Novel phenylpyrazinones as kinase inhibitors

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

 

The present invention relates to the use of new derivatives, which inhibit Btk and useful for the treatment of autoimmune and inflammatory diseases caused by impaired b-cell activation Described here new derivatives of 5-phenyl-1H-pyrazin-2-it is useful for the treatment of arthritis.

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; Ellmeier, etc., J. Exp. Med., 2000, 192, s). The Btk mutation in humans leads to a state of X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al., New Eng. J. Med., 1995, 333, s.431 and Lindvall Friday, February etc., Immunol. Rev., 2005, 203, s). These patients are immunocompromised 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 olmdahl, Clin. Exp.Immunol., 1993, 94, s). Selective inhibitor of Btk showed dose-dependent efficacy in a model of arthritis in mice (article Pan, etc., Chem. Med Chem., 2007, 2, SS-61).

Btk is also expressed by cells other than b cells, which may be involved 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, s). 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). 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, 49,and hence, 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).

In the first embodiment, the present invention relates to derivatives of 5-phenyl-1H-pyrazin-2-she formulas I-V:

where

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted by one or more R1'; where each R1'independently represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, cycloalkyl-lower alkyl, heteroseksualci, a cyano, a nitro-group or a lower halogenated;

R2represents-C(=O)- C(=O)O -(CH2)qC(=O)O, -C(=O)N(R2')2, -(CH2)q, -O(CH2)q, -CH2C(=O), -CH2C(=O)N(R2')2or-S(=O)2; where each R2'independently represents H, lower alkyl, lower alkoxygroup, lower halogenated or lower hydroxyalkyl; and q denotes 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower heteroalkyl, lower alkoxygroup, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected and is lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH2CH(Y') or NH; where Y' is a halogen, a hydroxy-group 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;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2'aor Y2'b; where Y2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents halogen or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of Hydra is syrupy, low alkoxygroup, amino and halogen;

m denotes 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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or their pharmaceutically acceptable salts.

In one embodiment, the present invention relates to a compound of formula I, where:

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted by one or more R1'; where each R1'independently represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, the amino group, cycloalkyl, heteroseksualci, a cyano, a nitro-group or a lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2')2, -(CH2)q, -(CH2)qC(=O)O, -O(CH2)qC(=ON(R2'), -CH2C(=O)N(R2'or-S(=O)2; where R2'represents H or lower alkyl; and q denotes 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or heteroseksualci alkyl, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH or N;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2aor Y2'b; where Y2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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; 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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

the sludge is its pharmaceutically acceptable salt.

In one embodiment of formula I, Y1represents methyl.

In one embodiment of formula I, n denotes 0, and m is 0.

In one embodiment of formula I, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula I, Y2represents hydroxymethyl.

In one embodiment of formula I, Y1represents methyl and Y2represents hydroxymethyl.

In one embodiment of formula I, Y2represents hydroxymethyl, n represents 0 and m is 0.

In one embodiment of formula I, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, Q represents n

In one embodiment of formula I, Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, Q represents CH.

In one embodiment of formula I, Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, Y4represents a group (a),

where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula I, Y4pre is is a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, R is-R1-R2-R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; and R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl,

In one embodiment of formula I, R is-R1-R2-R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, R is-R1-R2-R3; and R1is heteroaryl.

In one embodiment of formula I, R is-R1-R2; and R1represents heteroaryl.

In one embodiment of formula I, R is-R1; and R1is heteroaryl.

In one embodiment of formula I, R is-R1-R2-R3; R1is heteroaryl; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, R is-R1-R2; R1is heteroaryl; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, R is-R1; R1is heteroaryl; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, Y4represents a group (b),

where Y5and Y6 independently represent H or lower alkyl.

In one embodiment of formula I, Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula I, R is-R1-R2-R3; R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl; Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl; Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In another embodiment, the present invention relates to a compound of formula I, where:

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted R1'; where R1'represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, GoLoG is h, the nitro-group, amino group, cycloalkyl, heteroseksualci, cyano or lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2'), -(CH2)qor-S(=O)2; where R2'represents H or lower alkyl; and q denotes 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or heteroseksualci alkyl, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH or N;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2'aor Y2'b; gdau 2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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; 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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salts (compounds of formula (I').

In one Varian is e implementation of the formula I', Y1represents methyl.

In one embodiment, formula I', n is 0 and m is 0.

In one embodiment, formula I', Q represents n

In one embodiment, formula I', Y1represents methyl, and Q represents n

In one embodiment, formula I', Y1represents methyl, Q is an N, n is 0 and m is 0.

In one embodiment, formula I', Y2represents hydroxymethyl.

In one embodiment, formula I', Y1represents methyl and Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, and Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is O and m is 0.

In one embodiment, formula I', Q represents CH.

In one embodiment, formula I', Y1represents methyl, and Q represents CH.

In one embodiment, formula I', Y1represents methyl, Q represents CH, n is 0 and m is 0.

In one embodiment fo the mules I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment, formula I', Y2represents methyl.

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

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

In one embodiment, formula I', Q represents n

In one embodiment, formula I', Y1represents methyl, and Q represents n

In one embodiment, formula I', Y1represents methyl, Q is an N, n is 0 and m is 0.

In one embodiment, formula I', Y2represents hydroxymethyl.

In one embodiment, formula I', Y1represents methyl, Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y represents hydroxymethyl, n is 0 and m is 0.

In one embodiment, formula I', Q represents CH.

In one embodiment, formula I', Y1represents methyl, and Q represents CH.

In one embodiment, formula I', Y1represents methyl, Q represents CH, n is 0 and m is 0.

In one embodiment, formula I', Q represents CH, Y1represents methyl, and Y2represents hydroxymethyl.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxyethyl, n is 0 and m is 0.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2is a halogen, n is 0 and m is 0.

In one embodiment, formula I', Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, formula I', Q represents CH, Y1isone methyl, Y2represents hydroxymethyl, n is 0, m is 0, and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, formula I', Y4represents lower alkyl.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4represents lower alkyl,

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, formula I', Y4represents lower alkyl.

In one Varian is e implementation of the formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4represents lower alkyl.

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula I', R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In one embodiment, formula I', Y4is a group (C),

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

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0, and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, opisanog the above variant of implementation of the formula V, 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 alkyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, formula I', Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4represents a group (b),where Y 5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula I', R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, the OS is supervising the formula I', Y4is a group (d),

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

In one embodiment, formula I', Q represents CH, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula I', R is-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 alkyl.

In one embodiment, formula I', Q represents N, Y1represents methyl, Y2represents hydroxymethyl, n is 0, m is 0 and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula I', R is-R1-R2-R3; R1represents phenyl or pyridyl; R2predstavljaet a-C(=O); R3is an R4; and R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl.

In another embodiment, 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, and optionally substituted by one or more R1'; each R1'independently represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, cycloalkyl-lower alkyl, heteroseksualci, a cyano, a nitro-group or a lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2')2, -(CH2)q, -O(CH2)q,

-CH2C(=O), -CH2C(=O)N(R2')2or-S(=O)2; where each R2'independently represents H, lower alkyl, lower alkoxygroup, lower halogenated or lower hydroxyalkyl; and q denotes 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes,cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH2CH(Y') or NH;

Y' represents a halogen, a hydroxy-group 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;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2'aor Y2'b; where Y2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3 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, amino and halogen;

m denotes 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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salt.

In one embodiment of formula II, Y1represents methyl.

In one embodiment of formula II, n is 0 and m is 0.

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

In one embodiment of formula II, Y2represents hydroxymethyl.

<> In one embodiment of formula II, Y2represents a hydroxymethyl and Y1represents methyl.

In one embodiment of formula II, Y2represents hydroxymethyl, n is 0 and m is 0.

In one embodiment of formula II, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II, Q represents NH.

In one embodiment of formula II, Q is a CH2.

In one embodiment of formula II, Q represents NH, Y2represents hydroxymethyl, Y1represents methyl, n denotes 0, and m is 0.

In one embodiment of formula II, Q is a CH2, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II, Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula II, Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH2, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II, R is-R1-R -R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; and R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl.

In one embodiment of formula II, R is-R1-R2-R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH2, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II, R is an R1; where R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II, R is an R1; R1represents pyrazolyl, optionally substituted R1'; Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated; Q represents CH2, Y2represents hydroxymethyl, Y1is the battle methyl, n denotes 0 and m is 0.

In one embodiment of formula II, Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula II, Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl; Q represents CH2, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II, R is-R1-R2-R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; and R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl.

In one embodiment of formula II, R is-R1-R2-R3; where R1represents phenyl or pyridyl; R2represents-C(=O); R3is an R4; R4represents a morpholine or piperazine, optionally substituted by one or more lower alkyl; Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl; Q represents CH2, Y2represents hydroxymethyl, Y1represents methyl, p denoted by the AET 0 and m is 0.

In one embodiment of formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II, R is an R1; R1represents pyrazolyl, optionally substituted R1'; Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl; Q represents CH2, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In another embodiment, the present invention relates to the compound of formula II, where:

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted R1'; where R1'represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, heteroseksualci, cyano or lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2'), -(CH2)qor-S(=O)2; where R2'represents H or lower alkyl; q represents 1, 2 or 3;

R3represents N or R4; where R4represents the lower lcil, the lower alkoxygroup, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH2CH(Y') or NH; where Y' is a halogen, a hydroxy-group 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;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup halogen;

each Y2'independently represents Y2'aor Y2'b; where Y2'ais a halogen; Y2'brepresents lower alkyl, the optional Sames the config one or more Y 2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salts (compounds of formula II').

