33 mmole). After stirring for 18 hours the mixture was separated between ethyl acetate and water. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution from 2 to 5% methanol/dichloromethane) to give 6-dimethylamino-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6 - dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (36 mg, 0,059 mmole). MS (ESI) 609,1 (M+H)+

Example 93. 6-Chloropyridazine-3-ylamine

3,6-Dichloropyridazin (7.5 g, 50,35 mmole) was dissolved in ethanolic ammonia solution (100 ml) and was heated at 130°C) during the night in the vessel for high pressure. Then the ethanol was evaporated under reduced pressure and the crude product was purified accelerated by chromatography on silica gel (230-400 mesh mesh) using a mixture of EtOAc/hexane (6:4) to obtain the specified title compound (4 g, 61%) as a solid.

Example 94. 4-Bromo-6-chloropyridin-3-ylamine

To a solution of 6-chloropyridazine-3-ylamine (4 g, 31 mmol) in methanol (60 ml) was added NaHCO3(5,2 g, 62 mmole). The reaction mixture was stirred for 30 minutes at RT, then was added dropwise Br2(4.9 g, 31 mmol). Then the resulting reaction mixture was stirred additionally for 16 h at RT. After the reaction, the reaction mass was concentrated under reduced pressure, the crude product was purified by chromatography on silica gel (100-200 mesh) using EtOAc/hexane (8:2) to give 4-bromo-6-chloropyridin-3-ylamine (2.3 g, 36%) as a solid.

Example 95. 4-Bromo-6-chloro-2H-pyridazin-3-one

To a cooled solution (0-5) NaNO2(1 g, 13,20 mmole) in conc. H2SO4(15 ml) was added 4-bromo-6-chloropyridin-3-ylamine (2.3 g, 11 mmol) in 50 ml of acetic acid. Then the reaction mixture was stirred for 1 h at 20°C, C which was added water (75 ml), and stirring continued for 5 h at RT. The reaction mixture was extracted with EtOAc, dried Na2SO4concentrated under reduced pressure and the crude product was purified by chromatography on silica gel (100-200 mesh) using EtOAc/hexane (8:2) to give 4-bromo-6-chloro-2H-pyridazin-3-one (2.2 g, 95%) as a yellowish solid.

Example 96. 4-Bromo-6-chloro-2-methyl-2H-pyridazin-3-one

4-Bromo-6-chloro-2H-pyridazin-3-one (5,02 g, 23,97 mmole) was dissolved in 40 ml of dimethylformamide. Added cesium carbonate (9,37 g, 28,76 mmole). After 5 min was added dropwise logmean (5,103 g, 35,95 mmole) for 20 minutes, the Reaction mixture was stirred teenies hours at RT. The precipitate was filtered and concentrated, and the obtained residue was treated with 20 ml dichloromethane. Undissolved material was filtered again and washed with dichloromethane. The filtrate was concentrated in vacuum to obtain 4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (5,223 g, 23,37 mmole). MS (ESI) 224,9 (M+N)+.

Example 97. 6-Chloro-2-methyl-4-(1-methyl-1H-pyrazole-3-ylamino)-2H-pyridazin-3-one

1-Methyl-1H-pyrazole-3-amine (806 mg, 8.3 mmole) was dissolved in 40 ml of dioxane. Added tert-piperonyl potassium (1,793 g, 15,98 mmole). Then were added 4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (1.7 g, to 7.61 mmole) and the mixture was stirred for 3 hours at room temperature

The reaction mixture was transferred into an Erlenmeyer flask of 150 ml, and acidified 15 ml of 1 M aqueous solution of hydrochloric acid, then was treated with a saturated solution of sodium bicarbonate until the pH is about 8. The mixture was extracted two times each with 100 ml of dichloromethane; the organic phase was dried with sodium sulfate, filtered and concentrated in vacuum to obtain 1.5 g of a light orange solid. The crude material was treated with a mixture of dichloromethane and hexane. The suspension was filtered, and the obtained residue on the filter was dried in high vacuum to obtain 6-chloro-2-methyl-4-(1-methyl - 1H-pyrazole-3-ylamino)-2H-pyridazin-3-one (967 mg, a 4.03 mmole). MS (ESI) 240,0 (M+N)+.

Example 98. 2-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl]benzyl ester of acetic acid

6-Chloro-2-methyl-4-(1-methyl-1H-pyrazole-3-ylamino)-2H-pyridazin-3-one (0.09 g, 0,376 mmole), 2-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (0,191 g, 0,414 mmole) and cesium carbonate (0,428 g of 1.31 mmole) was treated with degassed solution mixture of 2 ml of dioxane/0.2 ml water. After 5 min stirring was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0,031 g of 0.038 mmole) and heated Ave is 135°C for 30 min under microwave irradiation. The reaction mixture was filtered through cellulose, washed with 10 ml of dioxane and concentrated in vacuum. The residue was purified by chromatography on silica gel (gradient elution 0-10% methanol in dichloromethane for 20 min) to give the crude 2-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl]benzyl ester of acetic acid (0,200 g, 0,371 mmole). MS (ESI) 540,1 (M+N)+.

Example 99. 6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino-6-oxo-1,6-dihydropyridin-3-yl)phenyl}-3,4-dihydro-2H-isoquinoline-1-he

2-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-[1-methyl-5-(1-methyl-1H-pyrazole-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl]benzyl ester of acetic acid (0,200 g, 0,371 mmole) was dissolved in 2 ml of tetrahydrofuran, 1 ml water and 1 ml of methanol. Added 1 M aqueous solution of lithium hydroxide (1.1 ml, 1,11 mmole), and stirred for several hours at RT. The mixture was extracted with a mixture of dichloromethane/solution of ammonium chloride, and the organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution from 0 to 10% methanol in dichloromethane for 20 min) to obtain the b-cyclopropyl-2-{2-hydroxymethyl-3-[1-met is l-5-(1-methyl-1H-pyrazole-3-ylamino-6-oxo-1,6-dihydropyridin-3-yl)phenyl}-3,4-dihydro-2H-isoquinoline-1-it (0,087 g, 0,175 mmole). MS (ESI) 597,2 (M+N)+.

Example 100. 2-('6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridin-3-yl}benzyl ether acetic acid

6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-2H-pyridazin-3-one (0,070 g, 0.2 mmole), 2-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (is 0.102 g, 0,221 mmole) and cesium carbonate (0,228 g, 0.7 mmole) was treated with degassed solution of a mixture of 1 ml of dioxane/0.1 ml water. After 5 min stirring was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0,016 g, 0.02 mmole), and the mixture was heated at 135°C for 30 min in a microwave oven. The reaction mixture was filtered through cellulose; washed with 5 ml of dioxane and concentrated in vacuum. The residue was purified by chromatography on silica gel (gradient elution 0-10% methanol in dichloromethane for 20 min) to give the crude 2-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridin-3-yl}benzyl ether acetic acid (0,121 g, 0,187 mmole). MS (ESI) 671,1 (M+Na)+.

Example 101. 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-1,6-dihydropyridin-3-yl}Fe who yl)-3,4-dihydro-2H-isoquinoline-1-he

2-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-b-oxo-1,6-dihydropyridin-3-yl}benzyl ether acetic acid (0,121 g, 0,187 mmole) was dissolved in 2 ml of tetrahydrofuran, 1 ml water and 1 ml of methanol. Added 1 M aqueous solution of lithium hydroxide (0,560 ml, 0,561 mmole) and stirred for several hours at RT. The mixture was extracted with a mixture of dichloromethane/solution of ammonium chloride, and the organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution 0-10% methanol in dichloromethane for 20 min) to give 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-1,6-dihydropyridin-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it (0,070 g, 0,115 mmole). MS (ESI) 607,2 (M+N)+.

Example 102. Methyl ester of 4-Isopropenyl-2-methylbenzoic acid

Methyl ester of 4-bromo-2-methylbenzoic acid (4 g, 17,46 mmole), pinacolyl ether of isopropylmalonic acid (3,228 g, 19,21 mmole) and cesium carbonate (19,913 g, 61,11 mmole) was treated with degassed solution of a mixture of 15 ml of dioxane/5 ml of water. After 5 min stirring was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) whom the Lex (0,718 g, 0,873 mmole) and heated at 120°C for 40 min under microwave irradiation. The reaction mixture was filtered through cellulose; washed with 20 ml of dioxane and concentrated in vacuum. The residue was purified by chromatography on 120 g of silica gel (gradient elution 0-50% ethyl acetate in hexane over 50 min) to give the methyl ester 4-Isopropenyl-2-methylbenzoic acid (2,94 g, 15,45 mmole). MS (ESI) 191,3 (M+N)+.

Example 103. Methyl ester of 2-methyl-4-(1-methylcyclopropyl)benzoic acid

Getting diazomethane: N-Nitroso-N-metalmachine (9,1 g, 61,8 mmole) was added with stirring in portions to a two-phase mixture of 50 ml of a solution of potassium hydroxide (23,9 g in 50 ml water and 50 ml of diethyl ether at 0°C. the Color of the organic phase changed from colorless to yellow. A two-phase mixture was intensively stirred for 40 min at 0°C. the Organic layer, which contained diazomethane, was separated. Cyclopropylamine adding diazomethane solution for methylstyrene, methyl ester 4-Isopropenyl-2-methylbenzoic acid (2,94 g, 15,45 mmole) was dissolved in 15 ml diethyl ether and cooled to 0°C. was Added palladium (II) acetate (0,173 g, 0,773 mmole). Was added dropwise yellow organic phase (containing diazomethane). Have just added 20 ml of organic phase (about 4 equiv. diazomethane) before the end of the reaction. Viewers is whether the nitrogen adding diazomethane to methylsterols intermediate connection. The reaction mixture was filtered through cellulose; washed with diethyl ether; concentrated; the residue (brown liquid) was purified by chromatography on 40 g of silica gel (gradient elution 0-100% ethyl acetate in hexane for 15 min) was obtained 2.9 g of crude light yellow liquid. NMR showed 8% methyl ester 2-methylbenzoic acid. The crude residue was purified again accelerated by chromatography on 110 g of silica gel (gradient elution 0-20% EtOAc in Hex over 30 minutes) to give the methyl ester of 2-methyl-4-(1-methylcyclopropyl)benzoic acid (2,75 g, 13,46 mmole) MS (ESI) 268,9 (M+Na++ACN).

Example 104. 2-Methyl-4-(1-methylcyclopropyl)benzoic acid

Methyl ester of 2-methyl-4-(1-methylcyclopropyl)benzoic acid (2,75 g, 13,46 mmole) was treated with methanol and 5 M aqueous solution of sodium hydroxide (20,46 ml, 102,32 mmole). This solution was heated at 80°C for 4 hours. The reaction mixture was concentrated under evaporation of methanol. Received a white solid. The solid was dissolved in 50 ml of water under heating, and then cooled in an ice bath; acidified with 10 ml conc. hydrochloric acid. Got a white precipitate; was filtered;

washed with water, dried in high vacuum overnight to obtain 2-methyl-4-(1-methylcyclopropyl)benzoic acid (2,18 g, 11,46 mmole) MS (ESI) 189,1 (M-N) .

Example 105. 2-Methyl-4-('1-methylcyclopropyl)benzoyl chloride

2-Methyl-4-(1-methylcyclopropyl)benzoic acid (2,139 g 11,243 mmole) and postcentral (2,575 g, 12,37 mmole) were loaded into a flask with a volume of 50 ml with stirring. Both solids were dissolved at 100°C. the Reaction mixture was stirred for 2 hours at 120°C at boiling under reflux in an atmosphere of N2. After that, the obtained phosphorus oxychloride drove at 140°C from the reaction mixture. The reaction mixture was cooled to CT, and the reaction mixture was still a solution. Target product drove by distillation Kugelbake (150°C. /4 mbar) to give 2-methyl-4-(1-methylcyclopropyl)of benzoyl chloride (1.92 g, 9.2 mmole).

Example 106. N-[3-Bromo-2-('- tert-butyldimethylsilyloxy)phenyl]-2-methyl-4-(1-methylcyclopropyl)benzamid

3-Bromo-2-(tert-butyldimethylsilyloxy)phenylamine (2.91 in g, 9.2 mmole), 2-methyl-4-(1-methylcyclopropyl)benzoyl chloride (1.92 g, 9.2 mmole), N,N-diisopropylethylamine (2,41 ml of 13.8 mmole) and 4-dimethylaminopyridine (0,112 g of 0.92 mmole) was dissolved in 20 ml of anhydrous tetrahydrofuran. The reaction mixture is boiled under reflux during the night; the precipitate was filtered; concentrated and extracted with ethyl acetate; washed with 2 M phosphate buffer with a pH of 5.5, then with water and saturated is the first solution of sodium chloride; dried sodium sulfate; filtered; and concentrated. Received 4,69 g of oil. The crude product was purified by chromatography on 80 g of silica gel (gradient elution 0-20% ethyl acetate in hexane over 25 min, then 20-100% ethyl acetate in hexane for 30 min) to give N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-2-methyl-4-(1-methylcyclopropyl)benzamide (3.51 g, 7,185 mmole) MS (ESI) 510 (M+Na+).

Example 107. 2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-hydroxy-7-(1-methylcyclopropyl)-3,4-dihydro-2H-isoquinoline-1-he

2,2,6,6-Tetramethylpiperidine (2.28 g, 16,17 mmole) was dissolved in 13 ml of anhydrous tetrahydrofuran under stirring; were cooled with a bath ethylene glycol/ice to -15°C. was added dropwise utility, 2.5 M in hexane book (6.16 ml, 15.4 mmole), and the temperature was maintained around -15°C, and stirred additionally for 30 min at -15°C. was Added dropwise to the reaction mixture a solution of N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-2-methyl-4-(1-methylcyclopropyl)benzamide in 20 ml of anhydrous tetrahydrofuran for 10 minutes at -15°C. the Reaction mixture was stirred for 2 hours. After this was added 3.55 ml of dimethylformamide in one piece. The reaction mixture was left to warm to CT. The mixture was stirred for 2 hours at RT, then cooled to 0°C, extinguished 25 ml of 1 M restorereplica potassium; was extracted with a mixture of ethyl acetate/water, the organic phase is washed with a saturated solution of sodium chloride; dried sodium sulfate; filtered and concentrated. Got a 2.71 g of brown oil. Crystallization of dichloromethane and hexane resulted in the receipt of 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-hydroxy-7-(1-methylcyclopropyl)-3,4-dihydro-2H-isoquinoline-1-it (1,134 g, 2.2 mmole) MS (ESI) 516,0 (M-H)-.

Example 108. 2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-7-(1-methylcyclopropyl)-2H-isoquinoline-1-he

2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-hydroxy-7-(1-methylcyclopropyl)-3,4-dihydro-2H-isoquinoline-1-he (1,134 g, 2.2 mmole) was dissolved in 13 ml of dichloromethane at RT; after adding triethylamine (1.31 ml, 9,44 mmole) was added methanesulfonamide (0,478 g 4,171 mmole). The mixture was stirred for 1.5 hours at RT, but the reaction was held for 10 minutes in accordance with the LCMS. The reaction mixture was extracted with a mixture of dichloromethane/water, the organic phase is washed with a saturated solution of sodium chloride; dried sodium sulfate; filtered; and concentrated to obtain 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-7-(1-methylcyclopropyl)-2H-isoquinoline-1-it (1,094 g, 2.2 mmole) MS (ESI) 520,0 (M+Na+).

Example 109. 2-(2-tert-Butyldimethylsilyloxy)-3-{1-methyl-5-[-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he

2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-7-(1-methylcyclopropyl)-2H-isoquinoline-1-he (is 0.102 g, 0,205 mmole) and 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (0.1 g, 0,227 mmole) was dissolved in 2.5 ml of dioxane with heating; was added 0.5 ml of water, then cesium carbonate (0,259 g, 0,795 mmole). After this was added [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex is 0.019 g, is 0.023 mmole) and heated at 135°C for 30 min under microwave irradiation. The reaction mixture was filtered through cellulose; washed with dioxane; concentrated; the residue was purified by chromatography on a 24 g silica gel (gradient elution dichloromethane for 5 min, then 0-10% methanol in dichloromethane for 25 min, then dichloromethane 9:1 methanol for 10 min) to give 2-(2-tert-butyldimethylsilyloxy)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-it (0,095 g of 0.13 mmole) MS (ESI) 732,2 (M+N)+.

Example 110. 2-(2-Hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he

2-(2-tert-Butyldimethylsilyloxy)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he (0,095 g, of 0.13 mmole) was dissolved in 3 ml dioxans. Added a 3 M aqueous solution of hydrochloric acid (0,22 ml to 0.39 mmole) at RT. The mixture was stirred for 30 min, then was extracted with a mixture of ethyl acetate/sodium bicarbonate solution; the organic phase is washed with a saturated solution of sodium chloride; dried sodium sulfate; and concentrated. The crude product was purified by chromatography on 12 g of silica gel (gradient elution 0-10% methanol in dichloromethane for 30 min) to give 2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-(1-methylcyclopropyl)-2H-isoquinoline-1-it (0,045 g, 0,0728 mmole) MS (ESI) 618,3 (M+N)+.

Example 111. 6-Bromo-3,4-dihydro-2H-isoquinoline-1-he

Methansulfonate acid (100 ml) was added to a solution of 5-bromoindene (25 g, 46 mmol) in CH2Cl2(200 ml) at 0°C. Slowly in portions to this mixture was added sodium azide (10.5 g, 162 mmole). After the addition of sodium azide and the mixture was stirred for 30 min, and added to an aqueous mixture of NaOH (20 wt.%) to obtain a slightly alkaline mixture. The mixture was extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure. Purification of the mixture accelerated column chromatography on silica gel (0% to 50% EtOAc/hexane, then from 0% to 7% MeOH/CH2Cl2) resulted in the doctrine of 11.5 g of 6-bromo-3,4-dihydro-2H-isoquinoline-1-it. MS (ESI) 226,1 (M+N)+.

Example 112. 6-Cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he

In a round bottom flask was loaded 6-bromo-3,4-dihydro-2H-isoquinoline-1-he (16,9 g, 74.7 mmole), cyclopropylboronic acid (of 9.45 g, 1.5 equiv.), tricyclohexylphosphine (1,04 mg of 0.025 equiv.) and K3PO4the uranyl (50 g, 2 equiv.) in toluene (210 ml) and N2About (15 ml), was added Pd(OAc)2 (100 mg, of 0.05 equiv). The combined mixture was heated for 4 h at 100°C. the Reaction mixture was cooled, filtered and washed with toluene. The organic phase was separated and washed with water and saturated sodium chloride solution, dried Na2SO4, was filtered and was concentrated to obtain oil. The addition of hexane resulted in the receipt of 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a yellow-brown solid (13,6 g). MS (ESI) 187,1 (M+N)+.

Example 113. 2-Bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde

In a round bottom flask was loaded 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (13,4 g, 5 mmol), 2,6-dibromobenzene (47,5 g, 72,0 mmole), Pd2(dba)3·l3(660 mg, 0.72 mmole), Xanthos (832 mg, 1.44 mmole) and cesium carbonate (46,8 g, 144 mmole). The vessel was filled with argon, was added 140 ml of dioxane, and the reaction mixture was heated at 110°C for 4 hours

The reaction mixture is cooled to CT, and added 30 ml of water and 60 ml of ethyl acetate, then was filtered through Solka-Floc®. The organic phase was separated and washed with a saturated solution of sodium chloride, then dried Na2SO4. After filtration the solvent was removed and the resulting brown mass was treated with methylene chloride and diethyl ether to obtain 6.5 g of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde. The second game of 7.5 g of material was collected by addition of diethyl ether. MS (ESI) 370,0 (M+N)+.

Example 114. 2-(3-Bromo-2-hydroxymethylene)-6-cyclopropyl-3.4-dihydro-2H-isoquinoline-1-he

To a solution of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde (5.0 g, 13.5 mmole) in 60 ml of toluene and 10 ml of THF at -10°C portions) was added sodium borohydride (740 mg, 20 mmol). After 30 minutes the reaction mixture was extinguished with water and divided diethyl ether. The organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate and was filtered. After concentration under reduced pressure, purification by chromatography on silica gel resulted in the receipt of 3.7 g of 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a colorless solid. MS (ESI) 372,0 (M+H)+.

Example 115. 6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[5-(morpholine-4-carbonyl)pyridine-ylamino]-2-oxo-1,2-dihydropyridines-4-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

Into the flask were loaded 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (3,70 g of 9.9 mmole), 1-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (to 4.38 g of 9.9 mmole), Pd2(dba)3-l3(229 mg, 0.25 mmole), 2-dicyclohexylphosphino-2',4',6'-tri-ISO-propyl-1,1'-biphenyl (238 mg, of 0.50 mmole) and K3PO4the uranyl (7.5 g, 20 mmol), was added 40 ml of a mixture of 4:1 dioxane: water, and the mixture was heated at the boil under reflux for 4 h, cooled and filtered through Solka-Floc®, washing with ethyl acetate. Were separated and the organic phase is washed with water and saturated sodium chloride solution. Dried sodium sulfate, filtered, and concentrated to obtain a dark oil. Purification by chromatography on silica gel (methylene chloride/methanol) resulted in obtaining 3.2 g of 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-2-oxo-1,2-dihydropyridines-4-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it is in the form of a colorless solid. MS (ESI) 606,1 (M+N)+.

Example 116. Getting 6-tert-butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it

Scheme 1

Example 117. 1-(4-tert-Butylphenyl)-3-chloropropane-1-he

To aluminium chloride (29,33 g, 220 mmol) in dichloromethane (300 ml) at 0°C under stirring was added dropwise a solution of tert-butylbenzene (31 ml, 200 mmol) and 3-chloropropionitrile (19 ml, 200 mmol) in dichloromethane. After the addition the reaction mixture was stirred at a temperature from 0°C to CT during the night. Then the next morning, TLC showed that all of tert-butylbenzoyl has slashdowns, and the reaction mixture was cooled to 0°C. With stirring was added dropwise water (about 120 ml) to stop the rapid selection. Then the layers were separated, and the organic layer was washed with water (3×150 ml) and then saturated sodium chloride solution (1×150 ml). The dichloromethane layer was dried with magnesium sulfate, was filtered, concentrated and pumped by pump dry with obtaining specified in the title compounds as a light yellow-brown powder (45.6 g).