In one embodiment of formula II', Y1represents methyl.

In one embodiment of formula II', Y2is the Wallpaper hydroxymethyl.

In one embodiment of formula II', n denotes 0, and m is 0.

In one embodiment of formula II', Y2represents hydroxymethyl, n is 0 and m is 0.

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

In one embodiment of formula II', Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II', Q represents NH.

In one embodiment of formula II', Q represents NH, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II', Y2represents hydroxymethyl, Q represents NH, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II', Q is a CH2.

In one embodiment of formula II', Q is a CH2, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II', Y2represents hydroxymethyl, Q is a CH2, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula II', Y2pre is is a methyl.

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 group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula II', Y2represents hydroxymethyl, Q is a CH2, Y1represents methyl, n denotes 0, and m is 0, and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula II' R is a-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of the westline formula II', R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y2represents hydroxymethyl, Q represents NH, Y1represents methyl, n denotes 0, and m is 0, and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula II', Y4represents lower alkyl.

In one embodiment of formula II', Y2represents hydroxymethyl, Q is a CH2, Y1represents methyl, n denotes 0, and m is 0 and Y4represents lower alkyl.

In one embodiment, the above-described variant of implementation of the formula II' R is a-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4is soboleski alkyl.

In one embodiment of formula II', Y2represents hydroxymethyl, Q represents NH, Y1represents methyl, n denotes 0, and m is 0 and Y4represents lower alkyl.

In one embodiment, the above-described variant of implementation of the formula II' R is a-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula II', Y2represents hydroxymethyl, Q is a CH2 , Y1represents methyl, n is 0 and m is 0, and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula II, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y2represents hydroxymethyl, Q represents NH, Y1represents methyl, n denotes 0, and m is 0 and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

<> In one embodiment, the above-described variant of implementation of the formula II, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula II', Y2represents hydroxymethyl, Q is a CH2, Y1represents methyl, n denotes 0, and m is 0 and Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula II, R represents Soboh the-R 1-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y2represents hydroxymethyl, Q represents NH, Y1represents methyl, n denotes 0, and m is 0 and Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula II, R is-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 of the nih is to them alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula II', Q is a CH2, Y1represents methyl, n is 0 and m is 0, and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula II, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II', R p is ecstasy a-R 2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula II', Q represents NH, Y1represents methyl, n is 0 and m is 0, and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula II, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula II, R is an R1; and R1 represents pyrazolyl, optionally substituted R1'.

In another embodiment, the present invention relates to the compound of formula III, where:

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted R1'; where R1'represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, heteroseksualci, cyano or lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2'), -(CH2)qor-S(=O)2; where R2'represents H or lower alkyl; q represents 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl Il is lower halogenoalkane;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2aor Y2b; where Y2'bis a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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; where

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 and lowest alkoxygroup;

Y4cis particularly 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salt.

In one embodiment of formula III, Y1represents methyl.

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

In one embodiment of formula III, Y2represents hydroxymethyl.

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

In one embodiment of formula III, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula III, Y2represents methyl.

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 group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one variant of the implementation of the formula III, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula III, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula III, Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula III, Y2represents hydroxymethyl, Y1represents meth is l, n represents 0, m represents 0, and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula III, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula III, Y4represents a group (b) where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula III, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4represents a group (b), where Y5and Y independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula III, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula III, Y4is a group (d), where Y5and Y6independently represents H, lower alkyl or lower halogenated.

In one embodiment of formula III, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

One in which the approaches described above variant of implementation of the formula III, 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 alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula III, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In another embodiment, the present invention relates to the compound of formula IV, where:

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

R1represents aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted R1'; where R1'represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, heteroseksualci, cyano or lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2'), -(CH2 qor-S(=O)2; where R2represents H or lower alkyl; q represents 1, 2 or 3;

R3represents N or R4;

R4represents lower alkyl, lower alkoxygroup, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2b'; where Y2b'represents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2'aor Y2'b; where Y2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; where Y2'b'represents a hydroxy-group, lower ALK is xygraph or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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; where

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 and lowest 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salt.

In one embodiment of formula IV, Y1represents methyl.

In one embodiment of formula IV, n is 0 and m is 0.

In one embodiment of formula IV, Y2represents hydroxymethyl.

In one embodiment, about what westline formula IV, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula IV, Y2represents methyl.

In one embodiment of formula IV, Y2represents a hydroxyethyl.

In one embodiment of formula IV, Y2represents a halogen.

In one embodiment of formula IV, Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula IV, R is-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 alkyl.

In another embodiment, the above-described variant of the implementation of the formula IV, R represents-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula IV, Y4represents lower alkyl.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0, and Y4represents lower alkyl.

In one embodiment, the above-described variant of implementation of the formula IV, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula I, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula IV, Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0, and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula IV, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is-R2-R3; R3represents-C(=O)NH; R2represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is an R1; and R1represents pyrazolyl, optional the nutrient substituted R 1'.

In one embodiment of formula IV, Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula IV, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula IV, Y4is a group (d), where Y5and Y6independent who represent H, lower alkyl or lower halogenated.

In one embodiment of formula IV, Y2represents hydroxymethyl, Y1represents methyl, n represents 0, m represents 0 and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula IV, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula IV, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In another embodiment, the present invention describes a compound of formula V where:

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

R1presented yet an aryl, heteroaryl, cycloalkyl or heteroseksualci, and optionally substituted R1'; where R1'represents a lower alkyl, a hydroxy-group, a lower hydroxyalkyl, lower alkoxygroup, halogen, the nitro-group, amino group, cycloalkyl, heteroseksualci, cyano or lower halogenated;

R2represents-C(=O)- C(=O)O, -C(=O)N(R2'), -(CH2)qor-S(=O)2; where R2represents H or lower alkyl; q represents 1, 2 or 3;

R3represents N or R4; where R4represents lower alkyl, lower alkoxygroup, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylether, heteroallyl, cycloalkyl, alkylsilanes, cycloalkenyl, heteroseksualci, alkylchlorosilanes or geterotsiklicheskikh, and optionally substituted by one or more substituents selected from lower alkyl, hydroxy-group, carbonyl group, lower hydroxyalkyl, low alkoxygroup, halogen, nitro, amino, ceanography, lower alkylsulfonyl or lower halogenoalkane;

Q represents CH2CH(Y') or NH; where Y' is a halogen, a hydroxy-group or lower alkyl, where the lower alkyl optionally substituted by one or more substituents selected from the group consisting of hydroxy-group, the lower alkoxy PPI, the amino and halogen;

Y1represents H or lower alkyl;

Y2represents the Y2aor Y2b; where Y2arepresents H or halogen; Y2brepresents lower alkyl, optionally substituted by one or more Y2'b; where Y2'brepresents a hydroxy-group, the lower alkoxygroup or halogen;

each Y2'independently represents Y2'aor Y2'b; Y2'ais a halogen; Y2'brepresents lower alkyl, optionally substituted by one or more Y2'b'; Y2'b'represents a hydroxy-group, the lower alkoxygroup or halogen;

n denotes 0, 1, 2 or 3;

Y3represents 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 and lowest alkoxygroup;

Y4c represents 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 and lowest alkoxygroup; and

Y4drepresents an amino group, optionally substituted by one or more lower alkyl;

or its pharmaceutically acceptable salt.

In one embodiment of formula V, Y1represents methyl.

In one embodiment of formula V, Q represents CH2.

In one embodiment of formula V, Y2represents hydroxymethyl.

In one embodiment of formula V, n is 0 and m is 0.

In one embodiment of formula V, Y1represents hydroxymethyl, n is 0, and m is 0.

In one embodiment of formula V, Y1represents methyl, n denotes 0, and m is 0.

In one embodiment of formula V, Y1represents methyl, Q is a CH2n denotes 0 and m is 0.

In one embodiment of formula V, Y2represents hydroxymethyl, Y1represents methyl, n is 0 and m is 0.

In one embodiment of formula V, Y2is the Wallpaper hydroxymethyl, Y1represents methyl, Q is a CH2n denotes 0 and m is 0.

In one embodiment of formula V, Y2represents methyl.

In one embodiment of formula V, Y2represents a hydroxyethyl.

In one embodiment of formula V, Y2represents a halogen.

In one embodiment of formula V, Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment of formula V, Y2represents hydroxymethyl, Y1represents methyl, Q is a CH2n denotes 0 and m is 0, and Y4represents a group (a), where Y5represents H, halogen, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula V, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is-R2-R3; R2is Soboh is-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula V, Y4represents lower alkyl.

In one embodiment of formula V, Y2represents hydroxymethyl, Y1represents methyl, Q is a CH2n denotes 0, and m is 0, and Y4represents lower alkyl.

In one embodiment, the above-described variant of implementation of the formula V, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is an R1; and R1represents pyrazolyl, n is necessarily substituted R 1'.

In one embodiment of formula V, Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment of formula V, Y2represents hydroxymethyl, Y1represents methyl, Q is a CH2n denotes 0, and m is 0, and Y4is a group (C), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula V, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment, formula , Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment of formula V, Y2represents hydroxymethyl, Y1represents methyl, Q is a CH2n denotes 0, and m is 0, and Y4represents a group (b), where Y5and Y6independently represent H or lower alkyl.

In one embodiment, the above-described variant of implementation of the formula V, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

In one embodiment of formula V, Y4is a group (d), where Y5and Y6independently represent what, lower alkyl or lower halogenated.

In one embodiment of formula V, Y1represents methyl, Q is a CH2n denotes 0, and m is 0, and Y4is a group (d), where Y5and Y6independently represent H, lower alkyl or lower halogenated.

In one embodiment, the above-described variant of implementation of the formula V, R is-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 alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is-R2-R3; R2represents-C(=O)NH; R3represents N or R4; and R4represents lower alkyl.

In another embodiment, the above-described variant of implementation of the formula V, R is an R1; and R1represents pyrazolyl, optionally substituted R1'.

The 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 I-V or their variants in Ter is piticescu effective amount.

The invention relates to a method of treating rheumatoid arthritis, comprising the administration to a patient in need this, the compounds of any of the above formulas I-V or their variants in therapeutically effective amounts.

The invention relates to a method of inhibiting b-cell proliferation comprising administration to a patient in need this, the compounds of any of the above formulas I-V or their variants in therapeutically effective amounts.

The invention relates to a method of treating an inflammatory condition comprising co-administration to a patient in need this, anti-inflammatory compounds in therapeutically effective amounts in combination with any of the above formulas I-V or options.

The 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 any of the above formulas I-V or options.

The invention relates to a method for the treatment of lymphoma or leukemia cells BCR-ABL1+the introduction of the patient, the needy in this connection, any of the above formulas I-V or their variants in therapeutically effective amounts.

The invention relates to pharmaceutical compositions, vklyuchayuschimisya inhibitor of Btk any one of the above formulas I-V or their variants, in a mixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

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

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

In one embodiment of the above method, the compound is an inhibitor of Btk shows the value of the IC50100 nm or less in the biochemical analysis on the activity of Btk in vitro.

In one embodiment of the above method, the compound is an inhibitor of Btk shows the value of the IC5010 nm or less in the biochemical analysis on the activity of Btk in vitro.

The 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 one of the above formulas I-V or options.

The present invention relates to compounds of General formulas I-V, which include the connection Btk inhibitors of formulas I-V, where the variables Q, R, Y1, Y2, Y3, Y4n and m have the above values.

In one embodiment, the present invention describes a compound of General formula I, which consists of the submitted compound inhibitor of Btk formula I-1. In another embodiment, the present invention describes a compound of General formula II, which consists of the submitted compound inhibitor of Btk formula II-1-II-36.

In another embodiment, the present invention describes a compound of General formula III, which includes compounds inhibitors of Btk formula III. In another embodiment, the present invention describes a compound of General formula IV, which includes connection Btk inhibitors of formula IV. In another embodiment, the present invention describes a compound of General formula V, which includes compounds inhibitors of Btk formula V.

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 I 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 formulas I-V, including substituted side chains 3,4-dihydro-2H-isoquinoline-1-it, 2,3-dihydro-1H-hinzelin-4-she 2H-isoquinoline-1-it, 3H-hinzelin-4-she 1H-quinoline-4-it, 2N-phthalazine-1-or 3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide, 5-phenyl-1H-pyrazin-2-nowych ring systems are unexpectedly high inhibitory activity compared to counterparts without these bicyclic side chains. In addition, the inhibitory activity increases when Y2represents lower alkyl, optionally substituted hydroxy-group. Inhibitory activity increases when Y2represents hydroxymethyl. Compounds of formulas I-V are useful for the treatment of arthritis and other inflammatory and autoimmune diseases. Compounds in accordance with formulas I-V, respectively, are useful for the treatment of arthritis. Compounds of formulas I-V are useful for inhibiting Btk in cells and to modulate b-cell development. The present invention also includes pharmaceutical compositions containing the compounds of formulas I-V in a mixture with a pharmaceutically acceptable carrier, excipients or diluents.

The indeterminate form as here uses the I 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 specified in the most broad definition.

As used in the description, in a transitional phrase or in the claims, the terms "include (includes" and "including" 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 moretake to 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 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:

MeC(=O)OR4where.

<> 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 link indicates that the link 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, are connected directly.

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 compounds of formulas I-V may be tautomerism. Tautomer the s 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 the present 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/and and methods well-known specialist in this field of technology 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. For 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 the" as here used refers to 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 "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 refers to a 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 "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, the pet-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" refers to the radical R R"-, where R' is 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' is 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 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 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, ethoxy, n-propyloxy, out-propyloxy, n-Butylochka, out-Butylochka, tert-Butylochka, pentyloxy, hexyloxy, including their isomers. "The lowest alkoxygroup" as used here refers to alkoxygroup with "lower alkyl" group as defined above. "C1-140alkoxy" as used here refers to-O-alkyl, where alkyl represents a C1-10.

The term "alkoxyalkyl" as used here denotes the radical R R"-, where R' is alkoxyalkyl as defined above, and R" represents alkalinity radical as defined above, provided that the attachment point alkoxyalkyl group is Allenova radical. With1-6alkoxyalkyl refers to a group where the alkyl part is of 1 to 6 carbon atom sole carbon atoms in alkoxides group. With1-3alkoxy-C1-6alkyl refers to a group where the alkyl part of sostoi is of 1-6 carbon atoms, and alkoxygroup from 1-3 carbon atoms. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropan, propylacetate, methoxybutyl, ethoxymethyl, propylacetate, butylacetate, tert-butylacetyl, methoxyphenyl, ethoxyphenyl, proproxyphene, including of isomers.

The term "heteroassociative" as used here denotes-O-(heteroalkyl) group, where heteroalkyl is the same as here defined. With1-10heteroassociative" as used here denotes-O-(heteroalkyl), where alkyl represents a C1-10. Some examples include, but are not limited to, 2-dimethylaminoethoxy and 3 sulphonamido-1-propoxylate.

The term "hydroxyalkyl" as used here refers to an alkyl radical as defined here, where 1-3 hydrogen atoms at different carbon atoms substituted by hydroxyl groups.

"Aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tricyclic aromatic ring. The aryl group may be optionally substituted as herein defined. Examples of aryl groups include, but are not limited to, optionally substituted phenyl, naphthyl, tenantry, fluorenyl, indenyl, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfide, diphenylsulfone, diphenylethylene, benzodioxane, benzodioxole, benzoxazines, benzoxazinones, benzopyranyl, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity and the like. Aryl group optionally may be condensed with cycloalkyl or heteroseksualnymi ring, as defined here. Examples of the aryl group fused with geteroseksualnoe group include 3,4-dihydro-1H-quinoline-2-it, 3,4-dihydro-2H-benzo[1,4]oxazin and 1,2,3,4-tetrahydroisoquinoline. Preferred aryl include optionally substituted phenyl and optionally substituted naphthyl.

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 "heteroaryl" or "heteroaromatic" as used here denotes monocyclic or bicyclic radicals 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 concealed 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 may not necessarily 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, acylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, allylcarbamate, dialkylamino, arylcarbamoyl, alkylcarboxylic and arylcarboxylic. Examples of bicyclic groups including the Ute, but 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, arylaminomethylene, alkylsulfonamides, arylsulfonamides, alkylaminocarbonyl, arylenecarborane, alkylcarboxylic, arylcarboxamide, if not decree what about otherwise. 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 (Boc), di-tert-butylpyrocatechol or boc-anhydride (RE2Oh), benzyl (Bn), 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), 1,1'-bis(diphenylphosphino)ethane (dppe), 1,1'-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-carbon is howling 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'-BMS-2,2,b,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), monohydrate p-toluensulfonate acid (TsOH or TsOH), 4-Me-C6H4SO2or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA). The usual nomenclature, including consoles normal (n-), from- (and-), secondary (sec-), TriTech the first (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).

The term "arthritis" as used here, refers to acute rheumatoid arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, hilariously arthritis, arthritis, based on intestinal disease, filariasis arthritis, gonococcal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, juvenile chronic arthritis, arthritis Lima, neonatal arthritis foals, nodular arthritis, ochronosis arthritis, psoriatic arthritis or septic arthritis or related diseases which require the administration to the mammal of a compound of formulas I-V in a therapeutic effective dose sufficient for inhibition of CPD.