Example 118. 5-tert-Batiliman-1-he

1-(4-tert-Butylphenyl)-3-chloropropane-1-he (45.6 g, 447 mmol) was transferred into a concentrated sulfuric acid (200 ml) and the resulting mixture was heated at 100°C under stirring for 2.5 hours. TLC showed that all starting material disappeared. After cooling to CT, the reaction mixture is carefully poured into 1 kg raskroshennogo the ice. Then add some amount of diethyl ether, and the mixture is gently stirred while cooling to CT. Added ethyl acetate (1200 ml) and after separation of the layers were separated. The acid layer was then extracted with ethyl acetate (2×200 ml).

United an ethyl acetate layers were washed with saturated sodium bicarbonate solution (5×300 ml). Then an ethyl acetate layer was dried with magnesium sulfate, was filtered, concentrated and dried pump with obtaining specified in the title compound as a colourless oil (15,764 g).

Example 119. 6-tert-Butyl-3.4-dihydro-2H-isoquinoline-1-he

5-tert-Batiliman-1-ONU (15.7 g, of 83.4 mmole) in dichloromethane (150 ml) was added methanesulfonyl acid (100 ml) and the resulting mixture was cooled to 0°C. Then gently portions was added sodium azide (10,83 g, 2 equiv.) within 15 minutes. The resulting mixture was stirred at 0°C for about 2.5 hours. The TLC analysis confirmed that all 5-tert-Batiliman-1-he slashdowns. Under stirring at 0°C was added very carefully aqueous solution of sodium hydroxide (20%) until pH=14. Then added dichloromethane (1000 ml) and water (500 ml), which resulted in the receipt of the emulsion. The layers were separated, and the aqueous layer was then extracted with dichloromethane (2×200 ml). Then the combined dichloromethane layers were washed with a saturated solution of sodium chloride 9×200 ml), was dried with magnesium sulfate and was filtered through a layer of celite. After concentration and drying pump dry was obtained 13.5 g of crude product as a yellow-brown solid. Cleaning Analogix Column at 400g, elwira gradient from 10% to 60% ethyl acetate in hexane led to the obtaining of the desired isomer as a white powder (7,22 g) ((M+N)=204) and the undesired isomer (1,555 g) as a white powder.

Example 120. 2-Bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid

6-tert-Butyl-3,4-dihydro-2H-isoquinoline-1-he (4 g, 19,67 mmole), 2,6-dibromopropyl ether acetic acid (12.1 g, 2 equiv.), trehosnovnoy potassium phosphate (8,35 g, 2 equiv.) and copper iodide (787 mg, 0.2 equiv.) transferred in dioxane (40 ml). Then was added N,N'-dimethylcyclohexane-1,2-diamine (1,24 ml, 0.4 equiv.), and the resulting mixture was heated at the boil under reflux for 24 hours, after which was added copper iodide (394 mg, 0.1 equiv.) and N,N'-dimethylcyclohexane-1,2-diamine (of 0.62 ml, 0.2 equiv.). Was stirred for 64 hours, and then was added copper iodide (400 mg, 0.1 equiv.). Continued to stir while boiling under reflux for just 168 hours. Was cooled to CT, and then added ethyl acetate (300 ml) and water (100 ml), separated and divided layers. Washed with more water (2×100 ml), and then premillenarianism solution of sodium chloride (1×100 ml). An ethyl acetate layer was dried with magnesium sulfate, was filtered and was concentrated with the receipt of 4.45 g of crude product. Purification by Analogix column 240 g resulted in the receipt specified in the title compound as a white foamy solid (516 mg) ((M+N)=431), and extracted 6-tert-butyl-3,4-dihydro-2H-isoquinoline-1-he (2,188 g).

Example 121. 2-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzyl ether acetic acid

1-Methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (208 mg, 1 equiv.), 2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ether acetic acid (203 mg, 0,472 mmole), X-phos (14 mg, 0.06 to equiv.), trehosnovnoy potassium phosphate (200 mg, 2 equiv.), n-butanol (2.8 ml) and water (0,93 ml) were loaded into a round bottom flask of 50 ml volume, and then through a mixture missed nitrogen for 10 minutes, then was added Pd(dba)2(8 mg, of 0.03 equiv.). The resulting mixture was heated at 100°C for 40 minutes, TLC analysis showed no presence of starting material. The reaction mixture was cooled to CT, and then added ethyl acetate (150 ml) and water (40 ml). Divided and separated the layers and washed with more water (2×40 ml) and then saturated sodium chloride solution (1×40 ml). Then an ethyl acetate layer su is or magnesium sulfate, was filtered and concentrated and dried pump dry with obtaining specified in the title compound, which was used in the next stage without additional purification ((M+N)=664).

Example 122. 6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

2-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzyl ether acetic acid (0,472 mmole) was transferred to a THF (7 ml) and methanol (3 ml) and water (5 ml), and then added the monohydrate of lithium hydroxide (40 mg, 2 equiv.). The resulting mixture was stirred at RT over night. The next morning the reaction was completed according to TLC, and most of the THF and methanol were removed under reduced pressure at 55°C. Then was added ethyl acetate (75 ml) and water (30 ml) and the layers were separated and then shared. Then an ethyl acetate layer was washed with water (2×30 ml), saturated sodium chloride solution (1×30 ml) and then dried with magnesium sulfate, was filtered and was concentrated to obtain 286 mg of crude product. Purification preparative thin-layer chromatography, elwira on two 20×40 cm, 1000 μm plates using 6% methanol in dichloromethane, yielded specified in the title compound (99 mg) is a white powder ((M+N) +=622).

Example 123. tert-Butyl ether [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid (1)

6-Bromo-2-(4-methoxybenzyl)-3,4-Dihydro-2H-isoquinoline-1-he (1.9 g, 5.5 mmole), Q-phos (0,0632 g of 0.11 mmole) and Pd(dba)2(0,0781 g of 0.11 mmole) in 10 ml THF was added to chloride of 2-tert-butoxy-2-oxoethylidene 15 ml (0.55 M) in argon atmosphere. The reaction mixture was stirred at RT for 16 hours. Then add a third of the initial number of Q-phos, Pd(dba)2and enolate zinc, and the mixture was heated for 1 hour at 70°C until the end of the reaction. Target product (2 g, 95.6% of yield) was isolated by rapid chromatography using column chromatography on silica gel using 10%-40% ethyl acetate in hexane as eluent.

Example 124. 2-(4-Methoxybenzyl)-1-oxo-1,2,3.4-tetrahydroisoquinoline-6-yl]acetic acid (II)

tert-Butyl ether (I) (1 g, 5.7 mmole) was dissolved in 40 ml of methanol and to this solution was added LiOH monohydrate (0,72 g, a 17.3 mmole) in 6 ml of water. The mixture was stirred at RT for 16 hours, then concentrated in vacuo, acidified (2N HCl and was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, dried with sodium sulfate and concentrated in vacuum. The residue (1.8 g; 97% yield) was used in the next stage without complement the school clean.

Example 125. 2-[2-(4-Methoxybenzyl)-1-oxo-1,2.3,4-tetrahydroisoquinoline-6-yl]ndimethylacetamide (III)

To the carboxylic acid (II) (2.3 g, 7 mmol) in 22 ml of chloroform was added EEDQ (2,07 g, 8.4 mmole) and ammonium bicarbonate (1.66 g, 21 mmol). After stirring the mixture at RT for 16 hours amide precipitated with addition of water (20 ml). The solid was filtered, washed with water and dried in vacuum. The residue was treated with 50% ethyl acetate in hexane, filtered and dried in vacuum to obtain 1.4 g of amide (III), 63% yield.

Example 126. [2-(4-Methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetonitrile (IV)

Amide (III) (1.3 g, 4 mmole) suspended in 5 ml of THF and 10 ml of DMF. To this mixture was added the acid chloride cyanuric acid (0,370 g, 2 mmole), and after stirring at RT for 0.5 hours the reaction mixture was separated between ethyl acetate and a saturated solution of sodium chloride; the organic layer was washed with 5% sodium bicarbonate solution, then with saturated solution of sodium chloride, and then dried with sodium sulfate. Clearing accelerated by chromatography on a column of silica gel using 75% ethyl acetate in hexane as eluent, yielded 1.2 g (98% yield) of the nitrile (IV).

Example 127. 1-[2-(4-Methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarbonitrile (V):

To a suspension of sodium hydrate (0,228 g, 60%, 5.72 mmole) in 15 ml DMF was added to the nitrile (IV) (1.2 g, 3.9 mmole), and after stirring for 15 minutes at RT was added 1,2-dibromoethane (1.1 g, 5.8 mmole) in 1.5 ml DMF. The resulting mixture was stirred for 0.5 hour at RT, and then was added the sodium hydrate (0,114 g, 2.86 mmole) and the reaction mixture was heated for about 10 minutes at 30-35 °C. After cooling, the mixture was separated between ethyl acetate and a saturated solution of sodium chloride, the organic layer was dried with sodium acetate and concentrated in vacuum. Purification of column chromatography on silica gel using 30%-50% ethyl acetate in hexane resulted in the receipt of 1 g of compound (V) (77% yield).

Example 128. 1-[2-(4-Methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarboxaldehyde (VI)

To a solution of nitrile (V) (0,722 g, 2,17 mmole) in 3 ml of dichloromethane and 9 ml of toluene, cooled to -50°C., was added dropwise DIBAH (4.8 ml, of 4.77 mmole). After stirring for 1 hour at -50°C, the reaction was suppressed to 5 ml of IN HCl was left to warm to CT and was stirred for 0.5 hour. Then the mixture was extracted with ethyl acetate; the organic layer was washed with 0.5 N HCl, 5% sodium carbonate solution, saturated sodium chloride solution, then dried with sodium sulfate and concentrated in vacuum. The remainder acidalkaline chromatography on silica gel, using 30% -60% ethyl acetate in hexane to obtain 0.075 g of the aldehyde (VI) (10,3% yield).

Example 129. 6-(1-Deformational)-2-(4-methoxybenzyl)-3.4-dihydro-2H-isoquinoline-1-he (VII)

To a solution of DAST (0,042 g of 0.26 mmole) in 1.5 ml of dihlormetilen was added the aldehyde (VI) (0.075 g, 0.22 mmole) in 0.5 ml of dihlormetilen. This mixture was stirred at RT for 16 hours. After cooling in an ice bath to the reaction mixture were added 5 ml of water, and then ethyl acetate. The organic layer was washed with 5% sodium bicarbonate solution and saturated sodium chloride solution, then dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC on silica gel, obtaining the compound (VII) 0,068 g, 87% yield.

Example 130. 6-(1-Deformational)-3,4-dihydro-2H-isoquinoline-1-he (VIII)

The compound (VII) (0,068 g at 0.19 mmole) was dissolved in 1 ml TFUK and was heated at 70°C for 1.5 hours. To the reaction mixture, cooled to CT, was added ethyl acetate, and the solution was washed with a saturated solution of sodium chloride, then 5% sodium bicarbonate solution and again with saturated solution of sodium chloride. The organic layer was dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC on silica gel using 5% methanol in dihlormetilen, obtaining the compound (VIII) 0,030 g, 66% yield.

Example 131 2-Bromo-6-[6-(1-deformational)-1-oxo-3,4-dihydro-1H-itinerantly (IX)

To a mixture of compound (VIII) (0,030 g, 0.12 mmole), 2,6-dibromobenzene (0,064 g, 0.25 mmole), cesium carbonate (0,054 g, 0.16 mmole) and Xanthos (0.002 g, of 0.004 mmole) in a flask for microwave radiation in the atmosphere of argon was added Pd(dba)2(0,0014 g, 0,0024 mmole). The flask was closed and the reaction mixture was heated at 100°C for 16 hours. After cooling, the mixture was separated between ethyl acetate and a saturated solution of sodium chloride, the organic layer was dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC on silica gel using 40% ethyl acetate in hexane as the eluent, getting 0,024 g, 48% yield.

Example 132. 2-[6-(1-Deformational)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzaldehyde (X):

1-Methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,45,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (0.025 g, 0,057 mmole) and benzaldehyde IX (0,024 g 0,057 mmole) was dissolved in 0.5 ml of n-butanol. To this solution in an argon atmosphere was added To a3RHO4(0,024 g, 0,114 mmole), water 0,150 ml, Xphos (0.0027 g, 0,0057 mmole) and Pd(dba)2(0,0016 g, 0,0028 mmole). The mixture was heated for 1 hour at 100°C, and after cooling, was divided between ethyl acetate and a saturated solution of sodium chloride. Organic with the Oh was dried with sodium sulfate, concentrated in vacuo, and the residue was purified prep.TLC on silica gel with getting 0.025 g (67% yield) of compound X.

Example 133. 6-(1-Deformational)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl')pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he (XI)

2-[6-(1-Deformational)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzaldehyde (0.025 g, of 0.038 mmole) was dissolved in THF (2 ml). To this solution was added NaBH4(0,006 g, 0.015 mmole) and the mixture was stirred at RT for 0.5 h, then extinguished with ice water (4 ml) and was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, dried with sodium sulfate and concentrated in vacuum. The residue was purified preparative TLC to obtain 6-(1 - deformational)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-she (XI) 0,020 g (80% yield).

Example 134. 6-Bromo-3,4-dihydro-2H-isoquinoline-1-he

Methansulfonate acid (100 ml) was added to a solution of 5-bromoindene (25 g, 46 mmol) in CH2Cl2(200 ml) at 0°C. Slowly in portions to this mixture was added sodium azide (10.5 g, 162 the mole). After the addition of sodium azide and the mixture was stirred for 30 min, and added to an aqueous mixture of NaOH (20 wt.%) to get slightly basic mixture. The mixture was extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure. Purification of the mixture accelerated column chromatography on silica gel (0% to 50% EtOAc/hexane, then from 0% to 7% MeOH/CH2Cl2) resulted in the receipt of 11.5 g of 6-bromo-3,4-dihydro-2H-isoquinoline-1-it. MS (ESI) 226,1 (M+N)+.

Example 135. 6-Cyclopropyl-3.4-dihydro-2H-isoquinoline-1-he

In a round bottom flask was loaded 6-bromo-3,4-dihydro-2H-isoquinoline-1-he (16,9 g, 74.7 mmole), cyclopropylboronic acid (of 9.45 g, 1.5 equiv.), tricyclohexylphosphine (1,04 mg of 0.025 equiv.) and uranyl K2RHO4(50 g, 2 equiv.) in toluene (210 ml) and N2About (15 ml), was added Pd(OAc)2(100 mg, of 0.05 equiv.). The combined mixture was heated for 4 h at 100°C. the Reaction mixture was cooled, filtered and washed with toluene. The organic phase was separated and washed with water and saturated sodium chloride solution, dried Na2SO4, was filtered and was concentrated to obtain oil. The addition of hexane resulted in the receipt of 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1 - it is in the form of a yellow-brown solid (13,6 g). MS (ESI) 187,1 (M+N)+.

Example 136. 2-Bromo-6-(6-C is chlorophyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde

In a round bottom flask was loaded 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (13,4 g, 5 mmol), 2,6-dibromobenzene (47,5 g, 72,0 mmole), Pd2(dba)3·l3(660 mg, 0.72 mmole), Xanthos (832 mg, 1.44 mmole) and cesium carbonate (46,8 g, 144 mmole). The vessel was filled with argon, was added 140 ml of dioxane, and the reaction mixture was heated at 110°C for 4 h, the Reaction mixture was cooled to CT and was added 30 ml of water and 60 ml of ethyl acetate, then was filtered through Solka-Floc®. The organic phase was separated and washed with a saturated solution of sodium chloride, then dried Na2SO4. After filtration the solvent was removed and the resulting brown mass was treated with methylene chloride and diethyl ether to obtain 6.5 g of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde. The second game of 7.5 g of material was collected by adding additional quantities of diethyl ether. MS (ESI) 370,0 (M+H).

Example 137. 2-(3-Bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he

To a solution of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde (5.0 g, 13.5 mmole) in 60 ml of toluene and 10 ml of THF at -10°C portions) was added sodium borohydride (740 mg, 20 mmol). After 30 minutes the reaction mixture was extinguished with water and divided diethyl ether.

Organic f the zu was washed with a saturated solution of sodium chloride, was dried with sodium sulfate and was filtered. After concentration under reduced pressure, purification by chromatography on silica gel resulted in the receipt of 3.7 g of 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-it is in the form of a colorless solid. MS (ESI) 372,0 (M+N)+.

Example 138

6-Cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-2-oxo-1,2-dihydropyridines-4-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it: In the flask was loaded 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (3,70 g, to 9.9 mmole), 1-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (to 4.38 g of 9.9 mmole), Pd2(dba)3·l3(229 mg, 0.25 mmole), 2-dicyclohexylphosphino-2',4',6'-tri-ISO-propyl-1,1'-biphenyl (238 mg, of 0.50 mmole) and uranyl K2RHO4(7.5 g, 20 mmol), was added 40 ml of a mixture of 4:1 dioxane:water, and the mixture was heated at the boil under reflux for 4 h, cooled and filtered through Solka-Floc®, washing with ethyl acetate. Were separated and the organic phase is washed with water and saturated sodium chloride solution. Dried sodium sulfate, filtered, and concentrated to obtain a dark oil. Purification by chromatography on silica gel (methylene chloride/methanol) results in the sludge to obtain 3.2 g of 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-2-oxo-1,2 - dihydropyridines-4-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it is in the form of a colorless solid. MS (ESI) 606,1 (M+N)+.

Example 139

Into the flask was loaded 1.55 g (PPh3)2PdCl2and 5.0 g of 6-bromo-3,4-dihydro-2H-isoquinoline-1-it was added 25 ml of DMF. Then added 9,58 g tributyl-(1-ethoxyphenyl)stannane, and the reaction mixture was heated at 110°C and stirred until completion of the reaction. The reaction mixture was filtered through celite and diluted with diethyl ether. After washing with a saturated solution of ammonium carbonate, water and saturated sodium chloride solution, the solution was dried with sodium sulfate, filtered and concentrated in vacuum. The resulting mixture was dissolved in THF and was treated with 3.0 M aqueous solution of HCl for the implementation of hydrolysis. The mixture was then divided between water and diethyl ether. The organic phase was washed sequentially with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and then dried with sodium sulfate. After filtration the solution was concentrated and purified accelerated chromatography to obtain 3.28 g of 6-acetyl-3,4-dihydro-2H-isoquinoline-1-it.

Example 140

To a suspension of 680 mg of 6-acetyl-3,4-dihydro-2H-isoquinoline-1-it in 25 ml of THF, cooled to 0°C., was slowly added to 3.6 ml of 3.0 M MeMgBr in THF. After 1 h the mixture was poured into a solution of ammonium chloride in ice water. Added ethyl acetate, and the organization of the definition phase was separated, dried sodium sulfate, filtered, and concentrated. The accelerated cleanup chromatography led to obtain 380 mg of 6-(1-hydroxy-1-methylethyl)-3,4-dihydro-2H-isoquinoline-1-it.

Example 141

6-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he (1.9 g, 5.5 mmole), Q-phos (0,0632 g of 0.11 mmole) and Pd(dba)2(0,0781 g of 0.11 mmole) in 10 ml THF was added to 15 ml of the chloride of 2-tert-butoxy-2-oxoethylidene (0.55m) in argon atmosphere. The reaction mixture was stirred at RT for 16 hours. Then add one third of the initial amount of Q-phos, Pd(dba)2and enolate zinc, and the mixture was heated for 1 hour at 70 °C until the end of the reaction. 2 g of tert-butyl methyl ether [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid was isolated by rapid chromatography using column chromatography on silica gel using 10%-40% ethyl acetate in hexane as eluent.

Example 142

tert-Butyl ether [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid (1 g, 5.7 mmole) was dissolved in 40 ml of methanol and to this solution was added LiOH monohydrate (0,72 g, a 17.3 mmole) in 6 ml of water. The mixture was stirred at RT for 16 hours, then concentrated in vacuo, acidified (2N HCl and was extracted with ethyl acetate. The organic layer was washed with saturated dissolve the ohms of sodium chloride, was dried with sodium sulfate and concentrated in vacuum. Obtained 1.8 g of 2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid used in the next stage without additional purification.

Example 143

To a solution of 2.3 g of 2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid in 22 ml of chloroform was added EEDQ (2,07 g, 8.4 mmole) and ammonium bicarbonate (1.66 g, 21 mmol). After stirring the mixture at RT for 16 hours amide precipitated with addition of water (20 ml). The solid was filtered, washed with water and dried in vacuum. The residue was treated with 50% ethyl acetate in hexane, filtered and dried in vacuum to obtain 1.4 g of 2-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]ndimethylacetamide.

Example 144

To a suspension of 1.3 g of 2-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]ndimethylacetamide in 5 ml of THF and 10 ml of DMF was added 370 mg of chloride cyanuric acid, and after stirring at RT for 0.5 hours the reaction mixture was separated between ethyl acetate and a saturated solution of sodium chloride. The organic layer was washed with 5% sodium bicarbonate solution, then with saturated solution of sodium chloride, and then dried with sodium sulfate. Clearing accelerated by chromatography on a column of silica gel using 75% ethyl acetate in Huck is ane as eluent resulted in obtaining 1.2 g of [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetonitrile.

Example 145

To a suspension 228 mg of 60% sodium hydride in 15 ml of DMF was added 1.2 g of [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetonitrile, and after stirring for 15 minutes at RT was added 1.1 g of 1,2-dibromethane in 1.5 ml DMF. The resulting mixture was stirred for 0.5 hour at RT, and then was added sodium hydride (0,114 g, 2.86 mmole) and the reaction mixture was heated for 10 minutes at 30-35°C. After cooling, the mixture was separated between ethyl acetate and a saturated solution of sodium chloride, and the organic layer was dried with sodium acetate and concentrated in vacuum. Purification of column chromatography on silica gel using 30%-50% ethyl acetate in hexane resulted in the receipt of 1 g of 1-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarbonitrile.

Example 146

To a solution of 722 mg of 1-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarbonitrile in 3 ml of dichloromethane and 9 ml of toluene, cooled to -50 °C., was added dropwise 4.8 ml of 1.0 M DIBAL in THF. After stirring for 1 hour at -50 °C. the reaction was suppressed to 5 ml of IN HCl was left to warm to CT and was stirred for 0.5 hour. Then the mixture was extracted with ethyl acetate, and the organic layer was washed with 0.5 N HCl, 5% sodium carbonate solution and a saturated solution of chloride is the atrium. After drying with sodium sulfate and removal of solvent in vacuo, the residue was purified column chromatography on silica gel using 30%-60% ethyl acetate in hexane to obtain 0.075 g of 1-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarboxaldehyde.

Example 147

To a solution of DAST (0,042 g of 0.26 mmole) in 1.5 ml of dihlormetilen was added 75 mg of 1-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]cyclopropanecarboxaldehyde in 0.5 ml of dihlormetilen. This mixture was stirred at RT for 16 hours. After cooling in an ice bath to the reaction mixture were added 5 ml of water, and then ethyl acetate.The organic layer is washed with 5% sodium bicarbonate solution and saturated sodium chloride solution, then dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC on silica gel, receiving 0,068 g of 6-(1-deformational)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it.

Example 148

A solution of 68 mg of 6-(1-deformational)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it 1 ml TFUK was heated at 70°C for 1.5 hours. After cooling the reaction mixture to CT was added ethyl acetate, and the solution was washed with a saturated solution of sodium chloride, then 5% sodium bicarbonate solution and again with saturated solution of sodium chloride. Org the organic layer was dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC on silica gel using 5% methanol in dichloromethane, receiving 30 mg of 6-(1-deformational)-3,4-dihydro-2H-isoquinoline-1-it.

Example 149

To a mixture of 30 mg of 6-(1-deformational)-3,4-dihydro-2H-isoquinoline-1-it, 64 mg of 2,6-dibromosalicylic, 54 mg of cesium carbonate and 2 mg of Xanthos in the flask for microwave radiation in the atmosphere of argon was added 14 mg of Pd(dba)2. The flask was closed and the reaction mixture was heated at 100°C for 16 hours. After cooling, the mixture was separated between ethyl acetate and a saturated solution of sodium chloride, the organic layer was dried with sodium sulfate and concentrated in vacuum. The residue was purified prep.TLC on silica gel using 40% ethyl acetate in hexane as the eluent, getting 0,024 g of 2-bromo-6-[6-(1-deformational)-1-oxo-3,4-dihydro-1H-skinalleged.

Example 150

Methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (0.025 g, 0,057 mmole) and 24 mg of 2-bromo-6-[6-(1-deformational)-1-oxo-3,4-dihydro-1H-skinalleged was dissolved in 0.5 ml of n-butanol. To this solution in an argon atmosphere was added To a2RHO4(0,024 g, 0,114 mmole), water 0,150 ml, Xphos (0.0027 g, 0,0057 mmole) and Pd(dba)2(0,0016 g, 0,0028 mmole). The mixture was heated for 1 hour the ri 100°C, and after cooling was divided between ethyl acetate and a saturated solution of sodium chloride. The organic layer was dried with sodium sulfate, concentrated in vacuo, and the residue was purified prep.TLC on silica gel with getting 0.025 g of 2-[6-(1-deformational)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzaldehyde.

Example 151

To 25,0 g (166,15 mmole) 5-forindiana in a flask with a volume of 3 l equipped with a mechanical stirrer, was added 280 ml of dichloromethane and 200 ml methanesulfonic acid. The mixture was cooled to 0°C and portions were added br15.15 g (233,1 mmole) of sodium azide in 20 minutes. The mixture was stirred at 0°C for 2 h, then was added dropwise 490 ml of 20% aqueous sodium hydroxide solution for 30 minutes. The layers were separated, and the organic phase was dried MgSO4and concentrated. Purification of column chromatography, elwira a mixture of ethyl acetate/hexane, resulted in obtaining 16,76 g (61%) of the target isomer 6-fluoro-3,4-dihydroisoquinoline.

Example 152

To 2.5 g (15,13 mmole) of 6-fluoro-3,4-dihydroisoquinoline and 5.5 ml (they accounted for 60,54 mmole) isobutyronitrile dissolved in 30 ml of THF, was added 91 ml (of 45.42 mmole) of 0.5 M KHMDS in toluene. The mixture was heated at 70°C, and was intensively stirred for 12 hours the Mixture was cooled to CT, is asili water, was divided between ethyl acetate and a saturated solution of sodium chloride and dried MgSO4. Purification of column chromatography, elwira a mixture of ethyl acetate/hexane, resulted in the receipt of 3.23 g (100%) of the product 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)propionitrile.

Example 153

To 1.3 g (6,07 mmole) of 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)propionitrile dissolved in 20 ml of degassed dioxane, was added 6,40 g (24,27 mmole) of 2,6-dibromosalicylic, of 3.96 g (12,14 mmole) of cesium carbonate, 70 mg (0,121 mmole) of Pd(dba)2and 105 mg (of 0.182 mmole) of Xanthos. The mixture was heated at 110°C for 3 h, cooled to CT and was filtered through celite, washing with dioxane. The mixture was then concentrated and purified column chromatography, elwira a mixture of ethyl acetate/hexane to obtain 1.10 g(46%) 2-[2-(3-bromo-2-formylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile.

Example 154

NaOH (5,4 g, 8 equiv.) in N2O (16 ml) was added to a solution of the above cyanocyclohexane (5.6 g, to 16.9 mmole) in EtOH (50 ml). This mixture then was heated at 100°C for 9 h, then was cooled to CT, concentrated in vacuo to half the initial volume, and neutralized IN HCl. The mixture then was extracted with CH2Cl2off , washed with a saturated solution of sodium chloride, dried Na 2SO4and concentrated in vacuum to obtain product cyclopropanecarbonyl acid (5.9 g, 99%).

Example 155

LiCl (2.5 g, 5 equiv.) was added to the solution described above cyclopropanecarbonyl acid (4,2 g, 12.0 mmol) in benzene (60 ml). The mixture was degirolami for 30 min, then was added Pb(SLA)4 (6.6 g, 1.25 equiv.). Degassing was continued for 45 min at RT, after which the mixture was heated at 100°C for 2 hours After cooling, the mixture was applied onto a silica gel, concentrated in vacuo and was chromatographically directly (SiO2from 20% to 80% EtOAc/hexane) to obtain RMV-chlorocyclopropane product (1,11 g, 27%). Unreacted starting material (-2,2 g) can be extracted from the column further elution with the following gradient from 2% to 8% Meon/DHL.

Example 156

The solution described above RMV-chlorocyclopropane (1,11 g, 3.3 mmole) in TFOC (20 ml) was heated at 80°C for 2 hours then the mixture was cooled to CT, and concentrated in vacuum. The resulting residue was re-dissolved in EtOAc and washed successively feast upon. a solution of NaHCO3N2Oh and a saturated solution of sodium chloride. The organic layer was then dried Na2SO4and concentrated in vacuum to obtain chlorocyclopropane product (660 mg, 92%).

Note the p 157

To 25,0 g (166,15 mmole) 5-forindiana in a flask with a volume of 3 l equipped with a mechanical stirrer, was added 280 ml of dichloromethane and 200 ml methanesulfonic acid. The mixture was cooled to 0°C and portions were added br15.15 g (233,1 mmole) of sodium azide in 20 minutes. The mixture was stirred at 0°C for 2 h, then was added dropwise 490 ml of 20% aqueous sodium hydroxide solution for 30 minutes. The layers were separated, and the organic phase was dried MgSO4and concentrated. Purification of column chromatography, elwira a mixture of ethyl acetate/hexane, resulted in obtaining 16,76 g (61%) target 6-fluoro-3,4-dihydroisoquinoline isomer.

Example 158

To 2.5 g (15,13 mmole) of 6-fluoro-3,4-dihydroisoquinoline and 5.5 ml (they accounted for 60,54 mmole) isobutyronitrile dissolved in 30 ml of THF, was added 91 ml (of 45.42 mmole) of 0.5 M KHMDS in toluene. The mixture was heated at 70 °C and was intensively stirred for 12 hours the Mixture was cooled to CT, extinguished by water, was divided between ethyl acetate and a saturated solution of sodium chloride and dried MgSO4. Purification of column chromatography, elwira a mixture of ethyl acetate/hexane, resulted in the receipt of 3.23 g (100%) of the product 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)propionitrile.

Example 159

To 1.3 g (6,07 mmole) of 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)about what isonitrile, dissolved in 20 ml of degassed dioxane, was added 6,40 g (24,27 mmole) of 2,6-dibromosalicylic, of 3.96 g (12,14 mmole) of cesium carbonate, 70 mg (0,121 mmole) of Pd(dba)2and 105 mg (of 0.182 mmole) of Xanthos. The mixture was heated at 110 °C for 3 h, cooled to CT and was filtered through celite, washing with dioxane. The mixture was then concentrated and purified column chromatography, elwira a mixture of ethyl acetate/hexane to obtain 1.10 g(46%) 2-[2-(3-bromo-2-formylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile.

Example 160

Getting 6-tert-butyl-2H-isoquinoline-1-it: 6-tert-butyl-3,4-dihydro-2H-isoquinoline-1-he (1,709 g, 8.4 mmole) and 2,3-5,6-dicyano-p-benzoquinone (DDQ) (3,85 g, 2 equiv.) transferred in dioxane (130 ml) and the resulting mixture was heated at 100 °C for four days. After cooling to CT, most of the dioxane was removed under reduced pressure at 55 °C. To the residue was added ethyl acetate (300 ml) and 2N NaOH solution (100 ml) and the mixture was separated, and the layers were separated. Then washed again with 2N NaOH solution (3×100 ml), water (1×125 ml) and then saturated sodium chloride solution (1×125 ml). An ethyl acetate layer was dried with magnesium sulfate, filtered, and concentrated to obtain crude product (1,783 g). Purification on silica gel, elwira 30% ethyl acetate in hexane, resulted in obtaining specified in the connection header (779 mg) in the de light yellow-brown powder. MS (ESI) 202,0 (M+N)+.

Example 161. Obtain 2-bromo-6-(6-tert-butyl-1-oxo-1H-isoquinoline-2-yl)benzaldehyde

6-tert-Butyl-2H-isoquinoline-1-he (272 mg, of 1.35 mmole), 2,6-dibromobenzene (891 mg, 2.5 equiv.), Xanthos (35 mg, of 0.045 equiv.) and cesium carbonate (616 mg, 1.4 equiv.) transferred in dioxane (2.7 ml). Then through a solution of missed nitrogen for 10 minutes, then was added bis(dibenzylideneacetone)palladium (23 mg, of 0.03 equiv.). The resulting mixture was stirred at 100°C during the night. According to TLC and LCMS target product was not observed. Then was added copper iodide (55 mg, of 0.02 equiv.) and cesium carbonate (320 mg, 0,73 equiv.), and even dioxane (4 ml). The resulting mixture was heated at 100°C with stirring for 30 hours, and according to TLC, the reaction could go no higher. After cooling to CT was added ethyl acetate (175 ml) and water (50 ml). The layers were separated and divided. The organic layer is then washed with water (3×50 ml) and then saturated sodium chloride solution (G ml), then dried with magnesium sulfate, was filtered and was concentrated. Purification on silica gel, elwira Paladino gradient of 5% ethyl acetate to 20% ethyl acetate in hexane, resulted in obtaining specified in the title compounds as a light yellow-brown powder (215 mg). MS (ESI) 346,0 (M+N)+.

Example 162

Obtain 2-[2-(4-methoxime who yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionamidine: 6-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he (5 g, 14.4 mmole), SPHOS (361 mg, is 0.06 equiv.), the cesium carbonate (5,65 g, 1.2 equiv.) and palladium acetate (130 mg, of 0.04 equiv.) was placed in an open sealable flask and transferred in dioxane (58 ml). After the solution was passed argon for 15 minutes, and then added Isobutyraldehyde (2,9 ml, 2 equiv.), and the mixture was sealed and stirred at 80 C for the night. The next day, the reaction is still not gone, so was additionally added palladium acetate (65 mg) and SPHOS (181 mg) and Isobutyraldehyde (1.5 ml) and the reaction mixture was stirred at 80°C for 24 hours. At this time, the reaction is still not gone, so was additionally added palladium acetate (30 mg) and SPHOS (90 mg) and the reaction mixture was stirred at 100°C for 24 hours. After 3 days of starting material was not observed, and the reaction mixture was cooled to CT. Added ethyl acetate (300 ml) and water (100 ml) and the layers were separated and divided. An ethyl acetate layer was washed with a saturated solution of sodium chloride (100 ml) and dried with magnesium sulfate, filtered, and concentrated to obtain crude product. Purification on silica gel, elwira 20% ethyl acetate in hexane, resulted in obtaining specified in the title compound as fine colourless oil (428 mg). MS (ESI) 338,0 (M+N)+.

Example 163

Obtaining 2-methyl-2-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)Propionaldehyde: 2-[2-(4-Methodology dibenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionamide (420 mg, 1.25 mmole) was transferred into triperoxonane acid (5 ml) and the resulting mixture was stirred at 80 °C for 2.5 hours and then was cooled to CT. Triperoxonane acid was removed under reduced pressure at 60°C, and then were co-evaporated with ethyl acetate (5X). The residue was transferred into ethyl acetate (175 ml) and then washed with water (3×50 ml) and then saturated sodium chloride solution (1×50 ml). An ethyl acetate layer was dried with magnesium sulfate, filtered, and concentrated to obtain crude product. Purification on silica gel, elwira gradient 50% ethyl acetate in hexane to pure ethyl acetate, resulted in obtaining specified in the title compound as a white powder (228 mg). MS (ESI) 218,0 (M+N)+.

Example 164

Obtain 2-bromo-6-[6-(1,1-dimethyl-2-oxoethyl)-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl]benzaldehyde: 2-Methyl-2-(1-oxo-1,2,3,4 - tetrahydroisoquinoline-6-yl)Propionaldehyde (224 mg, of 1.03 mmole), 2,6-dibromobenzene (1,09 g, 4 equiv.), Xanthos (27 mg, of 0.03 equiv.) and cesium carbonate (470 mg, 1.4 equiv.) transferred in dioxane (2 ml) and the mixture was passed argon for 10 minutes, then was added bis(dibenzylideneacetone)palladium (18 mg, of 0.03 equiv.). The resulting mixture was placed in an atmosphere of argon and heated at 100°C under stirring for 2.5 hours, after which all the starting material disappeared on TLC data and analysis LC/S. After cooling to CT was added ethyl acetate (175 ml) and water (50 ml) and the layers were separated and divided. An ethyl acetate layer was washed with a saturated solution of sodium chloride (1×50 ml), and then dried with magnesium sulfate, filtered, and concentrated to obtain crude product. Purification on silica gel, elwira gradient of 5% ethyl acetate to 40% ethyl acetate in hexane, resulted in obtaining specified in the title compound as a pale yellow powder (302 mg). MS (ESI) 400,0 (M+N)+.

Example 165

2-(6-Azetidin-1-yl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-bromobenzaldehyde

5-Azetidin-1-Ilinden-1-he

5-fluoro-1-indanone (7,44 g, a 49.5 mmole), azetidin HCl (5,1 g, 54,4 mmole) and K2CO3(13,6 g, 99 mmol) was transferred into a 60 ml DMSO. The reaction mixture was heated at 100 °C for 6 hours.

The mixture was divided between water and ethyl acetate. The aqueous layer was then extracted with 250 ml ethyl acetate. The combined organic layers were washed with three portions of 250 ml of water, dried MgSO4, was filtered and was concentrated. Column chromatography (0-40% EtOAc/hexane) resulted in obtaining 3,41 g of the product.

Example 166

6 Azetidin-1-yl-3,4-dihydro-2H-isoquinoline-1-it. 5-azetidin-1-Ilinden-1-he (1,9 g, 10.14 mmole) and methanesulfonyl acid (10,8 ml) d is balali to CH 2Cl2(100 ml). The reaction mixture was cooled to 0°C and carefully portions was added sodium azide (1,32 g, 20,29 mmole) for 30 min, then the reaction mixture was stirred at 0°C for 2 hours. After the implementation of the reaction mixture was slowly added 20% aq. NaOH solution at 0°C.

The mixture was separated between water and CH2Cl2. The aqueous layer was then extracted with 100 ml of CH2Cl2. The combined organic layers were washed with three portions of 200 ml of water, dried MgSO4, was filtered and was concentrated. Column chromatography (0-60% EtOAc/hexane) resulted in the receipt of 1.02 g of the target isomer.

Example 167

2-(6-Azetidin-1-yl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-bromobenzaldehyde: 6 Azetidin-1-yl-3,4-dihydro-2H-isoquinoline-1-he (1.0 g, 4,94 mmole), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (0.11 g, 0.22 mmole) and cesium carbonate (of 2.26 g, 6.92 mmole) was transferred in dioxane (50 ml), and then through a mixture missed nitrogen for 10 minutes was Added bis(dibenzylideneacetone)palladium(0) (0,085 g,0,14 mmole) and copper iodide (1) (0,93 g, 4,94 mmole), and then the reaction mixture was heated at 100°C for 82 hours.

The mixture was divided between water and ethyl acetate. The aqueous layer was then extracted with 100 ml of ethyl acetate. The combined organic layers were washed with three portions of 100 ml of water, dried MgSO 4, was filtered and was concentrated. Column chromatography (0-50% EtOAc/hexane) resulted in the receipt of 0.74 g of product.

Example 168

180 mg of 2-[2-(4-Methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionamide (0.54 mmole, 1 equiv.) was cooled to 0°C in 20 ml of 1:1-mixture of ethanol and THF. Added 20 mg of sodium borohydride (0.54 mmole, 1 equiv.), and the mixture was stirred at 0°C for 1 hour. Extinguished with water, then 2 drops of glacial acetic acid was stirred for 5 minutes, and the mixture was concentrated in vacuo to remove most of solvent was added a saturated solution of sodium bicarbonate, extracted with ethyl acetate 2, dried ethyl acetate MgSO4and concentrated to obtain 180 mg of 6-(2-hydroxy-1,1-dimethylethyl)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it (M+N=340), which was used directly in the next reaction without purification.

The residue from the previous reaction (180 mg, of 0.53 mmole, 1 equiv.) was dissolved in a mixture of 1:1 DMF and THF, was added 0.2 ml of 2-(2-chloroethoxy)tetrahydropyran (3.2 mmole, 6 equiv.), then 80 mg of sodium hydride (95% dry, 3.2 mmole, 6 equiv.), and the mixture was heated at 90°C during the night. Cooled and extinguished 2 ml of water, concentrated to dryness and applied directly to a column of silica gel, elwira 50% ethyl acetate in hexane to obtain 140 mg of 6-{1,1-dimethyl-2-[2-(tetr gidropony-2-yloxy)ethoxy]ethyl}-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it. MS (ESI) 468,0 (M+N)+.

Example 169

140 mg of 6-{1,1-dimethyl-2-[2-(tetrahydropyran-2-yloxy)ethoxy]ethyl}-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-she (0.3 mmole, 1 equiv.) was dissolved in 5 ml triperoxonane acid, and the mixture was heated at 80°C for 16 hours. The reaction mixture was concentrated to dryness, was divided between ethyl acetate and saturated sodium bicarbonate solution, the layers were separated and washed with ethyl acetate, a saturated solution of sodium chloride, dried MgSO4and concentrated to obtain 75 mg of 6-[2-(2-hydroxyethoxy)-1,1-dimethylethyl]-3,4-dihydro-2H-isoquinoline-1-it, M+N=264, which was used without purification in the next stage.

Example 170

United 0,131 g (0.5 mmole, 1 equiv.), 6-(2-hydroxy-1,1-dimethylethyl)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he 0,528 g 2,6-dibromobenzene (2 mmole, 4 equiv.), 6 mg of Xanthos (0.01 mmole, of 0.02 equiv.), 9 mg of bis(dibenzylideneacetone)palladium (0.015 mmole, of 0.03 equiv.) and 0,326 g of cesium carbonate (1 mmol, 2.0 equiv.) in 5 ml of dioxane, through a mixture missed argon for 1 minute, the reaction vessel was closed and heated at 100°C for 13 hours, was filtered hot through a sintered glass filter, concentrated and purified on a column of silica gel, elwira from 5% to 10% methanol in CH2CL2to obtain 148 mg was Evaporated, was chromatographically (from 10% to 30% EA in hexane) to obtain a solid substance, 325 mg of 2-bromo-6-{6-[2-(2-hydroxyethoxy)-1,1-dimethylethyl]-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl}benzaldehyde. MS (ESI) 446,0 (M+H).

Example 171

4-Bromo-2-methylbenzoic acid (100,04 g, 465 mmol), 500 ml of anhydrous methanol and 5 ml of concentrated sulfuric acid was stirred at the boil under reflux with nitrogen for 24 hours was Cooled to CT and concentrated in vacuum. The residue was diluted with 500 ml EtOAc and washed with 200 ml of 1 M aqueous solution of NaOH, 200 ml of water and 200 ml of saturated solution of sodium chloride. Dried solution of MgSO4and concentrated in vacuo to obtain methyl 4-bromo-2-methylbenzoate in the form of a colorless transparent liquid (100,06 g, 437 mmol).1H NMR (300 MHz, chloroform-d) at 2.59 ppm (s, 3H) to 3.89 (s, 3H) 7,39 (d, J=8,29 Hz, 1H) 7,42 (s, 1H) 7,79 (d, J=8,67 Hz, 1H).