Compounds of the present invention can be used for the treatment of subjects with autoimmune conditions or disorders. As used here, the term "autoimmune condition" and similar terms refers to a disease, disorder or condition caused by the immune system of the animal. Autoimmune disorders are disorders in which one's own immune system of the animal mistakenly strikes themselves, thereby linking the cells, tissues and/or organs of his own body. For example, the autoimmune reaction is directed to the nervous system in multiple sclerosis and intestine in Crohn's disease. In other autoimmune disorders such as systemic red [system erythematous] lupus, lesions of tissues and organs may vary in patients with the same disease. One patient with systemic lupus erythematosus may be affected skin and joints, while others may be affected, the skin, kidneys and lungs. Finally, damage to some tissues of the immune system may be permanent, as with the destruction of insulin-producing cells of the pancreas in diabetes mellitus type 1. Specific autoimmune disorders, which can be facilitated by the compounds and methods of the present invention, include, without limitation, autoimmune disorders of the nervous system (e.g. multiple sclerosis, asthenic bulbar paralysis, autoimmune neuropathies such as Guillain-Barre syndrome and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), autoimmune disorders of the blood vessels (for example, temporal arteritis diagnostics, antiphospholipid syndrome, vasculitides, such as granulomatous's granulomatosis and disease Bechet), autoimmune disorders of the skin (e.g. psoriasis, dermatitis herpetiformis, vulgar disease and vitiligo), autoimmune disorders, gastrointestinal system (e.g., Crohn's disease, yaswen the th colitis, primary biliary cirrhosis and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., diabetes mellitus type 1 or immune diabetes mellitus, graves ' disease, thyroiditis Hashimoto's disease, autoimmune oophoritis and orchitis, autoimmune disease of the adrenal glands); autoimmune disorders, multiple agencies (including diseases of connective tissue and of the musculoskeletal system) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies, such as ankylosing spondylitis, and Sjogren syndrome) or the related diseases which require the administration to the mammal of a compound of formulas I-V in therapeutic effective dose sufficient for inhibition of CPD. In addition, other diseases mediated by the immune system, such as graft-versus-host and allergic disorders, also included in the definition of immune disorders. Due to the fact that a number of immune disorders caused by inflammation, there is some coincidence of disorders that are associated with immune disorders and inflammatory disorders. For the purposes of the present invention, in the case of such a matching violation, it may not be as immune disturbance or inflammatory disorder. "Treatment of immune disorders" refers to here is the introduction of the compounds or compositions according to the invention to a subject with an immune disorder, a symptom of such disease or prone to this disease, for the treatment, relief, change, mitigate or prevent autoimmune disorder, symptom or predisposition thereto.

As used here, the term "asthma" refers to a lung disease, disorder or condition characterized by reversible obstruction of the pulmonary tract, airway inflammation and increased sensitivity of the Airways to various stimuli.

The terms "treat" or "treatment" refer to both therapeutic treatment and prophylactic or prevent effects where the object is to prevent or slow down (reduce undesired physiological change or disorder, such as the development or spread of cancer. Beneficial or desired clinical results include, but are not limited to, alleviating symptoms, reducing the severity of disease, stabilized (i.e. not worsening) diseases, stopping or slowing down the development of the disease, alleviating or mitigating the disease, and remission (partial or complete), definable or indefinable. "Treatment" can also refer to life extension compared with the anticipated lifetime if untreated. Those in need of treatment include patients who have the condition jinaratana, as well as patients who are prone to the condition or violation, or patients in whom the condition or violation should be avoided. For example, treatment of an inflammatory condition indicates a reduction in the degree or severity of the inflammation. The reduction may mean, without limitation, the complete elimination of the inflammation. For example, the reduction may include the reduction of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or any value in between, compared to untreated or control the entity that defined any suitable method of measurement or analysis described here or analysis, known from the prior art.

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, computer system Beilstein Institute for the development of systematic IUPAC nomenclature, If there is a difference given the structure and names given to this structure, performance, and Alanna 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 all stereoisomers.

Table I lists examples of compounds of pyrazinone General formulas I-II:

Table I
StructureNomenclature
I-16-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-isoquinoline-1-he

StructureNomenclature
II-12-{3-[6-(2,2-Debtorrent[1,3]dioxol-5-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-it
tPL: 145,0-150,0; MS (M+H): 576
II-26-Dimethylamino-2-(2-what hydroxymethyl-3-{4-methyl-6-[4-(4-methylpiperazin-1-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 168,0-170,0; MS (M+H): 633
II-36-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-46-Cyclopropyl-2-{3-[6-(1-ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-he
II-56-Cyclopropyl-2-{2-hydroxymethyl-3-[4-methyl-6-(1-methyl-1H-pyrazole-4-ylamino)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-64-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N,N-dimethylbenzamide
MS (M+H); 564
II-74-{6-[3-(6-Cyclo is ropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N,N-diethylbenzamide
MS (M+H): 591
II-86-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-96-Cyclopropyl-2-{2-hydroxymethyl-3-[4-methyl-6-(4-(morpholine-4-iletilenlerin)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-106-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(pyrrolidin-1-carbonyl)phenylamino]-4,5-dihydropyrazol-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 178,0-180,0; MS (M+H): 590

StructureNomenclature
II-116-(1-Forciblepoppy)-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 172,0-174,0; MS (M+H): 624
II-12 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-hydroxypiperidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 171,0-173, 0mm; MS (M+H): 620
II-136-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-methoxypiperidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 146,0-148,0; MS (M+H): 634
II-146-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methylpiperazin-1-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-it
tPL: 172,0-175,0; MS (M+H); 619
II-154-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N-(2-hydroxyethyl)-N-methylbenzamide
tPL: 115,0-117,0; MS (M+H): 594

StructureNomenclature
II-16 6-Cyclopropyl-2-[3-(6-{4-[4-(2-hydroxyethyl)piperazine-1-carbonyl]phenylamino}-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-hydroxymethylene]-3,4-dihydro-2-isoquinoline-1-it
tPL: 175,0-180,1; MS (M+H): 649
II-176-Cyclopropyl-2-(3-{6-[4-(2,6-dimethylmorpholine-4-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2-isoquinoline-1-it
tPL: 173, 0mm-175,0; MS (M+H): 634
II-186-Cyclopropyl-2-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-it
MS (M+H): 653
II-196-Cyclopropyl-2-(3-{6-[4-(4-ethoxypyridine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-it
MS (M+H): 647
II-206-Cyclopropyl-2-(3-{6-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline--he
tPL: 153,0-155,0; MS (M+H): 633

StructureNomenclature
II-216-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(4-(morpholine-4-iletilenlerin)-5-oxo-4,5-dihydropyrazine-2-yl] phenyl} -3,4-dihydro-2H-isoquinoline-1-he
II-226-Dimethylamino-2-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-232-(3-{6-[4-(4-Acetylpiperidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he
II-246-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(3-oxopiperidin-1-carbonyl)phenylamino]-4,5-dihydropyrazol-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-256-Cyclopropyl-2-(3-{6-[4-(4,4-deformability-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-262-(3-{6-[4-(4-Aminopiperidin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he
II-276-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-hydroxy-4-methylpiperidin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-284-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N-(2-methoxyethyl)-N-methylbenzamide

StructureNomenclature
II-294-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N-ethyl-N-methylbenzamide
II-306-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methylpiperazin-1-yl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-316-Dimethylamino-2-{3-[6-(1-ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-he
II-326-Dimethylamino-2-(3-{6-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-334-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1 H-isoquinoline-2-yl)-2-Ki is oxymethylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N,N-bis-(2-methoxyethyl)benzamide
II-344-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N-(2-methoxyethyl)benzamide
II-354-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N,N-bis-(2-hydroxyethyl)benzamide
II-366-tert-Butyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-376-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepan-1-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-384-{6-[3-(6-Cycle is propyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-N-ethylbenzamide
II-396-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[4-(4-isopropylpiperazine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-406-Dimethylamino-2-(3-{6-[4-(4-ethoxypyridine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-416-Dimethylamino-2-(2-hydroxymethyl-3-{6-[4-(4-hydroxypiperidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-426-Cyclopropyl-2-(2-hydroxymethyl-3-{b-[4-(4-methoxypiperidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-43 6-Cyclopropyl-2-(2-hydroxymethyl-3- {6-[1-(2-methoxyethyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-446-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[1-(2,2,2-triptorelin)-1H-pyrazole-4-ylamino]-4,5-dihydropyrazol-2-yl} phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-452-(4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}pyrazole-1-yl)-N,N-dimethylacetamide
II-466-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(5-methyl-1H-pyrazole-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-476-Dimethylamino-2- {2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1H-pyrazole-3-ylamino)-4,5-dihydropyrazol-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-486-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)phenylamino]-4,5-dihydropyrazol-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-496-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(2-morpholine-4-yl-2-oxoethyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-506-Cyclopropyl-2-(2-hydroxymethyl-3-{6-[3-methoxy-4-(morpholine-4-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-517-{6-[3-(6-tert-Butyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-3,4-dihydro-1H-quinoline-2-he