Example 172

Cyclopropylboronic acid (25,08 g, 292 mmole), anhydrous trehosnovnoy potassium phosphate (178,12 g, 839 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (6,925 g, 14.5 mmole), methyl 4-bromo-2-methylbenzoate (55,93 g, 244 mmole) and 600 ml of toluene were loaded into a round bottom flask 1000 ml, equipped with a mechanical stirrer, septum and the input of nitrogen. The mixture was rapidly stirred and added 65 ml of water. Was barbotirovany through the mixture asotv for 30 minutes Added Tris(dibenzylideneacetone)dipalladium(0) (3,321 g, 3,63 mmole). The reaction mixture was barbotirovany nitrogen for 15 minutes, the Flask was closed with a lid, and the mixture was stirred at 90°C during the night. Added 150 ml of water and left to cool down to CT. Was filtered two-phase system through diatomaceous earth to remove solids, and washed the residue on the filter with EtOAc. Separated phases of the filtrate, and the organic phase is washed h ml of 5% NaHCO3, CH ml of 10% Na2S2O3and 200 ml of saturated solution of sodium chloride. Dried solution of MgSO4and concentrated in vacuum. The remaining liquid was distilled in a vacuum. The collected fractions were distilled at 108-111°C./3 Torr to obtain methyl 4-cyclopropyl-2-methylbenzoate in the form of a colorless transparent liquid (32,30 g, 170 mmol).1H NMR (300 MHz, chloroform-d) ppm 0,71 is 0.80 (m, 2H) 0,98-of 1.07 (m, 2H) 1,83-of 1.95 (m, 1H) of 2.58 (s, 3H) a 3.87 (s, 3H) 6,87-of 6.96 (m, 2H) 7,83 (d, J=to $ 7.91 Hz, 1H).

Example 173

Methyl 4-cyclopropyl-2-methylbenzoate (32,00 g, 168 mmol), 250 ml of 5 M aqueous solution of sodium hydroxide and 150 ml of methanol was stirred at 85°C for 18 hours Cooled the reaction mixture to CT and concentrated in vacuum. Had white residue dissolved in 500 ml of water, cooled the solution in an ice bath, was added 120 ml of concentrated hydrochloric acid. Was obtained a white precipitate. Extraheavy and water mixture 2×250 ml EtOAc. Combined organic extracts were washed with 250 ml of a saturated solution of sodium chloride. Dried solution of MgSO4and concentrated in vacuum to obtain 4-cyclopropyl-2-methylbenzoic acid in the form of a whitish solid (29,52 g, 168 mmol). MS (ESI) MS (ESI) 175,0 (M-H)-.

Example 174

4-Cyclopropyl-2-methylbenzoic acid (25,01 g, 142 mmole) and pentachloride phosphorus (32,84 g, 158 mmol) were loaded into a round bottom flask with a volume of 100 ml with a mechanical stirrer, reflux condenser and drying tube with calcium chloride, was evacuated through a dilute aqueous solution of NaOH to capture the gas. Boil the mixture at a bath temperature of 120°C for 2 h was Removed l3by-product by distillation at atmospheric pressure. The residue was distilled in a vacuum. The collected fractions were distilled at 116-118°C./3 Torr to obtain 4-cyclopropyl-2-methylbenzylamine in the form of a colorless transparent liquid (26,39 g, 136 mmol).1H NMR (300 MHz, chloroform-d) ppm 0,77 is 0.86 (m, 2H) 1,06 is 1.16 (m, 2H) 1,87 of 1.99 (m, 1H) 2,54 (s, 3H) 6,93-7,03 (m 2N) to 8.14 (d, J=8,29 Hz, 1H).

Example 175

To a solution of [3-bromo-2-(tert-butyldimethylsilyloxy)phenylamine (21,28 g, 67,3 mmole) and anhydrous pyridine (6.5 ml, 80 mmol) in 50 ml of anhydrous toluene was added dropwise a solution of 4-cyclopropyl-2-methylbenzonitrile (13,25 g, 68,1 mm is La) in 50 ml of anhydrous toluene. The precipitate was received immediately when added. Stirred the mixture at room temperature under nitrogen atmosphere overnight. Diluted the reaction mixture of 125 ml of hexane, and the precipitate was filtered. Washed filtrate 2×200 ml 1.0 M KHSO4, 2×200 ml of 5% NaHCO3and 250 ml of water. Dried solution of MgSO4and concentrated in vacuo to obtain N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-4-cyclopropyl-2-methylbenzamide in the form of a waxy light brown solid (31,54 g, 66,4 mmole). MS (ESI) 474, 476,0 (M+N)+.

Example 176

Kiln dried round bottom flask with a volume of 1000 ml was equipped with a mechanical stirrer, septum and cap for input of nitrogen. Installed and 5 maintained the atmosphere of N2. Into the flask was loaded 2,2,6,6-tetramethylpiperidine (25 g, 180 mmol) and 300 ml of anhydrous THF without inhibitor. Cooled the solution in a bath of ice/acetone to -15°C. Quickly mixed and added 58 ml of 2.5 M solution of n-utility (58 ml, 150 mmol) in hexane dropwise within 20 minutes, using an eyedropper. Mixed clear amber solution at - 15°C for 30 minutes. Was added dropwise a solution of N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-4-cyclopropyl-2-methylbenzamide (16,65 g, 35.1 mmole) dissolved in 100 ml anhydrous THF over 20 minutes, using an eyedropper. Mixed dark garnet is a new solution at -15°C for one hour. Added dimethylformamide (40 ml, 520 mmol) in one portion. The color changed from dark purple to dark amber, and the solution was heated to -5°C. Stirred the reaction mixture for 10 min at -5°C., then the ice bath was removed, and left to mix at room temperature for 1 h [Deleted 55 ml aliquots to separate experiment]. Cooled dark amber solution to 0°C in an ice bath, and 20 reaction was suppressed by the addition of 125 ml of 3 N hydrochloric acid to obtain a solution with a pH of 2. Poured the reaction mixture into 1000 ml of EtOAc and 500 ml of water. Separated phase and the organic phase is washed with 500 ml of 5% aqueous NaHCO3and 500 ml of saturated solution of sodium chloride. Dried solution of Na2SO4and concentrated in vacuum. The residue was purified accelerated chromatography (gradient elution, 0 to 50% EtOAc/hexane) to give 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-3-hydroxy-3,4-dihydro-2H-isoquinoline-1-it is in the form of a pale yellow solid (10,42 g of 20.7 mmole). MS (ESI) 500,0, 502,0 (M-N)+.

Example 177

To the rapidly stirred solution of 2-[3-ROM-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-3-hydroxy-3,4-dihydro-2H-isoquinoline-1-it (3,52 g, 7,00 mmol) and triethylamine (4.0 ml, 29 mmol) in 50 ml anhydrous CH2Cl; added 0,85 ml m is consultoriolarete. Filled the flask with nitrogen and stirred at RT over night. Added 25 ml of CH2Cl2and 50 ml of water, and the phases were separated. Washed the organic phase with 50 ml of saturated solution of sodium chloride. Dried solution of MgSO4and concentrated in vacuum. The residue was purified accelerated chromatography (gradient elution 0 to 50% EtOAc/hexane) to give 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-2H-isoquinoline-1-it is in the form of amber resin (2,90 g of 5.99 mmole). MS (ESI) 484, 486 (M+N)+.

Example 178

Methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine-2-he (99 mg, 0.22 mmole), 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-2H-isoquinoline-1-he (120 mg, 0,248 mmole), 2 ml of dioxane and a solution of cesium carbonate in water (370 mg/420 μl) were loaded into a flask with a volume of 4 ml, equipped with a mechanical stirrer and septum. Was barbotirovany through a mixture of nitrogen for 15 minutes was Added chloride [1,1'bis(diphenylphosphino)ferrocene]palladium(II) 1:1 complex with dichloromethane (12 mg, 0.015 mmole). The reaction mixture was barbotirovany nitrogen for 5 minutes Covered flask and stirred at 90°C for 16 hours was Cooled to CT, divided reaction mixture between 5 ml of 5% NaHCO3and 10 ml EtOAc and the phases were separated. Washed the organic phase with 5 ml of water and 5 ml saturated is astora sodium chloride, dried Na2SO4and concentrated in vacuum. Purified accelerated chromatography C18 reverse phase (gradient elution from 10 to 95% acetonitrile +0.1% TFWC/water+0.1% TFUC). Added 1 ml of saturated NaHCO3to the combined product fractions and concentrated in vacuum. The resulting aqueous was extracted with a mixture of 2×10 ml of CH2CL2, dried Na2SO4and concentrated in vacuum to obtain 2-(7-(tert-butyldimethylsilyloxy)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-cyclopropyl-2H-isoquinoline-1-it is in the form of a brittle amber foam. (70 mg, 0,097 mmole). MS (ESI) 718 (M+N)+.

Example 179

2-(2-(tert-Butyldimethylsilyloxy)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-cyclopropyl-2H-isoquinoline-1-he (56 mg, 0,078 mmole) was dissolved in 3 ml of anhydrous THF. Added a 1.0 M solution of tetrabutylammonium fluoride (466 μl, 466 mmol) in THF, and stirred at RT for 15 minutes Separated the reaction mixture is between 8 ml of water and 10 ml of CH2Cl2and the phases were separated. Washed the organic phase is 8 ml of 1.0 M KHSO4and 8 ml of a saturated aqueous solution of NaHCO3. Dried Na2SO4and concentrated in vacuum. Purified accelerated chromatography C18 reverse phase (gradient elution is t 10 to 95% acetonitrile+0.1% TFWC/water +0.1% TFUC). Added 1 ml of a saturated solution of NaHCO3to the combined product fractions, and concentrated in vacuum. The resulting aqueous was extracted with a mixture of 2×10 ml of CH2Cl2, dried Na2SO4and concentrated in vacuo to obtain 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it is in the form of a whitish solid. (29 mg, 0,048 mmole). MS (ESI) 604 (M+N)+.

Example 180

The catalytic solution was obtained by loading into a reaction vessel with a volume of 20 ml, equipped with a septum and cap for input of nitrogen, Tris(dibenzylideneacetone)dipalladium(0) (168 mg, 0,183 mmole), tricyclohexylphosphine (253 mg, 0,902 mmole) and 10 ml of dioxane. Was barbotirovany through the mixture for 15 min nitrogen, then stirred at RT for 1 h

2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-2H-isoquinoline-1-he (2.85 g, 5,88 mmole), potassium acetate (1,17 g, 11.9 mmole), bis(pinacolato)diboron (3,01 g, 11.9 mmole) and 20 ml of dioxane were loaded into the reaction vessel with a volume of 40 ml, equipped with a septum and cap for input of nitrogen. Was heated and stirred to dissolve all bis(pinacolato)diboron. The mixture was treated with ultrasound for 5 min, cooling to CT. Was barbotirovany through the mixture for 15 min nitrogen. Added by pipette kataliticheski the first solution, obtained above. Stirred the reaction mixture at 80°C for 23 hours was Added 126 mg of Tris(dibenzylideneacetone)diplegia(0) after 7 o'clock Cooled the reaction mixture to room temperature, and was filtered to remove solids. Solvent was removed from the filtrate in vacuo. The residue was dissolved in 100 ml of Et2O and washed with 50 ml water and 50 ml saturated sodium chloride solution. Dried solution of MgSO4and concentrated in vacuum. The residue was purified accelerated chromatography (gradient elution from 0 to 25% EtOAc/hexane). Recrystallized from hexane to obtain 2-[2-(tert-butyldimethylsilyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6-cyclopropyl-2H-isoquinoline-1-it is in the form of a whitish crystalline solid (1,16 g, 2.18 mmole). MS (ESI) 532 (M+H).

Example 181

Methyl-3-[5-(4-methylpiperazin-1-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine-2-he (104 mg, 0,256 mmole), 2-[2-(tert-butyldimethylsilyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6-cyclopropyl-2H-isoquinoline-1-he (124 mg, 0,233 mmole), 2 ml of dioxane, 200 ál of DMF and 0,86 mg/ml solution of cesium carbonate in water (450 μl, 1.2 mmole) was loaded into the reaction vessel with a volume of 4 ml, equipped with a mechanical stirrer and septum. Was barbotirovany through a mixture of nitrogen for 5 minutes was Added to the chloride

[1,1'bis(diphenylphosphino)ferrocene]palladium(P) 1:1 complex with dichloromethane (10 mg, a 0.012 mmole). The reaction mixture was barbotirovany nitrogen for 5 minutes, the Vessel was sealed and stirred at 90°C for 16 hours was Cooled to CT, and the reaction mixture was filtered through a 300 mg C18 cartridge. Washed the cartridge with 4 ml of EtOAc, 4 ml of water and 4 ml of EtOAc. Divided the phases of the filtrate, and the organic phase is washed with 5 ml water and 5 ml of saturated solution of sodium chloride. Dried solution of Na2SO4and concentrated in vacuum. Purified accelerated chromatography C18 reverse phase (gradient elution from 10 to 95% acetonitrile+0.1% TFWC/water+0.1% TFUC). Added 1 ml of a saturated solution of NaHCO3to the combined product fractions and concentrated in vacuum. The resulting aqueous was extracted with a mixture of 2×10 ml of CH2Cl2, dried Na2SO4and concentrated in vacuo to obtain 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-isoquinoline-1-it is in the form of a whitish solid. (80 mg, of 0.13 mmole). MS (ESI) 617 (M+H)+.

Example 182

Methyl-3-(5-morpholine-4-iletileri-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-pyridin-2-he (96 mg, 0.25 mmole), 2-[2-(tert-butyldimethylsilyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-diox brolan-2-yl)phenyl]-6-cyclopropyl-2H-isoquinoline-1-he (124 mg, 0,233 mmole), 2 ml of dioxane and 0,86 mg/ml solution of cesium carbonate in water (450 μl, 1.2 mmole) was loaded into the reaction vessel with a volume of 4 ml, equipped with a mechanical stirrer and septum. Was barbotirovany mixture with nitrogen for 5 min chloride was Added [1,1'bis(diphenylphosphino)ferrocene]palladium(P) 1:1 complex with dichloromethane (10 mg, a 0.012 mmole). The reaction mixture was barbotirovany nitrogen for 5 minutes Closed vessel and stirred at 90°C for 16 hours was Cooled to CT and was filtered the reaction mixture through a 300 mg With 18 cartridge. Washed the cartridge with 4 ml of EtOAc, 4 ml of water and 4 ml of EtOAc. Separated phases of the filtrate, and the organic phase is washed with 5 ml water and 5 ml of saturated solution of sodium chloride. Dried solution of Na2SO4and concentrated in vacuum. Purified accelerated chromatography With 18 reverse phase (gradient elution from 10 to 95% acetonitrile +0.1% TFWC/water+0.1% TFUC). Added 1 ml of a saturated solution of NaHCO3to the combined product fractions and concentrated in vacuum. The resulting aqueous was extracted with a mixture of 2×10 ml of CH2Cl2, dried Na2SO4and concentrated in vacuo to obtain 6-cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-iletileri-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-it is in the form of a whitish solid. (73 mg, 0.12 mmole). MS (ESI) 590 (M+N)+.

Example 183

p>

Fresh 2,2,6,6-tetramethylpiperidine (0,476 g, 3,37 mmole) was dissolved with stirring in 10 ml of anhydrous tetrahydrofuran, and cooled using a mixture baths ethylene glycol/dry ice to -40°C. was Added dropwise N-utility, 2.5 M in hexane (1,26 ml, and 3.16 mmole), and the temperature was maintained around -40°C and stirred additionally for 30 min at -40°C. was Added a solution of N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-4-cyclopropyl-2-methylbenzamide (0,200 g, 0,421 mmole) in 5 ml of anhydrous tetrahydrofuran is added dropwise within 10 minutes to the reaction mixture at -40°C. the Reaction mixture was stirred additionally for 1 h then the solution was added N-methoxy-N-methylacetamide (0,435 g, or 33.7 mmole) in 2 ml of anhydrous THF in one piece in a very short period. Then the reaction mixture was left to warm to 0°C. the Mixture was stirred for 1 hour at 0°C. was Added 5 ml of 10% aqueous hydrochloric acid solution, and was stirred for 30 min at room temperature, extracted with ethyl acetate; washed with water and saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and concentrated. Received 0,223 g orange resinous substance. The residue was purified by chromatography on a 24 g silica gel (gradient elution 0-10% methanol in dichloro is not within 30 min) to give 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-3-methyl-2H-isoquinoline-1-it (of 0.066 g, 0,132 mmole) MS (ESI) 522,0 (M+Na)+.

Example 184

2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-6-cyclopropyl-3-methyl-2H-isoquinoline-1-he (0,045 g, 0,0903 mmole), 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (0,040 g, 0,0903 mmole) and cesium carbonate (0,089 g, 0,271 mmole) was treated with degassed solution of 1.5 ml of dioxane/0.5 ml water. After 5 min stirring was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0,007 g 0,009 mmole) and heated at 135°C for 30 min in a microwave oven. The reaction mixture was filtered through cellulose, washed with 10 ml of dioxane and concentrated in vacuum. The residue was purified by chromatography on silica gel (gradient elution 0-10% methanol in dichloromethane for 20 min) to give 2-(2-(tert-butyldimethylsilyloxy)-3-{1-methyl-5-[5-morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-6-cyclopropyl-3-methyl-2H-isoquinoline-1-it (0,043 mg, 0,0587 mmole) MS (ESI) 732,2 (M+H)+.

Example 185

2-(2-(tert-Butyldimethylsilyloxy)-3-{1-methyl-5-[5-morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl} phenyl)-6-cyclopropyl-3-methyl-2H-isoquinoline-1-he (0,043 mg, 0,0587 mmole) was dissolved in 2 ml of anhydrous tetrahydrofuran, and cooled to 0°C in Leda the bath Oh. Added tetrabutylammonium fluoride, 1 M solution in THF (0,064 ml, 0,0646 mmole), and stirred for 1 hour at 0°C.

After the reaction mixture was extracted with a mixture of ethyl acetate/water. The organic phase was dried with sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution 0-10% methanol in dichloromethane for 20 min) to give 6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-3-methyl-2H-isoquinoline-1-it (0,010 g, 0,0162 mmole) MS (ESI) 618,2 (M+N)+.

Example 186

Morpholine (2,98 ml, 34.4 mmole), tert-butoxyethanol acid (4,485 g, 34.4 mmole) and HATU (13,093 g, 34.4 mmole) was dissolved in 15 ml of dimethylformamide. The reaction mixture was stirred over night at room temperature. The mixture was extracted with ethyl acetate, and the organic phase is washed with water, sodium bicarbonate solution, 1M HCl solution and then a saturated solution of sodium chloride. The organic phase was dried with sodium sulfate, filtered, and concentrated to obtain 2-tert-butoxy-1-morpholine-4-ratanana (2,170 g, 10,78 mmole).

Example 187

Fresh 2,2,6,6-tetramethylpiperidine (1.3 g, 9,48 mmole) was dissolved in 8 ml of anhydrous tetrahydrofuran, and cooled with OSU baths with a mixture of ethylene glycol/ice ice to -40°C. Was added dropwise N-utility, 2.5 M in hexane (2.7 ml, 8,43 mmole), and the temperature was maintained around -40°C and stirred additionally for 30 min at -40°C. To the reaction mixture was added dropwise a solution of N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-4-cyclopropyl-2-methylbenzamide (1 g, 2,11 mmole) in 3 ml of anhydrous tetrahydrofuran for 10 minutes at -40°C. the Reaction mixture was stirred additionally for 1 hour. After this solution was added 2-tert-butoxy-1-morpholine-4-ratanana (2,248 g, 11,17 mmole) in 4 ml of anhydrous tetrahydrofuran in one piece for a very short period of time. Then the reaction mixture was left to warm to 0°C. the Mixture was stirred for 1 hour at 0°C. was Added to 2.3 ml of 10% aqueous hydrochloric acid solution, and was stirred for 30 min at room temperature, extracted with ethyl acetate; washed with water and saturated sodium chloride solution. The organic phase was dried with sodium sulfate; filtered; concentrated; received orange resinous substance. The residue was purified by chromatography on 100 g of silica gel (gradient elution 0-50% ethyl acetate in hexane for 30 min) to obtain compound A: 2-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-tert-butoxymethyl-6-cyclopropyl-2H-isoquinoline-1-he (0,485 g of 0.85 mmole) MS (ESI) 594.1 nm (M+Na)+.

Por the measures 188

2-[3-Bromo-2-(tert-butyldimethylsilyloxy)phenyl]-3-tert-butoxymethyl-6-cyclopropyl-2H-isoquinoline-1-he (0,100 g, 0,175 mmole), 1-methyl-3-(5-morpholine-4-espiridion-2-ylamino)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-he (0,079 g, 0,193 mmole), cesium carbonate (0,200 g, 0,613 mmole) was treated with 2 ml of dioxane and 0.5 ml of water. Was added [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0,014 g, 0,0175 mmole) and heated at 135°C for 35 min under microwave irradiation. The reaction mixture was filtered; washed with dichloromethane; concentrated; purification column chromatography on 12 g of silica gel using 0-10% methanol in dichloromethane for 25 min;

received 124 mg of a brown resinous substance.

The crude material was dissolved in 3 ml of dioxane; was treated with 0.4 ml of 6 N HCl solution; heated heat gun in a closed vessel to microwave radiation for 30 seconds; were extracted with ethyl acetate and sodium bicarbonate solution. The organic phase was concentrated and purified by chromatography on 12 g of silica gel using a 0-30% methanol in dichloromethane for 25 min with a production of 6-cyclopropyl-3-hydroxymethyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-espiridion-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]phenyl}-2H-isoquinoline-1-she is 0.023 g of 0.038 mmole) MS (ESI) 606,1 (M+N)+.

Example 189/u>

To a clear solution of 5-fluoro-3-aminotoluene (4,00 g, 32.0 mmole) in glacial acetic acid (193 ml) was added paraformaldehyde (9,40 g, 313 mmole), then cyanoborohydride sodium (9,48 g, 151 mmol). Watched the evolution of gas, and cloudy white mixture was stirred at RT. After 7 h the reaction mixture was poured into ice 0.1 M NaOH solution (400 ml) and the aqueous solution was extracted with CH2Cl2(2×200 ml). The combined organic extracts were dried (MgSO4), was filtered and concentrated in vacuum to obtain a purple oil which was purified accelerated by chromatography (SiO2, 0%-5% EtOAc/hexane) to give (3-fluoro-5-were)amine as a yellow oil (2,84 g, 58%).

Example 190

To a solution of (3-fluoro-5-were)dimethylamine (2,82 g, an 18.4 mmole) in acetonitrile (28 ml), was added ammonium acetate (0,142 g of 1.84 mmole) and a solution of N-bromosuccinimide (3,27 g, an 18.4 mmole) in acetonitrile (23 ml) dropwise at 0°C. After 1 h at RT the solvent was changed in EtOAc and the solution washed with saturated NaHCO3(aq.), dried (MgSO4), was filtered and concentrated in vacuum to obtain an orange oily residue. Purification of this oil is accelerated by chromatography (SiO2with 5% EtOAc/hexane) yielded (4-bromo-3-fluoro-5-were)dimethylamine is a solid ivory (3,96 g, 93%).

Example 191

At 0°C to a solution of PrMgCl (9,10 ml, 2.0 M THF, 1.2 equiv.) in THF (14 ml) was added uLi (22,3 ml, 1.6 M hexane, 2.4 equiv.). After 10 min now yellow homogeneous solution was cooled to -78 C, and to the mixture was added a solution of (4-bromo-3-fluoro-5-were)dimethylamine (3,52 g, 15.2 mmole) in THF (18 ml). Yellow color then disappeared, according to TLC after 20 min of starting material was not detected. COr(gas) cannula transferred into the reaction mixture, which was heated up to CT, 20 min, and added to IN the NaOH solution. The aqueous layer was acidified IN a solution of HCl (aq.) and was extracted with EtOAc. The organic extracts were dried (MgSO4), was filtered, concentrated in vacuo to obtain a crude solid, which was purified accelerated by chromatography (SiO2, 40%-100% EtOAc/hexane) to give 4-dimethylamino-2-fluoro-6-methylbenzoic acid as a white solid (2.91 in g, 97%).

Example 192

To a suspension of 4-dimethylamino-2-fluoro-6-methylbenzoic acid (0,896 g, 4.54 mmole) in THF (11 ml) was added carbonyldiimidazole (0,958 g, 5,91 mmole). The solution became homogeneous when bubbling. After 30 min this solution was added to concentrated ammonium hydroxide solution (7 ml), and the solution became turbid. After removal of the solvent after 1 h, the residue was transferred into a H2About who was filtered to obtain 4-dimethylamino-2-fluoro-6-methylbenzamide in the form of a white solid (0,696 g, 78%).

Example 193

A suspension of 4-dimethylamino-2-fluoro-6-methylbenzamide (0,696 g, 3,55 mmole) dimethylphenylpiperazinium (0,551 ml, 3,90 mmole) in THF (3 ml) was heated at 60°C. After 14 h, the solvent was removed to obtain 4-dimethylamino-N-[1-dimethylamino-(E)-ilidene]-2-fluoro-6-methylbenzamide in the form of oil, which gradually painted in white solid (0,890 g, 100%).

Example 194

To a clear solution of 4-dimethylamino-N-[1-dimethylamino-(E)-ilidene]-2-fluoro-6-methylbenzamide (0,709 g, 2,82 mmole) in THF (2 ml) was added tert-piperonyl potassium (2,8 ml, 1.0 M in THF, 1.0 equiv.), and the resulting brown homogeneous reaction mixture is boiled under reflux. After 1 h the reaction mixture was extinguished 1M citric acid solution (1 equiv.), dried (MgSO4), was filtered and concentrated in vacuum to obtain a yellow solid, which was purified by preparative chromatography on a plate (50% 60/10/1 CH2Cl2/MeOH/NH4OH in CH2CL2) to give 6-dimethylamino-8-fluoro-2H-isoquinoline-1-it is in the form of a white solid (0.104 g g, 18%).

Example 195

2-Bromo-6-chloro-3-forbindelse: To the solution at -78°C. 2-bromo-4-chloro-1-fervently (2,90 g, 13.9 mmole) in 30 ml of tetrahydrofuran under nitrogen atmosphere was added Rast the EOS diisopropylamide lithium (1.8 M) in a mixture tetrahydrofuran/heptane/ethylbenzene, 10.0 ml, 18.0 mmol) with such a rate that the internal reaction temperature did not exceed -69°C. After 1 hour at -78°C was added dimethylformamide (1.39 ml of 18.0 mmole) such a rate that the internal reaction temperature did not exceed -69°C. After 30 minutes at -78°C. the reaction was suppressed saturated aqueous solution of ammonium hydroxide. The resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous magnesium sulfate, concentrated in vacuum and purified accelerated chromatography (gradient elution 0 to 5% ethyl acetate/hexane) to give 2-bromo-6-chloro-3-forventelige (440 mg, of 1.85 mmole). MS (ESI) EUR 236.9 (M+H)+.

Example 196

For dissolved copper sulfate (II) (3,56 g, 22 mmole, 1.2 equiv.) in 15 ml of water was added 10 g of ice, stirred to homogeneity. Added KCN (6,05 g, 93 mmole, 5 equiv.), with internal thermometer, slowly, keeping the temperature below 20°With periodic addition of ice. The precipitate was dissolved at the end of the Appendix. Added NaHCO3(12.5 g, 149 mmol, 8 equiv.) and benzene (20 ml). Heated the mixture to 50°C. In a separate flask was dissolved 2,6-dibromo-4-ftoranila (Aldrich, 5.0 g, 19 mmol, 1 equiv.) in 8 ml of water and 13 ml of acetic acid. Was added dropwise H2SO4, (5.6 g, 2.8 equiv.). The mixture was heated, and it became homogeneous is. Was cooled to 5 °C., was added NaNO2(1.4 g, 20 mmol, 1.1 equiv.), was dissolved in 10 ml water is added slowly with rapid stirring, keeping the temperature at 10°C (internal thermometer). Was stirred 15 minutes, and then the solution was added the page to a solution of CuCN, heating a solution of CuCN at 50°C with rapid stirring, dropwise over 20 minutes. Was stirred 45 minutes at 50°C, cooled to room temperature in a water bath, was extracted with benzene 2, washed with benzene 1 N NaOH solution was again extracted with water and ether 1x, were combined, washed with a saturated solution of sodium chloride, dried MgSO4. Was evaporated on a rotary evaporator, was chromatographically (5% ethyl acetate in hexane) to give a pink solid, 2,22, M+N=278.

Example 197

Cooled 2.2 g of 2,6-dibromo-4-perbenzoate (8 mmol, 1 equiv.) to 0°C in 10 ml of CH2Cl2added to 8.7 ml of a 1 molar solution of DIBAL in CH2Cl2within 5 minutes. Left to warm to room temperature for 30 minutes was Added 20 ml of ether, then extinguished 10 ml of 3 N HCl. Mixed, heated at 40°C for 1 hour. Was cooled, diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried MgSO4. Was evaporated on a rotary evaporator, was chromatographically (elwira 10% ethyl acetate/hexane) from gaining the m of 2.1 g of solid substance. Dissolve the solid in 10 ml of THF, was added 5 ml of 1 N HCl solution. Was stirred at RT for 30 min, diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried MgSO4. Solvent was removed under reduced pressure to obtain a solid substance, 1.68 g of 2,6-dibromo-4-forventelige. MS (ESI) 281,0 (M+N)+.

Example 198

United 0,948 g (3.4 mmole, 2 equiv.) 2,6-dibromo-4-forventelige, 0,320 g (1.7 mmole, 1 equiv.) 6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-it, 29 mg of Xanthos (0,050 mmole, of 0.03 equiv.), 19 mg of bis(dibenzylideneacetone)palladium (0,033 mmole, of 0.02 equiv.) and 1.09 g of cesium carbonate (3 mmole, 2.0 equiv.) in 5 ml of dioxane, was passing argon through the mixture for 1 minute, closed reaction vessel and heated at 100°C for 3 hours, then was cooled to 80°C. and was heated for 14 hours. Was cooled, diluted with ethyl acetate, washed with water 2, a saturated solution of sodium chloride, dried MgSO4. Was evaporated on a rotary evaporator, was chromatographically (from 10% to 30% ethyl acetate in hexane) to obtain a solid substance, 325 mg of 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-4-forventelige. MS (ESI) 391,0 (M+H).

Example 199

To a mixture of hydroxylamine hydrochloride (18,4 mg of 0.26 mmole) and NaOMe (14 mg, of 0.26 mmole) in Meon (2 ml) add the Yali aldehyde (100 mg, of 0.18 mmole) in THF (2 ml). The reaction mixture was stirred at 60°C overnight and then was cooled to CT. The solvent was evaporated under reduced pressure, and the residue was purified accelerated chromatography (0-10% Meon/DHM) to give 64 mg (57%) of the target oxime as a brown solid. MS (ESI) 623,0 (M+N)+

Example 200

To a stirred solution of 5-bromopyridin-2-ylamine (100 mg, 0,578 mmole) in dry THF was added acetic anhydride (70,25 mg, 0,693 mmole). The reaction mixture was stirred at 20°C for 12 h THF drove away, and to the residue was added ethyl acetate. The organic layer was washed with saturated solution of NaHCO3and dried with anhydrous sodium sulfate. Removal of solvent resulted in the receipt of M-(5-bromopyridin-2-yl)ndimethylacetamide (100 mg, 80%). It was used in the next stage without additional purification.

Example 201

To a stirred solution of M-(5-bromopyridin-2-yl)ndimethylacetamide (1 g, 4.6 mmole) in 30 ml of CH3CN was added ClCF2COONa (848 mg, to 5.58 mmole), then 18-crown-6 (244 mg, of 0.93 mmole). The reaction mixture was heated at the boil under reflux for 12 hours Then the reaction mixture was cooled, and the solvent was removed under reduced pressure. To the mixture was added methylenechloride and washed with water. The organic layer was dried with dry sulphate of soda is I and concentrated under reduced pressure to obtain crude N-[5-bromo-1-deformity-1H-pyridin-(2E)-ilidene]ndimethylacetamide. It was used in the next stage without additional purification.

Example 202

To a stirred solution of crude 1M-[5-bromo-1-deformity-1H-pyridin-(2E)-ilidene]ndimethylacetamide (1 g) in 10 ml of CH3CN was added 1% KHSO4in water (10 ml). The reaction mixture was heated at the boil under reflux for 3 hours, the Reaction mixture was cooled, and the solvent was removed under reduced pressure. Without treatment, this crude product was purified column chromatography using 10% ethyl acetate in hexane to obtain 5-bromo-1-deformity-1H-pyridine-2-she (550 mg, 52%).

Example 203

To a stirred solution of 5-bromo-1-deformity-1H-pyridine-2-it (1 g, of 4.46 mmole) in 7 ml of acetic acid was added bromine (0,24 ml of 4.46 mmole) dropwise at 0°C, and then the reaction mixture was stirred at RT for 12 h Acetic acid was removed under reduced pressure. To the mixture was added ethyl acetate and washed with aq. a solution of NaHCO3. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was purified column chromatography using 5% ethyl acetate in hexane to obtain 3,5-dibromo-1-deformity-1H-pyridine-2-she (900 mg, 66.5 per cent).

Example 204

Solid NaBH4(44 mg, 1.16 mmole) was added four what orciani to a solution of oxime (120 mg, to 0.19 mmole) and NiCl2·6H2O (276 mg, 1.16 mmole) in Meon (2 ml) at 0°C. After the gas evolution stops the solution was left to warm to CT, and maintained at RT for 30 minutes was added dropwise aqueous HCl (2 ml) (gas evolution) and the resulting suspension was stirred intensively at RT for 30 min the Mixture was brought to pH~7 by adding saturated aqueous solution of NaHCO3, was extracted with EtOAc (3×15 ml) and concentrated in vacuum. The residue was purified by chromatography on SiO2(0-15% MeOH/CH2Cl2) to obtain 40 mg (34%) of the target amine as a white foam.

Example 205

Degassed dioxane (5 ml) was added to a sealable flask equipped with a Teflon septum containing aminopyridin (601 mg, 1.44 mmole), 2-chloropyridin (378 mg, 1.44 mmole), Pd(dba)2(42 mg, 0,072 mmole), chloride 1,3-bis(2,6-diisopropylphenyl)-1H-imidazole (62 mg, of 0.14 mmole) and tert-BuOK (242 mg, of 2.15 mmole) in Ar atmosphere. The mixture was maintained at 100°C for 4.5 h, the Mixture was cooled to CT, diluted in CH2Cl2(50 ml), washed with H2O (25 ml) and saturated sodium chloride solution (25 ml), dried MgSO4and concentrated in vacuum. The obtained brown solid was purified by chromatography on SiO2(0-5% MeOH/CH2Cl2) to give 620 mg (67%) of the target diaminopyridine in the form of a whitish amorphous powder.

P the emer 206

A suspension of Pd/C (10%, 30 mg) in N2About (2 ml) was added by pipette to a suspension of carbamate (601 mg, of 0.93 mmole) in degassed Meon (50 ml). The suspension was saturated with H2from a container and stirred intensively at RT for 18 hours

The suspension was filtered through celite and concentrated in vacuum.

The brown residue was then purified by chromatography on SiO2(0-15% MeOH/CH2Cl2with getting 342 mg (72%) of the target diaminopyridine in the form of transparent foam.

Example 207

Acetylchloride (9 μl, 0.12 mmole) was added dropwise to a solution of diaminopyridine (58 mg, of 0.11 mmole) in CH2Cl2(1.0 ml) at 0°C. the Solution was left to warm to CT, and maintained at RT for 1.0 hours the Solution was diluted with CH2CL2(10 ml), washed with saturated solution of NaHCO3(2×10 ml) and a saturated solution of sodium chloride (10 ml), dried Na2SO4and concentrated in vacuum. The brown residue was then purified by chromatography on SiO2(0-12% MeOH/CH2Cl2) to obtain 32 mg (52%) of the target ndimethylacetamide in the form of transparent foam.

Example 208

Degassed toluene (5 ml) was added to a sealable flask equipped with a Teflon septum, containing aminoimidazole (117 mg, of 0.56 mmole), dibromopyridin (167 mg, 0.67 mmole), Pd(dba) (29 mg, 0.03 mmole), ligand Xanthos 935 mg to 0.06 mmole) and Cs2CO3(550 mg, 1.68 mmole) in Ar atmosphere, and the mixture was maintained at 100°C during the night. The solvent was removed in vacuum and the brown residue was then purified by chromatography on SiO2(0-4% MeOH/CH2Cl2) to obtain 75 mg (30%) of the desired product as a white solid. (M+N)=297.

Example 209

A mixture of bromopyridine (60 mg, 0.15 mmole), boronate (75 mg, 0.15 mmole), Pd(dba)z (4 mg, 0,0075 mmole), XPhos ligand (7 mg, 0.015 mmole)3RHO4(63 mg, 0.3 mmole) in tert-BuOH (3.0 ml) and N2O (0.3 ml) was maintained at 100°C in a microwave reactor for three hours. After removal of solvent the residue was purified accelerated chromatography (0-8% Meon/DHM), then preparative TLC (5% Meon/DHM) to give 7 mg (10%) of the desired product as a yellow film (M+1)+=513.

Example 210

A mixture of 2-chloro-5-chloromethylpyridine (486 mg, 3 mmole), 2-methoxy-ethylamine (310 μl, 3.6 mmole) and triethylamine (300 μl) in 10 ml of acetonitrile was heated at 60°C over night. The solvent was removed in vacuum. The residue was separated between EtOAc and water. The organic phase was washed with a saturated solution of sodium chloride, dried MgSO4. The residue was purified accelerated chromatography (0-8% Meon/DHM) to give 287 mg (48%) of the target amine in videobesten fluid. MS (ESI) 201,0 (M+H).

Example 211

A mixture of chloropyridine (160 mg, 0.8 mmole), di-tert-BUTYLCARBAMATE (210 mg, 096 mmole) and diisopropylethylamine (210 μl, 1.2 mmole) in 10 ml DHM was left at RT overnight. The solvent was removed in vacuum. The residue was purified accelerated chromatography (0-25% EtOAc/hexane) to give 215 mg (90%) of the target carbamate as a colourless liquid.

Example 212

A mixture of chloropyridine (42 mg, of 0.14 mmole), aminopyridine (58 mg, of 0.14 mmole), Pd(dba)2(4 mg, 0,0075 mmole), chloride 1,3-bis(2,6-diisopropylphenyl)-1H-imidazole (6 mg, of 0.014 mmole), Kotleti (24 mg, of 0.21 mmole) in dioxane (5.0 ml) were subjected to reaction using the method described in example 210 (method 3). The product mixture was then concentrated and dissolved in a mixture of TFUCK:DHM (1:1, 5 ml) and left at RT for 2 h the Reaction mixture was concentrated, and the residue was purified accelerated chromatography (0-10% Meon/DHM) to obtain 28 mg (35%) target secondary amine as light yellow film. MS (ESI) 583,0 (M+N)+.

Example 213

A suspension of Pd/C (10%, 40 mg) in H2O (2 ml) was added by pipette to a solution of intorimidazole (300 mg, 0,1,23 mmole) in degassed EtOH (10 ml).

The reaction mixture was saturated with H2from the container, and stirred intensively at RT for 18 h, the Suspension of adfilter the Wali through celite and concentrated in vacuum to obtain 271 mg sensitive to air 2-aminoimidazole, who was directly subjected to the reaction with N-methyl-3,5-dibromopyridine (260 mg, 1.0 mmol), Pd(dba)2(52 mg, 0.05 mmole), ligand xanthosoma (58 mg, 0.10 mmole) and Cs2CO3(577 mg, 3.0 mmole) in PhMe (5 ml) under conditions described in method 6, to obtain 100 mg (25%) of the desired product as a brown foam.

Example 214

Bromperidol (60 mg, 0.15 mmole) and boronat (70 mg, 0.15 mmole) was subjected to a condensation Suzuki and saponification of the acetate using the conditions described in example 209 (method 7). After removal of the solvents the crude residue (30 mg) was treated with a mixture of TFUCK:DHM (1:1, 5 ml) and maintained at RT for 2 h to remove the SEM protective group. The reaction mixture was concentrated, and the residue was purified preparative thin-layer chromatography (5% Meon/DHM) to obtain 15 mg (30%) target 2-aminoimidazole in the form of a light yellow foam. MS (ESI) 485,0 (M+N)+.

Example 215

Phenylchloropyruvate (2,32 ml, 3 equiv.) in acetone (3 ml) was added dropwise to a suspension of potassium thiocyanate (1,79 g, 3 equiv.) in acetone (12 ml) within 5 minutes After stirring for 10 min, the suspension was heated at 60°C for 10 min, after which the mixture was cooled to room temperature. To this suspension was added aminopyridin (1,25 g, x 6.15 mmole) in acetone (5 ml) and the mixture stirred the night. The mixture then was filtered, washed with dichloromethane, concentrated in vacuo and was chromatographically (from 50% to 100% EtOAc/hexane) to give the slightly polluted brompheniramine (1.80 g, ~77%).

Example 216

Methylhydrazine (500 μl, 2 equiv) was added dropwise to a solution of brompheniramine (1.80 g, ~4,70 mmole) in THF (30 ml). After stirring for 1 h the suspension was diluted with Et2O (30 ml), was filtered and washed still Et2O (30 ml) to produce bromhidrosis (800 mg, 51%).

Example 217

Bromhidrosis (800 mg, 2,39 mmole) suspended in EtOH (50 ml) was boiled under reflux for 48 hours After the reaction according to the LCMS, the suspension was diluted with Et2O (50 ml), was filtered and washed still Et2O (25 ml) to obtain patriation (575 mg, 80%).

Example 218

2-Chloro-5-chloromethylpyridine (1 g, 6.2 mmole) was dissolved in 15 ml of dry ethanol. After cooling in an ice bath to this solution was added NaH (248 mg, 60%, 6.2 mmole). The reaction mixture was heated to CT and was stirred for 16 hours. After this reaction extinguished 15 ml of a mixture of ice-water and was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with a saturated solution of sodium chloride, dried with sodium sulfate and concentrate the Wali in vacuum. The residue was purified column chromatography using 5% -10% ethyl acetate in hexane to obtain 400 mg of 2-chloro-5-ethoxymethyleneamino (yield 37%).

Example 219

3-Amino-5-bromo-1-methyl-1H-pyridine-2-he (392 mg, of 1.93 mmole) were placed in 13 ml of n-butanol. To this mixture in an argon atmosphere was added: Pddba2(55,2 mg, 0,096 mmole), X-Phos (91,2 mg, 0,191 mmole), 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl ether acetic acid (900 mg, of 1.93 mmole), potassium phosphate (814 mg, of 3.84 mmole) and 4 ml of water. The mixture was heated in an argon atmosphere in a sealed flask for 45 minutes at 100-110 C. After cooling, the mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuum. The residue was purified column chromatography using 5% methanol in dihlormetilen, to obtain 450 mg of 2-(5-amino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (49% yield).

Example 220

2-Chloro-5-ethoxypyridine (23 mg, 0,134 mmole) was dissolved in 2 ml of dioxane. To this solution was added in an argon atmosphere chloride 1,3-bis-(2,6-diisopropylphenyl)imidazoline (12 mg,0,028 mmole), Pd2dba3(12 mg, of 0.013 mmole), the compound (II) (56 mg, 0,143 mmole) and NaOTpBu (20 mg, of 0.21 mmole). The mixture was heated in an argon atmosphere at 100°C for 6 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuum. The residue was purified prep.TLC using 5% methanol in dihlormetilen, to obtain 23 mg of 6-dimethylamino-2-{3-[5-(5- ethoxymethylene-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-it (31% yield).