StructureNomenclature
II-522-{3-[6-(5-Cyclopropyl-1H-feast of the evils-3-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
II-537-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-3,4-dihydro-1H-quinoline-2-he
II-547-{6-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}-3,4-dihydro-1H-quinoline-2-he
II-556-tert-Butyl-2-{3-[6-(1-ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-he
II-566-Cyclopropyl-2-(3-{6-[4-((S)-3-ethoxypyrrolidine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-576-Cyclopropyl-2-(3-{6-[4-((R)-3-oxypyridine-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-586-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)phenylamino]-4,5-dihydropyrazol-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-596-Cyclopropyl-2-{2-hydroxymethyl-3-[6-(1-isopropyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-606-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-3-nitrophenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-612-(4-{6-[3-(6-Dimethylamino-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino} pyrazole-1-yl)-N,N-dimethylacetamide
II-626-Cyclopropa is-2-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-636-Dimethylamino-2-{3-[6-(3-fluoro-4-morpholine-4-ilfenomeno)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-he
II-642-[3-(6-{4-[Bis-(2-hydroxyethyl)amino]phenylamino}-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-hydroxymethylene]-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
II-656-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(4-piperidine-1-iletilenlerin)-4,5-dihydropyrazol-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-666-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[1-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazole-4-ylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-676-Cyclopropyl-2{3-[6-(1-cyclopropylmethyl-1ST-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-3,4-dihydro-2H-isoquinoline-1-he
II-686-Dimethylamino-2-(3-{6-[4-(2-hydroxyethoxy)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-696-(Ethylmethylamino)-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-706-Cyclopropyl-2-(3-{6-[1-(2,2-dottorati)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-712-(4-{6-[3-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}pyrazole-1-yl)-N-methylacetamide
II-726-Dimethylamino-2-{2-Ki is roximity-3-[4-methyl-5-oxo-6-(1-propyl-1H-pyrazole-4-ylamino)-4,5-dihydropyrazol-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-732-{3-[6-(1-Cyclobutylmethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
II-746-Cyclopropyl-2-{2-hydroxymethyl-3-[4-methyl-5-oxo-6-(1-propyl-1H-pyrazole-4-ylamino)-4,5-dihydropyrazol-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-756-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(4-(morpholine-4-ilfenomeno)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-762-{3-[6-(3,4-Dihydro-2H-benzo[1,4]oxazin-6-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
II-776-Cyclopropyl-2-(3-{6-[1-(2-hydroxide is)-1-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-786-Dimethylamino-2-{2-hydroxymethyl-3-[4-methyl-6-(2-morpholine-4-espiridion-4-ylamino)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-796-tert-Butyl-2-{2-hydroxymethyl-3-[4-methyl-6-(2-morpholine-4-espiridion-4-ylamino)-5-oxo-4,5-dihydropyrazine-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-802-{3-[6-(1-Ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-6-(1-hydroxy-1-methylethyl)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-816-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[6-(4-methylpiperazin-1-yl)pyridine-3-ylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-826-Dimethylamino-2-{2-hydroxy shall ethyl-3-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)-4,5-dihydropyrazol-2-yl]phenyl}-3,4-dihydro-2H-isoquinoline-1-he
II-832-(3-{6-[1-(2,2-Dottorati)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-6-(1-hydroxy-1-methylethyl)-3,4-dihydro-2H-isoquinoline-1-he
II-842-(3-{6-[1-(2,2-Dottorati)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
II-856-Dimethylamino-2-(3-{6-[4-(2-dimethylaminoethoxy)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he

StructureNomenclature
II-862-[2-(3-{6-[1-(2,2-Dottorati)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]-2-methylpropionitrile
II-87 6-Dimethylamino-2-(2-hydroxymethyl-3-{6-[1-(2-hydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-3,4-dihydro-2H-isoquinoline-1-he
II-886-Dimethylamino-2-(3-{6-[4-(1,4-dimethyl-3-oxopiperidin-2-yl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-3,4-dihydro-2H-isoquinoline-1-he
II-892-(3-{6-[1-(2,3-Dihydroxypropyl)-1H-pyrazole-4-ylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}-2-hydroxymethylene)-6-dimethylamino-3,4-dihydro-2H-isoquinoline-1-he
I-26-Dimethylamino-2-(2-hydroxymethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)phenylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-isoquinoline-1-he

I-4
StructureNomenclature
I-36-Cyclopropyl-2-{3-[6-(1-ethyl-1H-pyrazole-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl]-2-hydroxymethylene}-2H-isoquinoline-1-he
2-(4-{6-[3-(6-Dimethylamino-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}phenoxy)-N-methylacetamide
I-5(4-{6-[3-(6-Cyclopropyl-1-oxo-1H-isoquinoline-2-yl)-2-hydroxymethylene]-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino}pyrazole-1-yl)acetic acid
I-66-Cyclopropyl-2-(2-hydroxymethyl-3-{4-methyl-6-[1-(1-methyl-1H-imidazol-2-ylmethyl)-1H-pyrazole-4-ylamino]-5-oxo-4,5-dihydropyrazine-2-yl}phenyl)-2H-isoquinoline-1-he

Described herein derivative of pyrazinone 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 ingibirovaniem 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 is in the cancel method of treatment of a mammal, for example, a person 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. The effective concentration may be selected experimentally, for example, assessing 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 reaction, sensitive to ingabire aniu 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 rejection 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 NSAID VK is ucaut, but 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 NSAIDs include 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, and 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, Taco is 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 embodiments of the invention relate 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 village is edusim anti-apoptotic regulatory mechanism, including CPD and/or its substrates (article Vassilev and others, 3. Biol. Chem., 1998, 274, s-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 chemotherapeutic drugs that 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 anti 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), SS-1852).

Compounds of the present invention can be introduced into a wide range of metered the 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, intravenous, 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 is ngredient, 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 capsules 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 pharmaceutical compositions 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 this izopet the deposits can be entered 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 that is generally 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 is; 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-hydroxybenzoyl)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, louisanna 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 an organic base such as ethanolamine, diethanolamine is, 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 leavening agents 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 are also suitable for peroral the CSOs introduction, include a 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 can be obtained by dissolving the active component in water and adding suitable colorants, fragrances, 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 and the water-carriers, for example, the 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, stabiliziruyutsya and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by 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 places which CSOs 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 acids 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 is mo which should be carried out by introduction of a 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 obtained by methods 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, at otstavat 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 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 on the 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, for example, 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 .W.Martin, Mak Publishing Company, 19-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 (salt formation, esterification etc)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 entered the I and the preference 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 range may 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. Typically, treatment begins 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 a 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 depict ablate a Packed product, 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

The General scheme 1

Example 1: 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 closed vessel with 2 ml of DMSO. Through a mixture missed argon for 1 minute. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DHM (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-2 is-isoquinoline-1-she (137 mg, 0,349 mmole). MS (ESI) 393,2 (M+N)+.

Example 2: 6-Bromo-PLN-dihydro-2H-isoquinoline-1-he

Methansulfonate acid (31 ml, 10 equiv.) was added to a mixture of 5-bromantan-1-it (10 g, 47 mmol) in CH2Cl2(75 ml) at 0°C. Slowly in portions to this mixture was added sodium azide. 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 6-bromo-3,4-dihydro-2H-isoquinoline-1-she (6.5 g, 61%).

Example 3: 6-Cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he

A mixture of 6-bromo-3,4-dihydro-2H-isoquinoline-1-she (2.0 g, 8.8 mmole), cyclopropylboronic acid (1,14 g, 1.5 equiv.), tricyclohexylphosphine (250 mg, 0.1 equiv.) and K3PO4(3.8 g, 2 equiv.) in toluene (30 ml) and H2O (1.2 equiv.) was heated in N2rapidly to 100°C. was Added Pd(OAc)2(100 mg, of 0.05 equiv.), and the combined mixture was heated for 5 h at 100°C. the Reaction mixture was cooled, filtered, and purified accelerated column chromatography on silica gel, receiving 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (of 1.57 g, 95%).

Example 4: 2-Bromo-6-(6-cyclopropyl-1-oxo-3,4-Digi the ro-1H-isoquinoline-2-yl)benzaldehyde

In a sealable vessel was loaded 6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he (985 mg, 5 mmol), 2,6-dibromobenzene (2.6 g, 2 equiv.), Pd(dba)2(58 mg, of 0.02 equiv.), Xanthos (89 mg, of 0.03 equiv.) and cesium carbonate (2.28 g, 1.4 equiv.). The vessel was filled with argon, was added dioxane (5 ml), and the vessel was closed. The mixture was stirred at 100°C for 1 day, diluted with EtOAc, filtered through a short layer of silica gel and concentrated under reduced pressure. Purification of the mixture accelerated column chromatography on silica gel resulted in the receipt of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde (1,05 g, 56%).

Example 5: 2-(3-Bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-he

Superseded (22,4 ml, 1.75 equiv.) was added dropwise to a solution of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzaldehyde (4,75 g, 12.8 mmole) in THF (40 ml). The mixture was stirred for 30 min, and was suppressed by slow addition of 1N HCl. The aqueous mixture was extracted with CH2Cl2. The organic layers were concentrated and purified accelerated column chromatography on silica gel to obtain 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-she (3.2 g, 67%).

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

Acetic anhydride (121 μl, 1 equiv.) we use the and to a mixture of 2-(3-bromo-2-hydroxymethylene)-6-cyclopropyl-3,4-dihydro-2H-isoquinoline-1-it (475 mg, of 1.27 mmole), DMAP (16 mg, 0.1 equiv.) and the tea (178 μl, 1 equiv.) in anhydrous CH2Cl2(6 ml). The mixture was stirred for 1 h, and volatile materials were removed by evaporation. Purification of the mixture accelerated column chromatography on silica gel resulted in the receipt of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (525 mg, 100%).

Example 7: 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 ester of acetic acid

A mixture of 2-bromo-6-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)benzyl ester of acetic acid (660 mg, was 1.58 mmole), bis(pinacolato)diboron (490 mg, 1.2 equiv.), (dppf)PdCl2·CH2Cl2(58 mg, of 0.05 equiv.) and potassium acetate (471 mg, 3 equiv.) was heated at 80°C in an argon atmosphere in a closed vessel during the night. The reaction mixture was separated between EtOAc and H2O. the Organic phase was separated and evaporated under reduced pressure. Purification of the mixture accelerated column chromatography on silica gel resulted in obtaining 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 ester of acetic acid (0.56 g, 77%).