Example 221

A solution of 3,5-dibromo-1-methyl-1H-pyridine-2-she (200 mg, 0.75 mmole) in 4 ml of dioxane was placed in a flask microwave radiation, filled with argon. To this solution was added Xanthos (13 mg, of 0.022 mmole), Pd2dba3(16,8 mg, and 18.3 mmole), 5-methylisoxazol-3-ylamine (73,6 mg, 0.75 mmole) and phenoxide sodium (uniforms, 127.6 mg, 1.1 mmole). The flask was sealed and heated at 150°C using microwave radiation. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuum. The residue was treated with ethyl acetate. The resulting mixture was filtered, receiving 100 mg (47% yield) of 5-bromo-1-methyl-3-(5-methylisoxazol-3-ylamino)-1H-pyridine-2-it, which was used in the next stage without additional purification.

2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethylene]-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he (40 mg, 0,095 mmole) were placed in a mixture of 1.5 ml of dioxane and 0.5 ml of ethanol. To this mixture was added 2.5-dioxopiperidin-1 silt ether tsianuksusnogo acid, first 1 equivalent (17,4 mg, 0,095 mmole), and then within 3 days another 5 equivalents of this reagent with 2-4 hour intervals. At this time, the reaction mixture was heated at 50-60°C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuum. The residue was purified prep. TLC using 5% methanol in dihlormetilen with receiving 12 mg (26% yield) of 2-cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-yl}ndimethylacetamide.

Example 223

To a solution of 2-bromo-5-hydroxypyridine (1.0 g, of 5.75 mmole) and imidazole (0,59 g, 8,63 mmole) in 50 ml of dry dichloromethane was added tert-BUTYLCARBAMATE. The resulting suspension was stirred over night at RT. The mixture was washed 2×50 ml portions of water, dried Mg2SO4and concentrated on granular silica gel. The mixture was purified accelerated column chromatography on silica gel using 1:1 ethyl acetate/hexane to provide transparent yellow is the asle (1.1 g, 3.8 mmole).

Example 224

Were combined in a sealed flask 3-amino-5-bromo-1-methyl-1H-pyridine-2-he (or 0.38 g, 1.9 mmole), 2-bromo-5-(tert-butyldimethylsilyloxy)pyridine (0.54 g, 1.9 mmole) and Cs2CO3of 0.85 g, 2.6 mmole) in 5 ml of dry 1,4-dioxane. Through a mixture missed argon for 10 minutes. To the suspension was added Pd2(dba)3(0.12 g, of 0.13 mmole) and Xanthos (0.15 g, 0.26 per mmole). The vessel was closed and heated overnight at 85°C. the Cooled mixture was filtered through celite, concentrated and purified on preparative plate using 1:1 ethyl acetate/hexane to obtain 0,46 g (1.1 mmole) of the desired product as a pale yellow solid.

Example 225

To a solution of 5-bromo-3-(5-hydroxypyridine-2-ylamino)-1-methyl-1 H-pyridin-2-it in 35 ml of dry THF was added 1M TBAF in THF (2,59 ml, at 2.59 mmole) at 0°C. the Reaction mixture was stirred for 20 minutes and extinguished 10 ml of water. The reaction mixture was separated between water and ethyl acetate, dried Mg2SO4and concentrated to obtain 0,78 g of a white solid substance of the target phenol.

Example 226

In 4 ml of dry DMF was combined 5-bromo-3-(5-hydroxypyridine-2-ylamino)-1-methyl-1H-pyridine-2-he (0.1 g, 0.34 in mmole), 2-bromoacetamide (0.05 g, 0.37 mmole) and K2CO3(0.09 g, 0.68 mmole) at RT. WM is enzio was stirred for two hours at 60°C and over night at RT. The mixture was separated between ethyl acetate and water, dried Mg2SO4and concentrated to obtain 0.08 g of the desired product as a dark green solid.

Example 227

Were combined in a sealed flask 5-bromo-3-(5-hydroxypyridine-2-ylamino)-1-methyl-1H-pyridine-2-he (0.1 g, 0.34 in mmole), (2 bromoethoxy)-tert-butyldimethylsilyl (0,155 g 0,34 mmole) and K2CO3(0.09 g, 0.68 mmole) in 3 ml of dry DMF. The mixture was stirred over night at RT. The reaction mixture was separated between ethyl acetate and water, dried Mg2SO4concentrated and was purified on preparative plate using a mixture of 3:1 ethyl acetate/hexane. The target is protected alcohol was obtained in the form of a waxy solid (45 mg, 0.1 mmole).

Example 228

To a solution of TBS-protected alcohol (80 mg, of 0.13 mmole) in 1.5 ml mixture of 1:2 methylene chloride/methanol was added 3 drops of concentrated HCl. The solution was stirred in a closed vessel for three hours at RT. The reaction mixture was neutralized with 6 equivalents of MP-carbonate resin was filtered, concentrated and purified on preparative plate with 5% methanol in methylene chloride to obtain 13 mg of the desired product as a light brown solid.

Example 229

Closed in flask 2-the rum-6-yodellin-3-ol (6.0 g, 20 mmol), 2-bromoethoxy)-tert-butyldimethylsilyl (5.3 g, 22 mmole) and K2CO3(5.6 g, 40 mmol) in 10 ml dry DMF. The heterogeneous mixture was heated at 50°C during the night. To stir the reaction mixture was added portion 200 ml of water. Was obtained white precipitate was filtered under vacuum, washed with several small portions of water and dried in a vacuum oven at 60°C with getting to 8.62 g (18.9 mmole) light pink solid.

Example 230

In 4 ml of dry DMF suspended 86 mg (3.4 mmole) of NaH (95% in mineral oil) at RT. To this suspension was added 2-methoxyethanol (0,37 g, 4.9 mmole) and the mixture was stirred for one hour. To the reaction mixture was added a solution of 2-bromo-3-[2-(tert-butyldimethylsilyloxy)-ethoxy]-6-yodellin (1.5 g, 3.3 mmole) in 2.5 ml of dry DMF, and the combined suspension was heated at 100°C for two hours, and was cooled to CT during the night. The reaction was suppressed 100 ml of water and was extracted with diethyl ether. The combined organic material was concentrated and purified by chromatography on silica gel using a gradient of 10-20% ethyl acetate/hexane. The target product was isolated as a clear oil (0,47 g, the 1.04 mmole).

Example 231

Were combined in a sealable flask 3-amino-5-bromo-1-methyl-1H-pyridine-2-he (0.18 g, 0,86 mmole), tert-bout the l-{2-[4-iodine-2-(2-methoxyethoxy)phenoxy]ethoxy}dimethylsilane (0,47 g, the 1.04 mmole) and Cs2CO3(0,42 g, 1.3 mmole) in 10 ml of dry 1,4-dioxane. Through a mixture missed argon for 10 minutes. Added to this mixture, Pd(OAc)2(19 mg, and 0.09 mmole) and Xanthos (10 mg, 0,17 mmole). The reaction mixture was sealed and heated at 100°C for 3 hours, the Material was filtered through celite, dry inflicted on granules of silica gel, and was chromatographically gradient 30-75% ethyl acetate/hexane to obtain 0,19 g (0.35 mmole) of the target product.

Example 232

Were combined in a round bottom flask with a volume of 25 ml bromopyridin (0.18 g, 0.35 mmole), boronat (0.14 g, to 0.29 mmole) and Cs2CO3(0.24 g, 0.73 mmole) in 3 ml of 1,4-dioxane and 0.75 ml of water. Argon was passed through the stirred solution for ten minutes. To this solution was added PdCl2(dppf) (12 mg, 0.015 mmole) and the reaction mixture was heated for 3 hours at 100°C.

The cooled mixture was diluted with 2 ml of methanol, was added 0.75 ml of 1 M NaOH. The mixture was stirred for additional 2 hours, then treated with water and HCl2. The crude concentrated material was diluted in 2 ml of dry THF, was added dropwise a 1 M solution of TBAF in THF (0.15 ml, 0.15 mmole) and the reaction mixture was stirred at RT for 30 minutes. Added a portion of 10 ml of water to quench the reaction, and then was treated with water HCl3. The material was purified on preparative PL is the Steen using 5% methanol/methylene chloride to obtain a 13.1 mg (0.02 mmole) of the desired product as a light brown solid.

Example 233

A mixture of 5-bromo-2-nitropyridine (1.0 g, is 4.93 mmole), pyrrolidin-2-it (0,42 g is 4.93 mmole) and Cs2CO3(2.25 g, 6.9 mmole) in 15 ml dry toluene was stirred for 10 minutes in flowing argon. To the stirred suspension was added Pd2(dba)3(0,81 g, 0.2 mmole) and Binap (0.25 g, 0.4 mmole). The reaction mixture was heated at 80°C during the night. The cooled mixture was filtered through celite, concentrated and dry inflicted on granular silica gel. The reaction mixture was purified accelerated by chromatography on a column of silica gel, elwira 80% ethyl acetate/hexane to obtain the target product as a pale brown solid (0,821 g, 3.9 mmole).

Example 234

In a dry flask filled with argon, was added Pd/C Catalyst was carefully moistened with 10 ml of dry methanol. 1-(6-Methylpyridin-3-yl)pyrrolidin-2-he (0,82 g, 4.0 mmole) was diluted in 10 ml of dry dichloromethane and 20 ml of dry methanol and added to a suspension of the catalyst. Consistently through the reaction mixture missed three cylinder H2. The reaction mixture was stirred in an atmosphere of H2for 4 hours at RT. The suspension was filtered through Solka-Floc® and washed with methanol and ethyl acetate. Concentration of the filtrate resulted in the receipt of white solids Clevo what about aminopyridine (0,69 g, 3.9 mmole).

Example 235

Were combined in a sealable flask 3,5-dibromo-1-methyl-1H-pyridine-2-he (0.17 g, of 0.94 mmole), 1-(6-aminopyridine-3-yl)pyrrolidin-2-he (0.25 g, of 0.94 mmole) and Cs2CO3(of 0.43 g, 1.3 mmole) in 5 ml of dry 1,4-dioxane. Through a mixture missed argon for 10 minutes. To the suspension was added Pd2(dba)3(0.06 g, 0.07 mmole) and Xanthos (0.08 g, of 0.13 mmole). The vessel was closed and heated over night at 80°C. the Cooled mixture was filtered through celite, concentrated and purified on preparative plate using 2% Meon/DHM to obtain 0.08 g (0.2 mmole) light green solid.

Example 236. 4-tert-Butyl-N-(2-hydroxy-1,1-dimethylethyl)benzamide

30,95 g (347 mmol) of 2-amino-2-methyl-1-propanol was weighed in an Erlenmeyer flask of 500 ml, equipped with a mechanical stirrer and septum. Was added 200 ml of CH2CL2. Establishes and cultivates an atmosphere of nitrogen. They mixed the solution in a bath of ice/water. Was added dropwise 34 ml (174 mmole) of 4-tert-butylbenzoyl chloride for 30 minutes was Obtained a white precipitate. Was stirred at RT over night. Remove the solids by filtration and washed with CH2Cl2. Solvent was removed from the filtrate on a rotary evaporator, and dried at 60°C/4 Torr with getting 45,79 g is specified in the header connect the Oia in the form of a light yellow resinous substance. MS (ESI) 248 (M-H)-.

Example 237. 2-(4-tert-Butylphenyl)-4,4-dimethyl-4,5-dihydrooxazolo

All 4-tert-butyl-N-(2-hydroxy-1,1-dimethylethyl)benzamide obtained above (174 mmole) were loaded into a round bottom flask with a volume of 500 ml, equipped with a mechanical stirrer and septum. Establishes and cultivates an atmosphere of nitrogen. Was added dropwise 50 ml (685 mmol) of thionyl chloride for 20 minutes was Heated flask heat gun to dissolve a certain amount of resin and initiating the reaction. The reaction mixture was hardened. The flask was heated heat gun to dissolve all solids. Was cooled to CT. Poured the reaction solution in a thin stream into 500 ml of stirred Et2O. white precipitate was Formed. Collected precipitate filtered and washed with Et2O. was Dissolved collected solid in 300 ml of water and neutralized with 25% NaOH. Was extracted with yellow aqueous solution of 2×200 ml Et2O. Washed yellow 200 extracts a saturated solution of sodium chloride, dried MgSO4and solvent was removed on a rotary evaporator to obtain 28,50 g specified in the connection header in the form of a waxy white solid. MS (ESI) 232 (M+N)+.

Example 238. 5-tert-Butyl-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)benzaldehyde

Dried in the oven 3-g is rluu a round bottom flask of 250 ml, was equipped with a thermometer, mechanical stirrer, septum and cap for input of nitrogen. Added 8,02 g (to 34.7 mmole) of 2-(4-tert-butylphenyl)-4,4-dimethyl-4,5-dihydrooxazolo. Establishes and cultivates an atmosphere of N2. Added 100 ml of anhydrous THF. Were clear solution is cooled to -78°C. was Stirred rapidly and dropwise added 17 ml (43 mmole) of a 2.5 M solution of n-utility in hexane for 10 minutes. Mixed clear amber solution at -20°C for 4 h, the Reaction mixture became red-amber and cloudy. Cooled the mixture to -78°C. was Stirred rapidly and was added dropwise 12 ml of DMF with such a rate as to maintain the temperature below -60°C. was Stirred at -78°C for 15 minutes was Stirred at -20°C for 1 h was Stirred at RT for 1 h Extinguished 100 ml of 0.5 M aqueous solution of KHSO4. The aqueous phase was still strongly alkaline. Was added 1.0 M KHSO4to pH~2. Diluted two-phase solution of 300 ml Et2O. phase was Separated, and the aqueous phase is extracted with 100 ml of Et2O. Washed the combined organic phase 200 ml of a saturated solution of sodium chloride and was dried To2CO3. Was filtered through a 120 g silica gel, and washed with 300 ml Et2O to remove basic impurities. Solvent was removed on a rotary evaporator to obtain 8,18 g specified in the connection header in view of the clear yellow liquid. MS (ESI) 260 (M+N)+.

Example 239. 2-(4-tert-Butyl-2-1,3-dioxine-2-ylphenyl)-4,4-dimethyl-4,5-dihydrooxazolo

8,10 g (31,2 mmole) of 5-tert-butyl-2-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)benzaldehyde was weighed in a round bottom flask of 500 ml, equipped with a mechanical stirrer and a trap Dean-stark. Added 300 ml of benzene and stirred to obtain a transparent yellow solution. Added 383 mg (1.52 mmole) of n-toluensulfonate pyridinium. Added 11.3 ml (156 mmol) of 1,3-propane diol. Heated the solution at the boil under reflux for 17 hours was Cooled to CT. Washed the reaction mixture with 200 ml of 50% saturated aqueous NaHCO3200 ml water and 200 ml of saturated solution of sodium chloride. Dried MgSO4, and the solvent was removed on a rotary evaporator. Purified accelerated by chromatography on silica gel using isocrates elution with 10% EtOAc/CH2Cl2obtaining 4,93 g specified in the connection header in the form of a clear yellow resinous substance. MS (ESI) 318 (M+H).

Example 240. 2-(4-tert-Butyl-2-1,3-dioxine-2-yl-6-forfinal')-4,4-dimethyl-4,5-dihydrooxazolo

A round bottom flask with a volume of 200 ml containing 4,92 g (of 15.5 mmole) dried in a vacuum - 2-(4-tert-butyl-2-1,3-dioxine-2-ylphenyl)-4,4-dimethyl-4,5-dihydrooxazolo, was equipped with a mechanical is coy stirrer, septum and cap for input of nitrogen. Establishes and cultivates an atmosphere of N2. Added 100 ml of anhydrous THF. Cooled the solution to -78°C. was Stirred rapidly and was added 7.5 ml (19 mmol) of a 2.5 M solution of n-utility in hexane dropwise over 5 minutes. Mixed transparent yellow solution at -17°C for 3 hours the Solution became saturated red-orange. Cooled the solution to -78°C. was Stirred rapidly and added of 5.89 g (to 18.7 mmole) N-formentioned dissolved in 30 ml of anhydrous THF, is added dropwise within 10 minutes was Stirred reaction mixture at -78°C for 5 minutes was Stirred at -20°C for 30 minutes was Stirred at RT for 1 h then Poured the reaction mixture into 150 ml of 50% saturated aqueous NH4Cl and 300 ml Et2O. phase was Separated, and the organic phase is washed with 150 ml water and 150 ml of saturated solution of sodium chloride. Dried Na2SO4and solvent was removed on a rotary evaporator. Was purified column chromatography on silica gel using isocrates elution with 25% EtOAc/CH2Cl2. The isolated product was recrystallized from hexane to obtain 1.88 g specified in the title compound as a light amber crystals. MS (ESI) 336 (M+N)+.

Example 241. 5-tert-Butyl-7-fluoro-3-hydroxy-3H-isobenzofuran-1-he

1.8 g (5.4 mmole) of 2-(4-tert-butyl-2-1,3-diox the NAS-2-yl-6-forfinal)-4,4-dimethyl-4,5-dihydrooxazolo weighed in a round bottom flask with a volume of 200 ml, equipped with a mechanical stirrer and reflux condenser. Added 75 ml of ethanol, and stirred obtaining a clear solution. Added 50 ml of 50% aqueous solution of sulfuric acid. Was stirred at the boil for 18 hours then Poured the reaction mixture into 400 ml of water. Were extracted water mixture 2×200 ml of CH2Cl2. Combined organic extracts were washed with 200 ml of saturated solution of sodium chloride. Dried Na2SO4and solvent was removed on a rotary evaporator. Was dried in high vacuum to obtain 1.29 g specified in the connection header in the form of a whitish solid. MS (ESI) 223 (M-N)-.

Example 242. 6-tert-Butyl-8-fluoro-2H-phthalazine-1-he

1.2 g (5.4 mmole) of 5-tert-butyl-7-fluoro-3-hydroxy-3H-isobenzofuran-1-she weighed in a round bottom flask of 25 ml volume, equipped with a mechanical stirrer, reflux condenser and a nozzle for input of nitrogen. Added 7.5 ml (100 mmol) of hydrazinoacetate. Added 10 ml of glacial acetic acid. Was stirred in nitrogen atmosphere at 100°C during the night. Poured the reaction mixture into 100 ml of stirred water. Were extracted water mixture 2×50 ml of CH2Cl2. Dried combined extracts Na2SO4and solvent was removed on a rotary evaporator. Purified accelerated by chromatography on silica gel using radiant elution 0 -> 100% EtOAc/CH2Cl2obtaining 898 mg specified in the connection header in the form of a whitish solid. MS (ESI) 221 (M+N)+.

Example 243. 2-Bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzaldehyde

1518 mg (of 5.75 mmole) of 2,6-dibromosalicylic, 506 mg (2,30 mmole) of 6-tert-butyl-8-fluoro-2H-phthalazine-1-it, 1499 mg (4,60 mmole) of cesium carbonate, 42 mg (0.22 mmole) of copper iodide (I) and 115 mg (0,479 mmole) of 4,7-dimethoxy-1,10-phenanthroline was weighed into the reaction flask with a volume of 20 ml, equipped with a mechanical stirrer and septum. Added 8 ml of anhydrous dioxane. Saturated reaction mixture with nitrogen for 15 minutes was Stirred at 100°C for 16 hours Divided reaction mixture is between 25 ml of 10% MeOH/CH2Cl2and 25 ml of water. Was phase separated, and the aqueous phase is extracted with 25 ml 10% MeOH/CH2Cl2. Was filtered for breaking stable emulsions. The combined organic extracts were washed with 75 ml saturated sodium chloride solution, dried MgSO4, and the solvent was removed on a rotary evaporator. Purified accelerated by chromatography on silica gel using gradient elution 0→40% EtOAc/hexane to obtain 406 mg specified in the title compound as a yellow solid. MS (ESI) doublet 403, 405 (M+H)+.

Example 244. 2-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-{1-methyl-5-[5-(morpholine-4-Carboni is)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzaldehyde

88 mg (0,20 mmole) of 1-methyl-3-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine-2-she and 81 mg (0,20 mmole) of 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzaldehyde was weighed into the reaction flask with a volume of 4 ml, equipped with a mechanical stirrer and septum. Was added 2 ml of dioxane. Added 222 μl 0,88 mg/ml solution of cesium carbonate in water. Added 7.8 mg (0,0096 mmole) chloride complex [1,1'bis(diphenylphosphino)ferrocene]palladium(P) with dichloromethane 1:1. The reaction mixture was barbotirovany nitrogen for 5 minutes Covered flask with a lid and stirred at 100°C for 60 minutes Poured into the reaction mixture in 10 ml of CH2Cl2and 10 ml of water. Was phase separated, and the aqueous phase is extracted with 5 ml of CH2Cl2. Combined organic extracts were dried, Na2SO4and solvent was removed on a rotary evaporator. Purified accelerated by chromatography on silica gel, using a gradient elution from 100% hexane to 100% 5:6:1 hexane:CH2CL2:2-D. Recrystallized product from 2-D. Was dried in high vacuum at 120°C overnight to obtain 77 mg specified in the title compounds as a pale yellow solid. MS (ESI) 637 (M+H)+.

Example 245. 6-tert-Butyl-8-fluoro-2-('2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)Piri is in 2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}phenyl)-2H-phthalazine-1-he

69 mg of 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}benzaldehyde was weighed into the reaction flask with a volume of 20 ml, equipped with a mechanical stirrer and lid. Was added 2 ml of CH2Cl2and 2 ml Meon, and stirred to obtain a transparent amber solution. Added 14 mg of sodium borohydride. Was stirred at RT for 3 h Extinguished 5 ml of a saturated aqueous solution of NI-LtCl. Separated phase and the aqueous phase is extracted 2 x 2 ml of CH2Cl2. Washed the combined organic phases 5 ml saturated aqueous NaHCO3. Dried Na2SO3and solvent was removed on a rotary evaporator. Has led the rest of isopropylacetate to obtain 52 mg specified in the title compounds as white solids. MS (ESI) 639 (M+N)+.

Example 246. 1-(4-Bromo-2-forfinal)-3-chloropropane-1-he

A solution of 4-bromo-2-tormentilla (26,79 g, 113 mmole) in dichloroethane was added to a stirred suspension of aluminum chloride (15 g, 113 mmole) in dichloroethane at RT. The suspension became a dark solution after adding the carboxylic acid. The temperature was maintained using an ice bath. Gaseous ethylene was passed through the reaction mixture for 3 hours before and is eznoveniya the carboxylic acid. The reaction mixture was stirred over night at RT. The reaction mixture was cooled to 0°C and extinguished with 4 M hydrochloric acid (34 ml, 134 mmole). The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with sodium sulfate and was filtered. After concentration under reduced pressure were obtained crude 1-(4-bromo-2-forfinal)-3-chloropropane-1 he (27,45 g, 103 mmole), which was used in the next stage.

Example 247. 5-Bromo-7-Florinda-1-he

1-(4-Bromo-2-forfinal)-3-chloropropane-1-he (27,45 g, 103 mmole) was added to a suspension of aluminium chloride (164 g of 1.23 mole) and sodium chloride (43,19 g, 0,739 mol) at 130°C. the Mixture was stirred with a mechanical stirrer and was heated at 180°C for 6 hours. The whole mixture was suppressed by ice and concentrated hydrochloric acid solution (122 ml of 1.24 mol). The resulting mixture was extracted with dichloromethane. The organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with sodium sulfate and was filtered. After concentration under reduced pressure, purification by chromatography on silica gel resulted in the receipt of 5-bromo-7-Florinda-1-it (5 g, 1.8 mmole).

Example 248. 6-Bromo-8-fluoro-3,4-dihydro-2H-isoquinoline-1-he

5-Bromo-7-Florinda-1-he (2,07 g, 90,7 mmole) was dissolved in 15 ml dichloromethane, and cooled to 0°C. was Added methanesulfonyl acid a (10.6 ml, 163 mmole). Then to the solution slowly added sodium azide (1.18 g, 18,14 mmole). The reaction mixture was stirred for 2 hours at 0°C. To the mixture was slowly added to 40 ml of 20% sodium hydroxide solution at 0°C. After addition, the reaction mixture was extracted with dichloromethane. The organic phase is washed with water, saturated sodium chloride solution, dried with sodium sulfate and was filtered. After concentration under reduced pressure was obtained 5-bromo-7-Florinda-1-he (2 g, 81,95 mmole). MS (ESI) 244,0 (M+N)+.

Example 249. 6-Cyclopropyl-8-fluoro-3,4-dihydro-2H-isoquinoline-1-he (I)

To a mixture of 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinoline-1-she (1.6 g, 6.5 mmole), tricyclohexylphosphine (of 0.182 g, 0.65 mmole) and Pd(OAc)2 (0,072 g to 0.032 mmole) in 15 ml of toluene, placed in an argon atmosphere in the flask for high blood pressure, was added cyclopropylboronic acid (1.12 g, 13 mmole), potassium phosphate (6,9 g of 32.5 mmole) and 1.5 ml of water. The flask was closed and the mixture was heated under stirring for 4 hours at 100°C. After cooling, the reaction mixture was diluted with ethyl acetate, and the organic phase is washed on Ishenim solution of sodium chloride, was dried with sodium sulfate and concentrated. The residue was purified accelerated chromatography (ethyl acetate), obtaining 0,93 g (71,5% yield) of compound I.

Example 250. 6-Cyclopropyl-8-fluoro-2H-isoquinoline-1-he (II)

To a solution of compound I (0,272 g of 1.32 mmole) in 8 ml of dioxane is placed in a flask for high blood pressure, was added in an argon atmosphere DDQ (0,301 g of 1.32 mmole). The flask was closed and the mixture was heated at 100°C for 18 hours under stirring. After cooling, the reaction mixture was diluted with ethyl acetate, and the organic phase is washed with IN NaOH solution and saturated sodium chloride solution, dried with sodium sulfate and concentrated in vacuum. The residue was purified accelerated chromatography (75% ethyl acetate/hexane to 100% ethyl acetate) to give 90 mg (33% yield) of compound II.

Example 251. 2-Chloro-6-(6-cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)benzaldehyde (III)

To a solution of compound II (0,285 g, 1.4 mmole) in 6 ml of dioxane in the flask increased pressure was added in an argon atmosphere, 2-bromo-6-chlorobenzaldehyde (1.2 g, 5.6 mmole), cesium carbonate (0,912 g, 2.8 mmole) and copper iodide (0,053 g to 0.28 mmole). The flask was closed and the mixture was heated at 100°C with stirring for 18 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and a saturated solution of chlorine is Yes sodium, was dried with sodium sulfate and concentrated. The residue was purified accelerated chromatography (30% ethyl acetate/hexane) to obtain is 0.260 g (54% yield) of compound III.

Example 252. 2-(3-Chloro-2-hydroxymethylene)-6-cyclopropyl-8-fluoro-2H-isoquinoline-1-he (IV)

To a suspension of compound III (0.26 g, 0.76 to mmole) in 15 ml of dry THF which was cooled to 0°C in an ice bath, was added a solution of superseded 1M (1.5 ml, 1.5 mmole) in THF. After stirring for 0.5 hours at 0°C, the reaction was suppressed with a saturated solution of ammonium chloride, and diluted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate and concentrated to obtain 0.25 g (96% yield) of compound IV, which was used in the next stage without additional purification.

Example 253. 6-Cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-it (V)

To a mixture of compound IV (0.2 g, of 0.58 mmole), XPhos (0,027 g 0,058) and Pd(dba)2(0,016 g 0,029 mmole) in 4 ml of n-butanol, placed in the flask increased pressure, in an argon atmosphere was added compound A (0,255 g of 0.58 mmole), potassium phosphate (0,246 g of 1.18 mmole) and 1 ml of water. The flask was closed and the mixture was heated at 100°C with stirring for 1.5 hours. After cooling, R is the promo mixture was diluted with ethyl acetate, and the organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate and concentrated. The residue was purified twice accelerated chromatography (5% methanol, 0.5% conc. an aqueous solution of NH4OH in dichloromethane) to give 0.1 g (27% yield) of compound V. This material was dissolved in a hot mixture of 14 ml of isopropylacetate and 8 ml of dichloromethane. After cooling to 0°C. the resulting suspension was filtered to obtain 0,070 g of crystalline compounds V.

Example 254. N-{1-[6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl]-1-methylethyl}-2-chloracetamide

5-Bromo-3-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-1H-pyridine-2-he (4.7 g, 13.9 mmole) suspended in chloroacetonitrile (28 ml). To the suspension was added acetic acid (2.4 ml) at room temperature, and cooled to 0°C. To the cooled suspension was slowly added sulfuric acid, concentrated solution (2.4 ml). The reaction mixture was stirred for 4 h at RT, then poured into ice. Added ethyl acetate. Was slowly added sodium bicarbonate to neutralize the acid mixture. A white precipitate was collected by obtaining N-{1-[6-(5-bromo-l-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl]-1-methylethyl}-2-chloroacetamide (4 g, 70%) in the form of a whitish solid. MS (H+)=415,0.

Example 255. 3-[5-(1-Amino-1-methylethyl)pyridi the-2-ylamino]-5-bromo-1-methyl-1H-pyridine-2-he

N-{1-[6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl]-1-methylethyl}-2-chloroacetamide (2,97 g, 7.2 mmole) and thiourea (0,655 g, 8.6 mmole) suspended in ethanol (35 ml)/acetic acid (8 ml) and boiled under reflux during the night. The reaction mixture was left to cool to CT. Was added water, and the mixture was cooled to 0°C. was Added sodium bicarbonate (pH=8), and then the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried with sodium sulfate, filtered, and concentrated to obtain 3-[5-(1-amino-1-methylethyl)pyridine-2-ylamino]-5-bromo-1-methyl-1 H-pyridin-2-she (2.2 g, 91%) as a yellow solid. MS (H+)=339,0.

Example 256. 2-{5-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid

3-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-5-bromo-1-methyl-1H-pyridine-2-he (160 mg, 0,474 mmole), 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)benzyl ether acetic acid (235 mg, 0,474 mmole), X-phos (34 mg, 0,0712 mmole), potassium phosphate (252 mg, 1,186 mmole) was dissolved in dioxane (4 ml) and water (1 ml). Then was added bis(dibenzylideneacetone)palladium (41 mg, 0,0712 mmole) and heated at o the new radiation at 125°C for 30 minutes The reaction mixture was filtered, washed with dioxane, partially concentrated and dry was applied on the column with 24 g of SiOH. Purification by chromatography using 0-10% Meon (containing 1% NH4OH) in DHM for 30 min resulted in the receipt of 2-{5-[5-(1-amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ester of acetic acid (159 mg, 54%) as a yellow solid. MS (H+) 625,2.

Example 257. 2-(3-{5-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-he

2-{5-[5-(1-Amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)benzyl ether acetic acid (159 mg, 0,0255 mmole) was dissolved in dioxane (3 ml). Added 2 M solution of the monohydrate of lithium hydroxide (0,76 ml of 1.53 mmole), and stirred for 3 h at RT. Added Meon, and the mixture was purified by chromatography. The isolated product was dried in high vacuum at 50°C To produce 2-(3-{5-[5-(1-amino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-she (101 mg, 68%) as a whitish crystalline product. MS (H+)=583,3.

Example 258.N-(2-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamine is)pyridine-3-yl)propan-2-yl)ndimethylacetamide

5-Bromo-3-[5-(1-hydroxy-1-methylethyl)pyridine-2-ylamino]-1-methyl-1H-pyridine-2-he (180 mg, 0,532 mmole) was dissolved in acetonitrile (10 ml). Acetic acid (0.5 ml) was added at RT, and then cooled to 0°C. To the cooled solution was slowly added sulfuric acid, concentrated solution (0.5 ml). The reaction mixture was left to warm at RT after the addition and was stirred overnight. The reaction mixture was poured into ice, and added ethyl acetate. Was slowly added sodium bicarbonate to neutralize the acid mixture, and the mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride and dried with sodium sulfate. The mixture was filtered and concentrated. The crude material was purified on a column with 24 g of silica gel using 0-10% Meon in EtOAc 1:1 hexane, obtaining N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl)propan-2-yl)ndimethylacetamide (69 mg, 34%) as a yellow solid. MS (H+)=379,0.

Example 259. 5-Bromo-3-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino-1-methyl-1H-pyridine-2-he

N-(2-(6-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino)pyridine-3-yl)propan-2-yl)ndimethylacetamide (417 mg, 1.1 mmole) was dissolved in THF (40 ml). This solution was boiled under reflux, and boiling the mixture was slowly added complex 10 M porandamaterjalide (165 μl, 1.65 m is Olya). The reaction mixture is boiled under reflux for 2.5 hours Then added 0.5 ml of 6 M hydrochloric acid, and after stirring at boiling under reflux for 5 min the mixture was cooled to CT. Then was added a 3 M solution of sodium hydroxide, then water, and the material was extracted with ethyl acetate. The mixture was washed with a saturated solution of sodium chloride, dried with sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel using 0-10% Meon in DHM to obtain 5-bromo-3-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino]-1-methyl - 1H-pyridine-2-she (73 mg, 18%).1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 in (t,.7-to 7.18 Hz, 3H) 1,70 (s, 6N) to 2.67 (m, 2H) to 3.52 (s, 3H) 7,44 (d, J=9,06 Hz, 1H) 7,58 (d, J=2,27 Hz, 1H) 7,86 (dd, J=8,69, of 2.64 Hz, 1H) to 8.45 (d, J=2,64 Hz, 1H) 8,73 (d, J=2,64 Hz, 1H) 8,76-8,88 (m, 1H) 8,99 (s, 1H).

Example 260. 6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he

Into the flask to microwave radiation with a volume of 2 ml) was added 5-bromo-3-(5-(2-(ethylamino)propan-2-yl)pyridine-2-ylamino)-1-methylpyridin-2(1H)-he (70 mg, 192 μmol) and 2-(6-tert-butyl-8-fluoro-1-oxoproline-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoylacetate (123 mg, 249 mcmole), X-PHOS (13,7 mg, 28.7 mmol) and trehosnovnoy potassium phosphate (102 mg, 39,7 µl, 479, mcmo is her). The mixture was dissolved in dioxane (2 ml), DMF (2 ml) and water (1,00 ml). Then was added bis(dibenzylideneacetone)palladium (16.5 mg, 28.7 mcmole). The flask was sealed and heated under microwave irradiation at 120°C for 45 min, then was filtered, washed with dioxane and concentrated. The crude product was purified accelerated by chromatography (silica gel, 24 g, 0% to 10% Meon in DHM to obtain 70 mg of the protected intermediate compound). This intermediate compound was treated with dioxane (2 ml) and 0.5 ml of 3 M NaOH solution and stirred at RT for 9 h, and then was applied on the column with 24 g of silica gel and purified accelerated by chromatography (silica gel, 12 g, 0% to 10% Meon (contains NH40H) in a mixture of Hex 1:1 EtOAc) to give 6-tert-butyl-2-(3-{5-[5-(1-ethylamino-1-methylethyl)pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-it (29 mg, 24%) as a pale green crystalline product. MS (H+)=611,2, tPL=195-200°C.1H NMR (400 MHz, chloroform-d) δ ppm of 1.05 (t, J=7,07 Hz, 3H) 1,43 (s, N) of 1.46 (s, 3 H) of 2.38 (d, J=7,07 Hz, 2H) 3,71 (s, 3H) to 3.73-of 3.80 (m, 1H) was 4.42 (d, J=5,56 Hz, 2 H) PC 6.82 (d,.7-8,59 Hz, 1 H) of 7.36 (dd, J=6,06, 3,03 Hz, 1H) 7,39 (d, J=2,53 Hz, 1H) 7,50-7,58 (m, 4H) 7,60-to 7.68 (m, 1H) of 7.90 (s, 1H) compared to 8.26 (d, J=2,02 Hz, 1H) 8,29 (d, J=2,53 Hz, 1H) 8,71 (d, J=2,02 Hz, 1H).

Analysis of the inhibition-Bruton tyrosine kinase (Btk)

The analysis is based on the capture of radioactive P phosphorylated product by filtration. Interaction of Btk biotinylated SHz peptide substrate (Src homology) and ATP leads to the phosphorylation of the peptide substrate. Biotinylated product is associated with separately granules streptavidin. All bound peroxidase radioactively labeled substrates was determined with a scintillation counter.

Analyzed the tablets represented a 96-well polypropylene (Greiner) and 96-well 1.2 μm hydrophilic PVDF filter plates (Millipore). Recorded concentrations were final concentrations of analyses: 10-100 μm of compounds in DMSO (Burdick and Jackson), 5-10 nm Btk enzyme (His-tagged, polnocny), 30 μm peptide substrate (BnoTHH-Aca-AAAEEIYGEI-NHz), 100 μm ATP (Sigma), 8 mm imidazole (Sigma, pH 7,2), 8 mm glycerol-2-phosphate (Sigma), 200 μm EGTA (Roche Diagnostics), 1 mm MnClz (Sigma), 20 mm MgCl2(Sigma), 0.1 mg/ml BSA (Sigma), 2 mm DTT (Sigma), 1 MX33P ATP (Amersham), 20% separatrix granules streptavidin (Amersham), 50 mm EDTA (Gibco), 2 M Nad (Gibco), 2 M Nad weight./ 1% phosphoric acid (Gibco), microscint-20 (Perkin Elmer).

Determine the IC50counted from 10 data points for the connection using the data obtained in the standard analyzer 96-lenoch tablet. One control connection and the seven unknown inhibitors were tested for each of the tablets, and each tablet was analyzed twice. Typically, compounds were diluted in half-log, starting with 100 μm and ending at 3 nm. The control connection was staurosporin. The background expected in the absence of peptide substrate. Total activity was determined in prisutstvie the peptide substrate. The following methodology was used to determine inhibition of Btk.

1) get sample: Test compounds were diluted with increase in half-log buffer for analysis (imidazole, glycerol-2-phosphate, EGTA, MnCl2, MgCl2, BSA).

2) Obtaining granules:

(a) the Pellets were washed by centrifugation at 500 g

b) Restored the pellet with PBS and EDTA with a 20% suspension of granules.

3) Pre-incubated reaction mixture without substrate (buffer for analysis, DTT, ATP, P ATP) and was mixed with substrate (buffer for analysis, DTT, ATP,33P ATP, peptide substrate) at 30°C for 15 minutes

4) pre-calculus pre-incubated with 10 microns of Btk in enzyme buffer (imidazole, glycerol-2-phosphate, BSA) and 10 μl of test compounds for 10 min at RT.

5) were Added to 30 μl of the reaction mixture, with or without a substrate for Btk and connections.

6) were Incubated with 50 μl of the total mixture for analysis within 30 min at 30°C.

7) Bore 40 μl of the mixture for analysis in 150 μl of the suspension of granules in the filter plate to stop the reaction.

8) Washed filter plate within 30 min following stages:

A. 3×250 μl NaCl

B. 3×250 μl NaCl containing 1% phosphoric acid

century 1×250 μl of N2O

9) Dried the plate for 1 h at 65°C or over night at RT

10) was Added 50 μl of microscint-20 and predelli 33P per minute on a scintillation counter.

Expected percentage activity of a number of data units per minute:

Percent activity=(sample-bkg)/(total activity - bkg)×100

Expected value IC50the percentage activity using one-sided dose-dependent sigmoidal model:

y=A+((B-A)/(1+((x/C)D))))

x=conc. Conn., y=% activity, And=min,=max, C=IC50D=1 (slope)

Inhibition of b-cell activation in whole blood, as measured by the expression of CD69

The method for determining the ability of Btk inhibitors to suppress b-cell receptor-mediated activation of b cells in human blood was performed as follows.

Whole human blood (HWB) was obtained from healthy volunteers, with the following restrictions: 24 h did not take drugs, do not smoke cigarettes. Blood was collected from a vein in Vacutainer tubes, antikoagulyatine heparin sodium. Test compounds were diluted ten-fold from the target initial concentration of the drug in PBS (20x), then the three-fold serial dilutions in 10% DMSO in PBS to obtain a nine point dose-dependent curve. Added a 5.5 µl of each dilution connection twice in 96-well plate with a V-shaped bottom with a volume of 2 ml (Analytical Sales and Services, #59623-23); was added to 5.5 μl of 10% DMSO in PBS for control and destimulate the data holes. Added HWB (100 μl) to each well, and after mixing, the plates were incubated at 37°C, 5% CO2, 100% humidity for 30 minutes. Added F(ab')2 anti-human IgM goat (Southern Biotech, #2022-14) (10 μl of a solution of 500 μg/ml, 50 μg/ml final concentration) to each well (except nastyalien holes) with stirring, and the plates were incubated for 20 hours.

At the end of the 20-hour incubation, the samples were incubated with fluorescent-breakdown-labeled antibodies (15 μl PE anti-human CD20 mouse, BD Pharmingen, #555623, and/or 20 μl of APC anti-human CD69 mouse, BD Pharmingen #555533) for 30 minutes at 37°C, 5% CO2100% humidity. Included induced control, neokrashivanija and separate staining for comparative experiments and the initial voltage setting. The samples were then subjected to lysis with 1 ml of IX buffer for lysis Pharmingen (BD Pharmingen # 555899), and the plates were centrifuged at 1800 rpm for 5 minutes. Supernatant was removed by suction, and the resulting residues were again subjected to lysis in 1 ml of IX buffer for lysis Pharmingen, and the plates were centrifuged as described above. Supernatant was aspirated and the resulting residues were washed in FACs buffer (PBS+1% FBS). After the final rotation supernatant was removed, and the residues re-suspended in 180 μl of FACs buffer. The sample was transferred into a 96-well plate, the approach is General for HTS 96-well system for a flow cytometer BD LSR II.

Using the appropriate wavelengths of excitation and emission for the used fluorophore, collected data, and the percentage of positive cell values were obtained using the software Cell Quest. The results were first analyzed using the software FACS (Flow Jo). The values of the IC50for the tested compounds was determined as the concentration that reduces by 50% the percentage of CD69-positive cells that are CD20-positive after stimulation with anti-IgM (mean 8 control wells after subtraction of the average values of the 8 holes for restimulating background). IC50 values were calculated using the software XLfit version 3, equation 201.

Data for some compounds of this analysis are summarized below in table II.

Table II
ConnectionWhole human blood (µm)
1-10,043
1-20,58
1-30,054
1-40,011
1-60,004
1-70,003
1-90,001
1-150,007

ConnectionWhole human blood (µm)
1-470,006

Inhibition of b-cell activation assay In cells in the FLIPR Ramos cells

Inhibition of b-cell activation by the compounds of the present invention is shown by determining the effect of test compounds on anti-IgM-stimulated b-cell responses.

The analysis In cells FLIPR cell functional way to determine the effect of potential inhibitors increase intracellular calcium in response to stimulation with anti-IgM antibodies. The Ramos cells (cell line lymphoma Burkitt person. ATCC-No. CRL-1596) were grown in medium for growth (described below). One day before analysis of Ramos cells suspended in fresh medium for growth (the same as described above) and placed in a concentration of 0.5×10 /ml in flasks for tissue cultures. On the day of analysis cells were counted and placed in a concentration of 1×10 /ml in the medium for growth with 1 μm FLUO-3AM (TefLabs Cat-No. 0116 obtained in anhydrous DMSO and 10% platonovoy acid) into the flask for tissue culture, Inc who has bated at 37°C (4%; within one hour. To remove extracellular dye, cells were collected by centrifugation (5 min, 1000 rpm), re-suspended in FLIPR buffer (described below) at a concentration of 1×10 cells/ml, and then transferred into 96-well plates coated with poly-D-lysine black/clear plates (BD Cat No. 356692) at a concentration of 1x10 cells per well. Test compounds were added at various concentrations ranging from 100 μm to 0.03 μm (7 concentrations, details below), and left incubated with cells for 30 min at RT. Transfer Sa Ramos cells were stimulated by addition of 10 μg/ml anti-IgM (Southern Biotech, Cat-No. 2020-01), and was measured by FLIPR (Molecular Devices, obtaining images for 96-well plate using a CCD camera with an argon laser at excitation 480 nm).