Example 8: 2-(6-Cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{6-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}benzyl ether acetic acid

A mixture of 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 ester of acetic acid (46 mg, 0.1 mmole), 5-bromo-3-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-1-methyl-1H-pyrazin-2-she (42 mg, 1 equiv.), Pd(dba)2(2 mg, of 0.03 equiv.), XPhos (3 mg, is 0.06 equiv.) and K3PO4(42 mg, 2 equiv.) was heated in a closed vessel in an atmosphere of Ar at 100°C for 1 h the Mixture was concentrated, the residue was dissolved in EtOAc and filtered. Volatile materials were evaporated and dissolved in THF (2 ml), Meon (0.5 equiv.) and H2About (0.5 equiv.). Added LiOH (12,2 mg, 5 equiv.), and the reaction mixture was stirred at RT for 2 h, the Mixture was carefully extracted with EtOAc. The combined extracts were washed with saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. Purification of the mixture accelerated column chromatography on silica gel resulted in obtaining 2-(6-cyclopropyl-1-oxo-3,4-dihydro-1H-isoquinoline-2-yl)-6-{6-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl}benzyl ether acetic acid (45 mg, 71%).

Example 9: 5-Bromo-3-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-1-methyl-1H-pyrazin-2-he

To a solution of 4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino)benzoic acid (200 mg, 0.6 mmole) and N-ethylpiperazine (75 mg, 1.05 equiv.) in CH2Cl2(5 ml) was added EDC (141 mg, 1.2 equiv.), HOt (100 mg, 1.2 equiv.) and Et3N (103 μl, 1.2 equiv.). The mixture was stirred at RT overnight, and the solution was concentrated under reduced pressure. Purification of the residue accelerated column chromatography on silica gel resulted in the receipt of 5-bromo-3-[4-(4-ethylpiperazin-1-carbonyl)phenylamino]-1-methyl-1H-pyrazin-2-she (220 mg, 85%).

Example 10: 6-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he

NaH (1.86 g, 1.5 equiv.) was added to a solution of 6-bromo-3,4-dihydro-2H-isoquinoline-1-it (7 g, 31 mmol) in DMF (100 ml) at 0°C. the Solution was stirred for 20 min, and added PMBCl. The reaction mixture was heated to CT and was stirred for 1×. Was added an aqueous solution of NH4Cl, the aqueous mixture was extracted with EtOAc, and the organic layer was separated. Volatile materials were evaporated under reduced pressure, and the residue was purified accelerated column chromatography on silica gel to obtain 6-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-she (7.6 g, 73%).

Example 11: 2-(4-Methoxybenzyl)-6-vinyl-3,4-dihydro-2H-isoquinoline-1-he

6-Bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he (1 g, 2.9 mmole), 2-methyl-2,4-pentanedionato ether vinylboronic acid (560 mg, 1.2 equiv.), tetranitropentaerithrite (168 mg, of 0.05 equiv.) and Kotleti (410 mg, 1.2 equiv.) in THF (19 ml) was heated in a closed vessel for 150 minutes in a microwave reactor. The mixture was concentrated under reduced pressure, and the mod is to purified accelerated column chromatography on silica gel to obtain 2-(4-methoxybenzyl)-6-vinyl-3,4-dihydro-2H-isoquinoline-1-it (469 mg, 79%).

Example 12: 6-(1-Porvenir)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he

Et3N·3HF (7.7 g, 3 equiv.) was added to a mixture of 2-(4-methoxybenzyl)-6-vinyl-3,4-dihydro-2H-isoquinoline-1-she (4.7 g, 16 mmol) in CH2Cl2(16 ml) at 0°C. After 1 min was added NBS (3.5 g, 1.2 equiv.), and the mixture was stirred at 0°C for 30 minutes the Solution was heated to CT, was stirred for 1 h and poured into ice-cold water. The mixture was podslushivaet concentrated solution of NH4OH and was extracted with CH2Cl2. The combined organic phase was evaporated under reduced pressure, and the residue was dissolved in THF (50 ml). Added Kotleti (3.8 g, 2 equiv.), and the reaction mixture was heated at 50°C. the Reaction mixture was poured into ice water and was extracted with methylene chloride. The organic layer was evaporated, and the residue was purified accelerated column chromatography on silica gel to obtain 6-(1-Porvenir)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it(1.97 g, 39%).

Example 13: 6-(1-Forciblepoppy)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-he

ZnEt2(19 ml of a 1.0 M solution in hexane, 4 equiv.) was added to a solution of CH2I2(5,1 g, 4 equiv.) in CH2Cl2(45 ml)and the solution was stirred for 20 min at 0°C. was Slowly added TFOC (1,47 ml, 4 equiv.), and the mixture was stirred for 20 minutes To this solution was slowly added a solution of 6-(1-Porvenir)-2-(4-methodology dibenzyl)-3,4-dihydro-2H-isoquinoline-1-it (1.47 g, 4.7 mmole) in CH2Cl2(20 ml)and the combined mixture was heated to CT and was stirred for 1 day. Was added an aqueous solution of ammonium chloride, and the mixture was extracted with methylene chloride. The combined organic layers were evaporated under reduced pressure, and the residue was purified accelerated column chromatography on silica gel to obtain 6-(1-forciblepoppy)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it (630 mg, 39%).

Example 14: 6-(1-Forciblepoppy)-3,4-dihydro-2H-isoquinoline-1-he

A mixture of 6-(1-forciblepoppy)-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinoline-1-it (626 mg, 1.9 mmole) in TFOC (5 ml) was heated in a closed vessel at 80°C for 2 hours the Mixture was concentrated under reduced pressure, the residue was transferred into a CH2Cl2and washed with an aqueous solution of sodium bicarbonate. The organic layer was evaporated, and the residue was purified accelerated column chromatography on silica gel to obtain 6-(1-forciblepoppy)-3,4-dihydro-2H-isoquinoline-1-she (400 mg, 100%).

Example 15: 2-(3-Bromo-2-ethylphenyl)-6-(1-forciblepoppy)-3,4-dihydro-2H-isoquinoline-1-he

A mixture of 6-(1-forciblepoppy)-3,4-dihydro-2H-isoquinoline-1-she (405 mg, 1.97 mmole), 1,3-dibromo-2-ethylbenzene (1.2 g, 2 equiv.), CuI (37 mg, 0.1 equiv.) and K2CO3(272 mg, 1 equiv.) in DMF (9.5 ml) was heated in an Ar atmosphere in a microwave reactor at 200°C for 90 min was Additionally added CuI (37 mg, 0.1 equiv., and the mixture was heated at 200°C. in a microwave reactor for 20 minutes the Mixture was cooled, poured into concentrated ammonium hydroxide solution, and was extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. The accelerated cleanup column chromatography on silica gel resulted in obtaining 2-(3-bromo-2-ethylphenyl)-6-(1-forciblepoppy)-3,4-dihydro-2H-isoquinoline-1-she (260 mg, 30%).

Example 16

The reaction was carried out as described above, to obtain the desired product with a yield of 62%.

Example 17: 5-Bromo-3-(1-ethyl-1H-pyrazole-4-ylamino)-1-methyl-1H-pyrazin-2-he

A solution of 1-ethyl-1H-pyrazole-4-ylamine (0.28 g, 2.5 mmole) and 3,5-dibromo-1-methyl-1H-pyrazin-2-it (0.74 g, 1.1 equiv.) was heated at 120°C in isopropanol for 1 h, the Reaction mixture was cooled to CT, and 5-bromo-3-(1-ethyl-1H-pyrazole-4-ylamino)-1-methyl-1H-pyrazin-2-he was isolated by filtration (0,43 g, 57%).

Example 18: 5-Bromo-3-(4-hydroxyethylamino)-1-methyl-1H-pyrazin-2-he

DIBAL (71 ml of 1 M solution in CH2Cl2, 5 equiv.) was added at -78°C to a suspension of ethyl ester of 4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino)benzoic acid (5 g, 14.2 mmole) in CH2Cl2(150 ml). The solution was left to slowly warm up to CT. After 1 h at RT the solution was cooled to 0°C in an ice bath, and add ~ 50 ml of 1.0 N NaOH solution. The reaction to shift the ü was extracted with CH 2Cl2and the organic layer was washed with a saturated solution of sodium chloride and dried MgSO4. Evaporation of the volatile materials under reduced pressure resulted in the receipt of solids. Recrystallization of this material from a mixture of CH2Cl2/Et2O/MeOH resulted in the receipt of 5-bromo-3-(4-hydroxyethylamino)-1-methyl-1H-pyrazin-2-it is in the form of a yellow solid (1.35 g, 31%).

Example 19: 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino)benzaldehyde

Iodine (0,82 g, 2 equiv.) was added to a suspension of 5-bromo-3-(4-hydroxyethylamino)-1-methyl-1H-pyrazin-2-she(0.5 g, of 1.61 mmole) in CH2Cl2(25 ml). Added TEMPO (38 mg, 0.15 equiv.), then a saturated solution of NaHCO3(3.2 ml). The reaction mixture was stirred at RT overnight and was filtered. The solid is washed with CH2Cl2and Et2O to obtain colorless extracts, to obtain 4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazine-2-ylamino)benzaldehyde as a pale brown solid (0,44 g, 88%).

Example 20: 5-Bromo-1-methyl-3-(4-(morpholine-4-iletilenlerin)-1H-pyrazin-2-he

Glacial acetic acid (100 μl) was added to a suspension of 5-bromo-3-(4-hydroxyethylamino)-1-methyl-1H-pyrazin-2-she (0.1 g, 0.3 mmole) and molecular sieves 3 A (0,37 g) and morpholine (0,043 ml, 1.5 equiv.) in DCE (10 ml). The solution was stirred for 10 min and was added NaHB(OAc)3 (0.172 g, 2.5 equiv.) one portion. The suspension was stirred at RT over night. To the reaction mixture was added water, and the precipitate was removed by filtration. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure to obtain 5-bromo-1-methyl-3-(4-(morpholine-4-iletilenlerin)-1H-pyrazin-2-it is in the form of a waxy solid (0,89 mg, 72%).

Example 21: 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 DHM and 5% aq. the ammonium hydroxide solution. DHM 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-(b-dimethylamino-1-oxo-3,4-dihydro-1H-from the quinoline-2-yl)benzyl ester of acetic acid (93 mg, 0.22 mmole). MS (ESI) 417,1 (M+N)+.

Example 22: 1-(4-tert-Butylphenyl)-3-chloropropane-1-he

To aluminium chloride (29,33 g, 220 mmol) in DHM (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 THM. After the addition, the reaction mixture was stirred at a temperature from 0°C to CT during the night. The next morning, TLC showed that all of tert-butylbenzoyl disappeared, and the reaction mixture was cooled to 0°C. With stirring was added dropwise water (about 120 ml) until gas evolution stops. 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), DHM layer was dried with magnesium sulfate, was filtered, concentrated and dried to dryness to obtain specified in the title compounds as a light yellow-brown powder (45.6 g).

Example 23: 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 had reacted. After cooling to CT, the reaction mixture was carefully poured into 1 kg of crushed ice. Then added a little diethyl ether, and the mixture is gently mixed up about what ladenia to CT. Added ethyl acetate (1200 ml)and after separation of the layers were separated. The acid layer is then further 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 to dryness to obtain specified in the title compound as a colourless oil (15,764 g).

Example 24: 6-tert-Butyl-3.4-dihydro-2H-isoquinoline-1-he

5-tert-Batiliman-1-ONU (15.7 g, of 83.4 mmole) in DHM (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 2.5 hours. The TLC analysis confirmed that all 5-tert-Batiliman-1-he reacted. Under stirring at 0°C was added very carefully aqueous solution of sodium hydroxide (20%) until pH=14. Then added DHM (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 DHM layers were washed with a saturated solution of sodium chloride (9×200 ml), dried with magnesium sulfate and was filtered through a layer of celite. After concentration and drying to dryness received 13.5 g of crude product as a yellow-brown firmly what about the substance. Purification on a column of 400 g Analogix, elwira gradient 10%to 60% ethyl acetate in hexane resulted in obtaining 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 25: 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 168 hours. Was cooled to CT and then added ethyl acetate (300 ml) and water (100 ml), separated, and separated layers. Was then washed with water (2×100 ml)and then washed with a saturated 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 on a column with 240 g Analogix resulted in the receipt specified in the header soy is inane in the form of 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 26: tert-Butyl ether [2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl]acetic acid (I)

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 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. Target product (2 g; output 95,6%) was isolated by rapid chromatography using column chromatography on silica gel with 10%-40% ethyl acetate in hexane as eluent.

Example 27: 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 the 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; yield 97%) was used in the next stage without additional purification.

Example 28: -[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), yield 63%.

Example 29: [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 chloride cyanuric acid (0,370 g, 2 mmole), and after stirring at RT for 0.5 h 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. The accelerated cleanup column chromatography on silica gel using 75% ethyl acetate in hexane as eluent, yielded 1.2 g (yield 98%) of the nitrile (IV).

Example 30: 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 IMO is I) 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 10 minutes at 30-35°Spoke 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 with 30%-50% ethyl acetate in hexane resulted in the receipt of compounds (V) 1 g (yield 77%).

Example 31: 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 DHM 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 1N 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 0,5N HCl, 5% sodium carbonate solution, saturated sodium chloride solution, then dried with sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using 30%-60% ethyl acetate in hexane to obtain the aldehyde (VI) 0.075 g (yield of 10.3%).

Example 32: 6-(1-Diftormetilirovaniya)-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 added legid (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, yield 87%.

Example 33: 6-(1-Diftormetilirovaniya)-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, yield 66%.

Example 34: 2-Bromo-6-[6-(1-diftormetilirovaniya)-1-oxo-3,4-dihydro-1H-izohinolinove (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 Zack is ivali, 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 vacuo, the Residue was purified prep. TLC on silica gel using 40% ethyl acetate in hexane as the eluent, getting 0,024 g, yield 48%.

The General scheme 2

Example 35: 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 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 36: 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 is kusnoy acid (420 mg, a 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. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DHM (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 of acetic acid (183 mg, 0,396 mmole). MS (ESI) 463,1 (M+N)+.

Example 37: Methyl ester of 4-Isopropenyl-2-methylbenzoic acid

Methyl ester of 4-bromo-2-methylbenzoic acid (4 g, 17,46 mmole), penacostal ether isopropenylbenzene acid (3,228 g, 19,21 mmole) and cesium carbonate (19,913 g, 61,11 mmole) was treated with degassed solution of 15 ml of dioxane/5 ml of water. After 5 min stirring was added the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0,718 g, 0,873 mmole)and heated at 120°C for 40 min in a microwave oven. The reaction to the offer was filtered through cellulose; were washed in 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 38: 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. Cyclopropylalanine the addition of a solution of diazomethane 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). A total of 20 ml of organic phase (about 4 equiv. diazomethane) was added during the test. Watched the nitrogen adding diazomethane to the intermediate connection methylstyrene. The reaction mixture was filtered through cellulose; washed with diethyl shall firom; 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 39: 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). The solution was heated at 80°C for 4 hours. The reaction mixture was concentrated until evaporation of the 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. Formed white precipitate; it 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 40: 2-Methyl-4-(1-methylcyclopropyl)benzoyl chloride

2-Methyl-4-(1-methylcyclopropyl)benzoic acid (2,139 g 11,243 mm is La) and pentachloride phosphorus (2,575 g, 12,37 mmole) were loaded into a flask with a volume of 50 ml with stirring. These solids were dissolved at 100°C. the Reaction mixture was stirred for 2 hours at 120°C. under reflux in an atmosphere of N2. After that, the obtained phosphorus oxychloride drove at 140°C from the reaction mixture. The entire reaction mixture was cooled to CT, and the reaction mixture was still a solution. The target product was distilled by a distillation Kugelbake (150°C./4 mbar) to give 2-methyl-4-(1-methylcyclopropyl)of benzoyl chloride (1.92 g, 9.2 mmole).

Example 41: 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) (example 40), 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 THF. 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 sodium chloride solution; 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 to 100% this is lazette 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 42: 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 THF under stirring; were cooled with a mixture of 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 was stirred for 30 min at -15°C. a Solution of N-[3-bromo-2-(tert-butyldimethylsilyloxy)phenyl]-2-methyl-4-(1-methylcyclopropyl)benzamide in 20 ml of anhydrous THF was added dropwise within 10 minutes to the reaction mixture at -15°C. the Reaction mixture was stirred for 2 hours. Then added in one portion 3.55 ml DMF. 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 solution of potassium hydrosulfate; 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. Recrystallization from DHM 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 43: 2-[3-Bromo-2-(the pet-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) (example 42) was dissolved in 13 ml DHM CT; after the addition of tea (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 proceeded for 10 minutes in accordance with the LCMS. The reaction mixture was extracted with a mixture DHM/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+).

The General scheme 3

Example 44: Ethyl ester of 2-(3-bromo-2-were)-3-(3-dimethylaminopropylamine)krolowej 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 reaction was suppressed 1M aq. HCl solution. 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 mmol who) 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 45: 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) (example 44) 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/DHM. 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/DHM) to obtain 3-(3-bromo-2-were)-7-dimethylamino-1H-quinoline-4-it (22 mg, 0,062 mmole). MS (ESI) 357,0 (M+N)+.

The General scheme 4

The General scheme 5

Example 46: 4-Bromo-2-(2-bromacil)benzosulphochloride

Chlorosulfonic acid (17 ml) was added dropwise to 1-bromo-3-(2-bromacil)benzene (5 g, 19 mmol) at 0°C. the Mixture was stirred at 0°C for 1 h, and then for 3 h at RT. The mixture is slowly pouring is whether in a mixture of ice-water and extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure to obtain 4.3 g of crude 4-bromo-2-(2-bromacil)benzosulfimide, which was used directly in the next reaction (see scheme 5). MS (ESI) 342,9 (M-Cl+OH)-.

Example 47: Analysis of the inhibition-Bruton tyrosine kinase (Btk)

The analysis is based on the capture of radioactive13P phosphorylated product by filtration. Interaction of Btk, biotinylated SH2peptide substrate (Src homology) and ATP leads to the phosphorylation of the peptide substrate. Biotinylated product is associated with sivaratnam 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 (Biotin-ACA-AAAEEIYGEI-NH2), 100 μm ATP (Sigma), 8 mm imidazole (Sigma, pH 7,2), 8 mm glycerol-2-phosphate (Sigma), 200 μm EGTA (Roche Diagnostics), 1 mm MnCl2(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 NaCl (Gibco), 2 M NaCl ve is./ 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 the presence of 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 granules with PBS and EDTA with a 20% suspension of granules

3. The pre-incubated reaction mixture without substrate (buffer for analysis, DTT, ATP, P ATP) and was mixed with substrate (buffer for analysis, DTT, ATP, P ATP, peptide substrate) at 30°C for 15 minutes

4. To begin the analysis of the pre-incubated with 10 microns of Btk in enzyme buffer (imidazole, glycerol-2-phosphate, BSA) and 10 μl of test compounds for 10 min p and CT.