Environment/Buffers:

Environment for growth: RPMI 1640 medium with L-glutamine (Invitrogen, Cat No. 61870-010), 10% calf serum (FBS, Summit Biotechnology Cat-No. FP-100-05); 1 mm sodium pyruvate (Invitrogen Cat. No. 11360-070).

The FLIPR buffer: HBSS (Invitrogen, Cat No. 141175-079), 2 mm CaCl2(Sigma Cat No. C-4901), HEPES (Invitrogen, Cat No. 15630-080), 2.5 mm probenecid (Sigma, Cat No. P-8761), 0.1% BSA (Sigma, Cat No.A-7906), 11 mm glucose (Sigma, Cat No.G-7528).

The details of the dilution connection: To achieve the highest final concentration for the analysis of 100 μm, 24 ál of 10 mm stock solution of the compound (obtained in DMSO) was added directly to 576 μl of FLIPR buffer. Test compounds Rabaul is whether in FLIPR buffer (using the Biomek 2000 automated papeterie device) getting the following dilution scheme: the carrier of 1.00×10-4M, and 1.00×10-5at 3.16×10-6are 1.00×10-6at 3.16×10-7are 1.00×10-7at 3.16×10-8.

Experiment and analysis

The intracellular increase of calcium was recorded using max - min statistics (subtracting the residual baseline of the peak caused by the addition of stimulating antibodies) using the control and statistical software, Molecular Devices FLIPR. The values of the IC50was determined using graphics non-linear curves (software GraphPad Prism).

The pharmaceutical compositions of the compounds according to the invention for the introduction of some ways was received as described in this example.

Composition for oral administration (A)

Ingredient% the weight.
The active ingredient20,0%
Lactose79,5%
Magnesium stearate0,5%

The ingredients were mixed and filled into capsules containing about 100 mg each; one capsule contains approximately total daily dosage.

Composition for oral administration (B)

Ingredient
% the weight.
The active ingredient20,0%
Magnesium stearate0,5%
Crosscarmelose sodium2,0%
Lactose76,5%
PVP (polyvinylpyrrolidine)1,0%

The ingredients were combined and granulated using a solvent, such as methanol. The composition was then dried and compressed into tablets (containing about 20 mg of active compound) using a suitable device to obtain tablets.

Composition for oral administration (B)

Ingredient% the weight.
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar 25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Perfumea 0.035 ml
Dyes0.5 mg
Distilled waterto 100 ml

The ingredients were mixed to obtain a suspension for oral administration.

Parenteral composition (G)

Ingredient% the weight.
The active ingredient0.25 g
Sodium chlorideTo obtain isotonic
Water for injection to100 ml

The active ingredient was dissolved in parts of water for injection. Then add a sufficient quantity of sodium chloride under stirring to obtain an isotonic solution. The solution is brought up to the desired weight of the remaining amount of water for injection was filtered through a filter with a membrane of 0.2 μm, and Packed in a sterile environment.

The suppository composition (D)

Ingredient% the weight.
The active ingredient1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

The ingredients are melted together and mixed in a steam bath, and poured into molds containing 2.5 g total weight.

Local composition (E)

Ingredientsgrams
Active connection0,2-2
Span 602
Tween 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Water100

Caused by collagen arthritis in mice (mCIA)

On the Yan 0 the mice were injected in the tail or in several sections on the back emulsion of collagen type II (CHK) in Complete Freund Freund (CFA). After immunization with collagen in animals developed arthritis after 21-35 days. The attacks of arthritis synchronized (supported) systematic introduction of collagen in Incomplete Freund Freund (IFA; CHK) on day 21. Animals were examined every day after 20 days on any attack moderate arthritis (score of 1 or 2; see description below), which was the signal to increase. After raising the mice were observed and introduced the candidate therapeutic agents over a predetermined time (usually 2-3 weeks) and frequency of the dose once daily (QD) or twice daily (BID).

Caused by collagen arthritis in rats (rCIA)

On day 0, rats were injected emulsion of collagen type II calf in Incomplete Freund Freund (IFA) cutaneous (CHK) in a few places back. Stimulant injections of collagen emulsion was injected approximately day 7 (CHK) in the base of the tail or alternative in several areas of the back. Arthritis is usually observed at 12-14 days after the first collagen injection. Animals can be assessed on the development of arthritis, as described below (assessment of arthritis) from 14 days onwards. Animals were injected candidate therapeutic agents, prophylactic method starting with secondary treatment and within a predefined time (usually 2-3 weeks) and frequency of the dose once daily (QD) or twice daily (BID).

Assessment of arthritis is that

In both models the development of inflammation of the feet and joints quantitatively determined using an evaluation system that includes an evaluation of 4 feet on the criteria described below:

Rating: 1=swelling and/or redness of the paw or one unit. 2=swelling of two or more joints. 3=severe swelling of the legs with the participation of more than two joints. 4=severe arthritis of all of the tabs and units.

Evaluation was performed on day 0 to measure the baseline, and started again at the first signs or swelling up to three times a week until the end of the experiment. Arthritic index for each mouse was obtained by folding the four estimates for the separate legs, receiving the maximum score of 16 for the animal.

Model In Vivo asthma in rats

The male rats Brown-Norway were injected intraperitoneally with 100 µg OA (ovalbumin) in 0.2 ml of serum once every week for three weeks (day 0, 7 and 14). On day 21 (one week after the last injection) rats were injected q.d. media or connection according to the invention subcutaneously for 0.5 hours prior to the introduction of OA aerosol (1% OA within 45 minutes), and stopped after 4 or 24 hours after injection. At the time of killing was collected serum and plasma from all animals on serology and RK, respectively. Built in the tracheal cannula, and the lungs were washed 3X PBS. BAL fluid was analyzed for the total number of leukocytes and difference the performance communications values of leukocytes. The total number of cells in the aliquot of cells (20-100 µl) was determined using a Coulter Counter. For the differential values of leukocytes 50-200 μl of the sample was centrifuged in a Cytospin, and exactly were stained with Diff-Quik. The proportion of monocytes, eosinophils, neutrophils and lymphocytes were determined using light microscopy using standard morphological criteria, and expressed in percentage. Some inhibitors of Btk showed a decrease in the total number of leukocytes in BAL treated OA, and changed the status of the rats compared to control levels.

The above invention is described in more detail with the help of illustrations and examples for purposes of clarity and understanding. Specialist in the art it is obvious that changes and modifications can be made within the scope of the attached claims. Therefore, it should be understood that the above description is intended for illustration and is not limiting. Scope of the invention should therefore be determined not with reference to the above description, but should be determined with reference to the following claims, along with the full scope of equivalents to which such claims are distributed.

All described in the patents, published applications and scientific articles have been included fully in ssy is key to the extent that as if each patent, published application and a scientific article would have been individually incorporated by reference.

````````````````````````````

1. The compound of formula III:

where:
Q represents C(Y3or N;
R represents H, -R1, -R1-R2-R3, -R1-R3or-R2-R3;
R1is heteroaryl or heteroseksualci, each of which is optionally substituted by one or more1-6alkilani, hydroxys1-6alkilani, exography or Halogens1-6alkilani;
R2represents-C(=O)- Oh,- C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2'C(R2')2N(R2')C(=O), -C(=NH), -C(R2')2NR2'or-S(=O)2;
each R2'independently represents H or C1-6alkyl;
R3represents N or R4;
R4represents a C1-6alkyl, C1-6alkoxygroup, the amino group, With1-6alkylamino, di(C1-6alkyl)amino group, heteroseksualci,1-10alkylchlorosilanes, heterocyclics1-10alkyl, each of which is optionally substituted by one or more1-6alkilani, C1-6alkylaminocarbonyl, di(C1-6alkyl)amino groups, hydroxy groups, sub> 1-6alkilani,1-6alkoxygroup, exography or Halogens1-6alkilani;
X represents CH;
X' represents CH;
Y1represents methyl;
Y2independently represents halogen, oxime, or1-6alkyl, where C1-6alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, C1-6alkoxygroup, C1-6halogenlampe, C1-6halogenoalkane, carboxypropyl, amino and halogen;
Y2'represents hydroxymethyl;
n denotes 0;
each Y3represents H;
m denotes 0;
Y4represents the Y4b, Y4cor Y4d;
Y4brepresents a C1-6alkyl, optionally substituted by one or more substituents selected from the group consisting of hydroxy-group and amino group;
Y4crepresents a C3-8cycloalkyl, optionally substituted by one or more C1-6alkilani;
Y4drepresents an amino group, optionally substituted by one or more1-6alkilani; and
Y5is a halogen;
where "heteroaryl" denotes monocyclic or bicyclic radicals containing from 5 to 12 atoms in the cycle containing at least one aromatic or what actiono unsaturated ring, containing 4 to 8 atoms in the ring, with one or more N, O or S heteroatoms, the remaining atoms in the ring are carbon atoms, and the connection point heteroaryl radical is aromatic or partially unsaturated ring,
"heteroseksualci" denotes a monovalent saturated cyclic radical, consisting of 1-2 rings, including spirocycles ring system containing three to eight atoms per ring, one or more ring heteroatoms selected from N, O or S(O)0-2,
or its pharmaceutically acceptable salt.

2. Connection on p. 1, where Y5is a F.

3. Connection on p. 2, where Q represents CH.

4. Connection on p. 2, where Q represents n

5. Connection on p. 3, where Y4represents tert-butyl.

6. Connection on p. 4, where Y4represents tert-butyl.

7. Connection on p. 3, where Y4represents ISO-propyl.

8. Connection on p. 4, where Y4represents ISO-propyl.

9. Connection on p. 5, where R is an R1-R3; R1represents pyridyl; R3is an R4; and R4is heteroseksualci substituted by one or more C1-6alkilani.

10. Connection on p. 6, where R is an R1-R3; R1p is ecstasy a pyridyl; R3is an R4; and R4represents heterocyclyl, optionally substituted C1-6the alkyl.

11. Connection on p. 7, where R is an R1-R3; R1represents pyridyl; R3is an R4; and R4represents heterocyclyl, optionally substituted C1-6the alkyl.

12. Connection on p. 8, where R is an R1-R3; R1represents pyridyl; R3is an R4; and R4represents heterocyclyl, optionally substituted C1-6the alkyl.

13. Connection on p. 5, where R is an R1-R2-R3; R1represents pyridyl; R2represents-C(CH3)2; R3is an R4; and R4represents a C1-6alkylamino, di(C1-6alkyl)amino group or heteroseksualci, optionally substituted by one or more1-6alkilani.

14. Connection on p. 6, where R is an R1-R2-R3; R1represents pyridyl; R2represents-C(CH3)2; R3is an R4; and R4represents a C1-6alkylamino, di(C1-6alkyl)amino group or heteroseksualci, optionally substituted one and the multiple 1-6alkilani.

15. Connection on p. 7, where R is an R1-R2-R3; R1represents pyridyl; R2represents-C(CH3)2; R3is an R4; and R4represents a C1-6alkylamino, di(C1-6alkyl)amino group or heteroseksualci, optionally substituted by one or more C1-6alkilani.

16. Connection on p. 8, where R is an R1-R2-R3; R1represents pyridyl; R2represents-C(CH3)2; R3is an R4; and R4represents a C1-6alkylamino, di(C1-6alkyl)amino group or heteroseksualci, optionally substituted by one or more C1-6alkilani.

17. A compound selected from the group consisting of:
6-Dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Dimethylamino-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-yl-pyridine-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
6-Dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)-pyridine-2-ylamino]-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-yl-pyridine-2-ylamino)-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-ylmethyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{3-[5-(1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethyl phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridine-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-phthalazine-1-he;
6-tert-Butyl-2-(3-{5-[5-(1,1-dimethy the-2-morpholine-4-yl-2-oxoethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he;
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-N,N-dimethylethanamine;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(1-methyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-6-oxo-5-[5-(2,2,2-Cryptor-1-hydroxyethyl)-pyridine-2-ylamino]-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-hydroxymethyluracil-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-2-hydroxymethyl-phenyl]-6-tert-butyl-8-fluoro-2H-phthalazine-1-he;
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-N-(2-ethoxyethyl)-isobutyramide;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-azetidin-3-yloxy)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
2-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-N-methylisoleucine;
6-tert-Butyl-2-{3-[5-(5-ethylpyridine-2-ylamino)-1-methyl-6-ox is-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
2-(3-{5-[5-(1-Amino-1-methylethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-tert-butyl-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-phthalazine-1-he;
6-tert-Butyl-2-{3-[5-(1-ethyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1-isopropyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxyethylamine)-methyl]-pyridine-2-ylamino}-1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-phenyl]-2H-phthalazine-1-he;
6-tert-Butyl-2-{3-[5-(4,5-dihydrooxazolo-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5,6,7,8-tetrahydro-[1,6]naphthiridine-2-ylamino)-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylamino-methyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-2-{3-[5-(5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-1-methyl-6-oxo-1,6-d is hydropyridine-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-4-hydroxy-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-2-(3-{5-[5-(1-ethylamino-1-methylethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he;
N-[1-(6-{5-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-1-methylethyl]-ndimethylacetamide;
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(6-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-phthalazine-1-he;
6-tert-Butyl-2-{3-[5-(1-tert-butyl-2-oxo-1,2-dihydropyrimidin-4-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-phthalazine-1-he;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-piperazine-1-yl-pyridine-2-ylamino)-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
8-Chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(2-HYDR shall kemetyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinoline-1-he;
8-Chloro-6-cyclopropyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
8-Fluoro-6-(1-hydroxy-1-methylethyl)-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
8-Fluoro-6-(1-hydroxy-1-methylethyl)-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-6-(1-methyl-cyclopropyl)-2H-isoquinoline-1-he;
8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonamido-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-6-(1-methylcyclopropyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridine-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-Ilam is but]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-(1-Ethyl-1-hydroxypropyl)-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-4-methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
2-[8-Fluoro-2-(3-{5-[5-(2-hydroxyethoxy)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-1-oxo-1,2-dihydro-isoquinoline-6-yl]-2-methylpropionitrile;
2-(6-{5-[3-(6-Cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-N-methylisoleucine;
2-(6-{5-[3-(6-Cyclopropyl-8-fluoro-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-1-methyl-2-oxo-1,2-dihydropyridines-3-ylamino}-pyridin-3-yl)-N,N-dimethylethanamine;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(1-methyl-azetidin-3-yloxy)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-ylmethyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(3-{5-[5-(1-hydroxyethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridine-2-ylamino}1-methyl-6-oxo-1,6-dihydropyridines-3-yl)-phenyl]-2H-isoquinoline-1-he;
2-(3-{5-[5-(1-Amino-1-methylethyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-6-cyclopropyl-8-fluoro-2H-isoquinoline-1-he;
6-Cyclopropyl-2-{3-[5-(5-ethylaminomethyl-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-yl]-2-hydroxymethylene}-8-fluoro-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(isopropylamino-methyl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(3-{5-[5-(2-hydroxyethoxy)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-2H-isoquinoline-1-he;
2-(3-{6-[1-(2,2-Defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-6-(1-hydroxy-1-methyl-ethyl)-2H-isoquinoline-1-he;
2-{3-[6-(1-Ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxymethylene}-8-fluoro-6-(1-hydroxy-1-methylethyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-phenyl)-2H-isoquinoline-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-2-(3-{6-[1-(2,2-defloratin)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he;
N-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl}-N'-methyl-guanidine; compound with formic acid;
6-tert-Butyl-2-(3-{5-[(1S,5R)-5-(3,8-diazabicyclo[3.2.1]Oct-3-yl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-phthalazine-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(2-methylamino-ethoxy)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-it; and
N-{6-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazine-2-yl)-2-hydroxymethyl-phenyl]-4-methyl-3-oxo-3,4-dihydropyrazine-2-yl}-N'-methylguanine.

18. A compound selected from the group consisting of:
6-Dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Dimethylamino-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholine-4-yl-pyridine-2-ylamino)-6-oxo-1,6-dihydropyridines-3-yl]-phenyl}-2H-isoquinoline-1-he;
6-Dimethylamino-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-isoquinoline-1-he;
6-Cyclopropyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-hydroxymethylene)-8-fluoro-2H-isoquinoline-1-he;
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-he;
6-tert-Butyl-2-(3-{5-[5-(4-ethylpiperazin-1-yl)-pyridine-2-ylamino]-1-methyl-6-oxo-1,6-dihydropyridines-3-yl}-2-guide oxymethylphenyl)-8-fluoro-2H-phthalazine-1-he; and
6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridines-3-yl}-phenyl)-2H-phthalazine-1-it.

19. The use of compounds according to any one of paragraphs.1-18 for the manufacture of a medicinal product for the treatment of inflammatory and/or autoimmune condition.

20. Pharmaceutical composition comprising a compound of the Btk inhibitor according to any one of paragraphs.1-18, in a mixture with at least one pharmaceutically acceptable carrier or excipient.

21. Pharmaceutical composition comprising a compound of the Btk inhibitor according to any one of paragraphs.1-18, in a mixture with at least one pharmaceutically acceptable carrier or diluent.

22. The method of obtaining the compounds of formula X, which includes stages:

a) heating the compounds of formula IX, where Y7represents Bronevoy acid or pinacolborane, to a temperature of from about 40°C to 150°C, in the presence of a palladium catalyst, base and phosphine; and
b) treating the product from step a) approximately 20% aqueous solution of 1,4-dioxane to obtain compounds of formula X, where Q represents N, R and Y4are as defined in paragraph 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a preparation which inhibits microbial growth, which includes an arylamide compound as an active compound and kleptose or captisol.

EFFECT: methods of producing the preparation, use and method of treating microbial infections are disclosed.

21 cl, 5 dwg, 11 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: group of inventions relates to an imine derivative, represented by formula , where "Ar" stands for pyridine, containing a chlorine atom on a ring or thiazole, which can contain the chlorine atom on a ring; "X" stands for a sulphur atom or CH2; when "Y" represents COR1, "R1" stands for a hydrogen atom or a C1-C5alkyl group, halogenated methyl group, except trifluoromethyl group, halogenated C2-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with an atom of chlorine, fluorine, methyl group or acetamide phenyl group, non-substituted (C6) aryl(C1-C3)alkyl group, (C1-C4)alkoxy (C1-C5)alkyl group, C1-C3alkoxycarbonyl group, (C1-C3) alkylsulphonyl (C1-C3)alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, non-substituted or substituted with a methyl group or a fluorine atom C3-C7cycloalkyl group, cyano(C1-C3) alkyl group, non-substituted phenoxy(C1-C3) alkyl group, non-substituted pyridylmethyl group, non-substituted imidazolylmethyl group, furanyl group, morpholine group, adamantly group, isothiocyanate group or a heterocyclic ring selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, substituted with one, two or five substituents, selected from chlorine, bromine, trifluoromethane or fluorine, and a non-substituted heterocyclic ring, selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, when "Y" represents CONR3R4 "R3" and "R4" stands for a hydrogen atom or C1-C5alkyl group, C1-C3alkoxygroup, non-substituted phenyl group, (C1-C3)alkoxy(C1-C3)alkyl group, C1-C3alkoxycarbonylmethyl group, non-substituted C3-C7cycloalkyl group, non-substituted benzenesulphonyl group; except the cases, when "R3" and "R4" simultaneously stand for hydrogen; when "Y" represents CONHCOR5, "R5" stands for a halogenated C1-C5alkyl group, non-substituted phenyl group; when "Y" represents CO2R9, "R9" stands for C1-C7alkyl group, halogenated C1-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with chlorine, fluorine or a nitro group naphthyl or a phenyl group, non-substituted (C6)aryl(C1-C3)alkyl group, (C1-C3)alkoxy (C1-C3) alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, tri(C1-C3alkyl)silyl(C1-C3)alkyl group, non-substituted C3-C7cycloalkyl group, 3-6-membered non-substituted heterocycloalkyl group, containing an oxygen atom as the heteroatom, non-substituted or substituted with methoxygroup phenylmethyl group, non-substituted furanylmethyl group, non-substituted thienylmethyl group, non-substituted pyridylmethyl group, succinimide group. The group of inventions also relates to methods of obtaining imine derivative of formula (1) (versions). The compound by the invention can be obtained from compounds, selected from the group, consisting of compounds, represented by formulas ACO-B (5), ACOOCOA (6), ACOOH (7), D-N=C=O (8) or HCO2Et(10) in the interaction with the compound of formula .

EFFECT: imine derivative, used as an insecticide, possessing the prolonged effect and wide spectrum of action.

5 cl, 22 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula I, their pharmaceutically acceptable salts and crystalline forms, which possess the properties of HCV polymerase inhibitor. In formula I is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 represents hydrogen; R2 is specified in a group consisting of hydrogen and halo; R3 represents hydrogen; R4 is specified in a group consisting of halo, C1-C6alkyl, C1-C6alkylsulphonyl and 5-6-merous heteroaryl containing heteroatom specified in N, O and S, wherein alkyl is optionally substituted by one or more hydroxy; R5 is specified in a group consisting of hygrogen, hydroxy, C1-C6alkyloxy and halo; L is specified in a group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently specified in a group consisting of hydrogen, C1-C6alkyl, C1-C6alkyloxy and halo; R6 represents C6aryl optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI and RJ; the substitutes RE, RF, RG, RH, RI and RJ are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to using the compounds for inhibiting HCV RNA-polymerase and treating hepatitis C and to a method of preparing the above compounds.

40 cl, 23 dwg, 7 tbl, 40 ex

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