5. Added 30 μl of the reaction mixture, with or without a substrate for Btk and connections.

6. 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

in) 1×250 μl of H2O

9. Dried the plate for 1 h at 65°C or over night at RT

10. Added 50 μl of microscint-20 was determined33P 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)

Some results are presented below in table II:

0,015
Table II
ConnectionIC50inhibition of Btk (µm)
II-50,016
II-6
II-110,01
II-120,01

Example 48: 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 0.5×106/ml. flask for tissue culture. On the day of analysis cells were counted and placed in a concentration of 1×106/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, and incubated at 37°C (4% CO2within 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 1×106tile is K/ml, and then transferred into 96-well plates coated with poly-D-lysine black/clear plates (BD Cat No. 356692) at a concentration of 1×105cells 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. The transfer of CA2+the 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 greatest 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 were diluted in FLIPR buffer (using the Biomek 2000 automated papeterie device)receiving the following dilution scheme: the carrier of 1.00×10-4M, and 1.00×10-5at 3.16×10-6are 1.00×10-6 at 3.16×10-7are 1.00×10-7at 3.16×10-8.

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).

Example 49: Caused by collagen arthritis in mice (mCIA)

On day 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).

Example 50: Caused by collagen arthritis in rats (rCIA)

On day 0, rats were injected emulsion of collagen type II calf in Incomplete Freund Freund (IFA) percutaneous (CHK) in not is how many places back. Stimulant injections of collagen emulsion was injected approximately day 7 (CHK) in the base of the tail or, alternatively, in a few places on 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), with 14 days and beyond. Animals were injected candidate therapeutic agents, prophylactic way since secondary treatment and within a predefined time (usually 2-3 weeks) and frequency of the dose once daily (QD) or twice daily (BID).

Example 51: Assessment of arthritis

In both models (examples 38 and 39) 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.

Example 52: Model of asthma I Vivo in rats

The male rats Brown-Norway were injected intraperitoneally with 100 µg OA (ovalbumin) in 0.2 ml of yeast once a week for three weeks (day, 7, and 14). On day 21 (one week after the last injection) rats were administered q.d. the carrier or the composition of subcutaneously for 0.5 hour to OA aerosol injection (1% OA within 45 minutes), and stopped after 4 or 24 hours after injection. After killing the serum and plasma were collected from all animals for serology and RK, respectively. Introduced tracheal cannula, and light washed SX PBS. The BAL fluid was analyzed for total leukocyte and differential leukocyte counts. The total number of cells in the aliquot of cells (20-100 µl) was determined using a Coulter Counter. For determination of differential leukocyte count, 50-200 μl of the sample was centrifuged in a Cytospin and stained with Diff-Quik. The proportion of monocytes, eosinophils, neutrophils and lymphocytes were counted using optical microscopy using standard morphological criteria, and expressed as a percentage. Some inhibitors of Btk showed a decrease in the total number of leukocytes in BAL from sensitive to OA rats compared to control levels.

Example 53: Pharmaceutical composition

Composition for oral administration (A)

Ing event % 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 (In)

Ingredient% the weight.
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 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
is lorid sodium To 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)

/tr>
Ingredientsgrams
Active connection0,2-2
Span 602
Tween 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Water100

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 the quality of the e reference 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 II:

where
R represents-R1or-R1-R2-R3;
R1represents aryl or heteroaryl, and optionally substituted with one or two R1'; where each R1'independently represents a C1-6alkyl, halogen or C1-6halogenated;
R2represents-C(=O), -CH2-;
R3is an R4; where R4represents an amino group or heteroseksualci, and optionally substituted by one or two substituents selected from C1-6of alkyl, hydroxy-group, carbonyl group, a C1-6hydroxyalkyl,1-6alkoxygroup;
Q represents CH2;
Y1represents a C1-6alkyl;
Y2represents the Y2b; where Y2brepresents a C1-6alkyl, optionally substituted with one Y2b'; where Y2b'represents a hydroxy-group;
n has a value of 0;
m has a value of 0;
Y4represents the Y4cor Y4d; where
Y4crepresents the lowest cycloalkyl, optionally substituted with halogen; and
Y4drepresents an amino group, optionally substituted by one or more the C 1-6by alkyl;
where "aryl" denotes phenyl or naphthyl,
"heteroaryl" denotes monocyclic or bicyclic radicals containing from 5 to 9 atoms in the cycle containing at least one aromatic ring containing from five to six atoms in the ring, with one or two N or O heteroatoms and the remaining atoms in the ring are carbon atoms, provided that interconnection point or heteroaryl radical is an aromatic ring,
"heteroseksualci" denotes a monovalent saturated cyclic radical, consisting of one ring containing from five to six atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2,
or its pharmaceutically acceptable salt.

2. The compound of formula II according to claim 1, where Y1represents methyl, Y2represents hydroxymethyl, n is 0 and m is 0.

3. The compound of formula II according to claim 1, where Q represents CH2.

4. The compound of formula II according to claim 1, where Y4represents the Y4cor Y4d; where Y4crepresents the lowest cycloalkyl, optionally substituted with halogen; and Y4drepresents an amino group, optionally substituted by one or more1-6alkilani.

5. The use of the compounds of formula II according to any one of claims 1 to 4 for the manufacture of Lek is stannage tools for the treatment of inflammatory and/or autoimmune condition or for inhibiting b-cell proliferation.

6. The use of the compounds of formula II according to any one of claims 1 to 4 for the manufacture of a medicine for treatment of arthritis.

7. Pharmaceutical composition having inhibitory activity against Btk, comprising a compound of the formula II according to any one of claims 1 to 4 in a mixture with at least one pharmaceutically acceptable carrier, excipient or diluent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to indolyl-substituted derivatives of thiadiazinones prepared from oxamic acid thiohydrazide of general formula: , wherein R represents H; R1 represents pyridinyl; phenyl substituted by alkyl C1-C5, Hal, CF3; R2 represents H; alkyl C1-C5; -CH2COOR4; benzyl substituted by Hal, OR4; benzoyl substituted by Hal, OR4, while R4 represents unsubstituted alkyl C1-C4.

EFFECT: there are prepared new compound which can find application in medicine for developing the therapeutic agent possessing pathogenic bacteria inhibitory activity.

2 cl, 2 dwg, 2 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where "----" denotes a bond or is absent; R1 is a C1-4alkoxy group or halogen; R1b is H or C1-3alkyl; U and V each independently denote CH or N; W is CH or N, or, if "----" is absent, W is CH2 or NH; under the condition that at least one of U, V and W is CH or CH2; A is -CH2-CH(R2)-B-NH-* or -CH(R3)-CH2-N(R4)-[CH2]m-*; where asterisks indicate a bond which binds said fragments through a CH2-group with an oxazolidinone fragment; B is CH2 or CO; and R2 is hydrogen, OH or NH2; R3 and R4 both denote hydrogen, or R3 and R4 together form a methylene bridge; m equals 0, 1 or 2; and G is a phenyl which is monosubstituted in position 3 or 4, or disubstituted in positions 3 and 4, where each substitute is independently selected from a group comprising C1-4alkyl, C1-3alkoxy group and halogen; or G is a group selected from groups G1 and G5 where M is CH or N; Q' is S or O; Z1 is N, Z2 is CH and Z3 is CH; or Z1 is CH, Z2 is N and Z3 is CH or N; or Z1 is CH, Z2 is CR5 and Z3 is CH; or Z1 is CH, Z2 is CH and Z3 is N; and R5 is hydrogen or fluorine; or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof are used as a medicinal agent for preventing or treating bacterial infections.

EFFECT: oxazolidinone derivatives used as antimicrobial agents.

15 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a medicinal agent for antagonistic action on angiotensin II, which contains a compound of formula (I) , in which R1 is a group of formula or , in which R2, R3, R4, R5, R6, R7 and R8, each independently, denote a hydrogen atom or a C1-6alkyl or salt thereof, which is intended for preventing or treating blood circulation disorders such as diabetes and diseases caused by insulin resistance. The invention relates to a medicinal agent which further contains a calcium antagonist and diuretic. The invention relates to use of said medicinal agents to treat said diseases, as well as methods of treating and preventing said diseases and disorders.

EFFECT: high efficiency of using said compounds.

17 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to nitro-derivatives of polycyclic heterocyclic compounds, more specifically to a heterocyclic compound containing two nitrofurazan rings, directly bonded to a furazan ring, and specifically to 3,4-bis(4-nitrofurazan-3-yl)-furazan .

EFFECT: 3,4-bis(4-nitrofurazan-3-yl)-furazan as an energy-rich compound.

1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula (I) wherein A, R1, R2, R3, R4, R5, R6 and R7 are presented in the description, preparing and using them as pharmaceutically active compounds possessing SP1/EDG1 receptor agonist activity.

EFFECT: using the declared compounds or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for preventing or treating the diseases or disorders associated with the activated immune system.

13 cl, 76 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

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