Pharmaceutical compounds

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

 

The text descriptions are given in facsimile form.

1. The connection, which is a condensed pyrimidine of formula (Ia) or (Ib):

where X represents O or S;
R1depict is to place a group of the formula:

R2represents H, halogen or C1-C6alkyl;
R4and R5form together with the N atom to which they are attached, a group selected from piperazine, piperidine, pyrrolidine, oxazolidinone, diazepan and 2,5-diazabicyclo[2,2,1]-heptane, where this group is unsubstituted or substituted by a group -[(alk)q-NR]r-S(O)2-(alk)q-Z or-C(O)-(alk)q-S(O)2Z, where Z is an R10or-NR11R12or unsubstituted C1-C6by alkyl, hydroxy-C1-C6the alkyl, oxo (=O)- (alk)q-OR, -C(O)-C(R')2-N(R)2, -C(R)2-C(O)-N(R)2, -C(O)-NRq-(alk)q-OR, -C(O)-ciclul, -C(O)R, -C(O)OR, -C(O)-Tet;
either one of R4and R5represents a C1-C6alkyl, -alk-heterocycle or -(alk)q-OR, and the other is a group of piperazine, piperidine, pyrrolidine, sulfonylureas or -(alk)q-heterocyclyl where the specified group, piperazine, piperidine, pyrrolidine, sulfonylureas or heterocyclyl is unsubstituted or substituted C1-C6by alkyl, -(alk)q-Or, or-S(O)2R10;
R represents H or C1-C6alkyl, which is unsubstituted;
each R' independently represents H or C1-C6alkyl, which is unsubstituted, or two groups which R' form together with the atom, to which they are attached, calilou group;
R10represents H, cilil, C1-C6alkyl, which is unsubstituted or CF3;
R11and R12each independently selected from H, C1-C6of alkyl, which is unsubstituted, and -(alk)q-OR,
or R11and R12together form with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatom selected from O, N;
Tet is a group of tetrahydrofuranyl;
heterocyclyl represents a 5 - or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatom selected from O, N;
was cilil represents a C3-C6cycloalkyl group;
each q independently is 0 or 1;
r is 0 or 1;
alk represents a C1-C6alkylen; and
R3chosen from:
(a) a group of the following formula:

where a represents a phenyl ring which is unsubstituted or substituted, and Z is selected from H, -OR, -SR, CH2OR, -(CH2)qOR-C(O)N(R)2, -NR2, -NRC(O)R, -S(O)mN(R)2, -NRS(O)mR, halogen, where each R is independently selected from N and C1-C6of alkyl, m is 1 or 2 and q is 0, 1 or 2;
(b) heteroaryl g is uppy, which contains 1, 2 or 3 ring nitrogen atom, where this group is monocyclic or bicyclic and is unsubstituted or substituted with halogen, =O, C1-C6by alkyl, -or, or-N(R)2;
and
(C) groups containing a benzene ring, which is condensed with a heteroaryl group, as defined above;
or its pharmaceutically acceptable salt;
under the following conditions:
(i) when X in the formula (Ia) is S, then R3is other than indole or 3-hydroxyproline group;
(ii) when X in formula (Ib) is S, then R3is other than indole group;
(iii) only in the formula (Ia), when X represents S and R2represents N and R3is indazol-4-yl, then R4and R5not constitute: (i) piperazine which is unsubstituted or substituted by a group selected from methyl, -S(O)2Me, -S(O)2NMe2, -alk-OH, -alk-OMe, -S(O)2-alk-NMe2and-S(O)2-alk-morpholino; or (ii) piperidine which is substituted by a group selected from-S(O)2Me, -C(O)-NR-(alk)q-OR, -NMe-S(O)2-Me, methyl, piperidine and-NR13R14where one of R13and R14represents a -(alk)q-OR.

2. The compound according to claim 1, which is a condensed pyrimidine of formula (Ia')

where X represents the or S;
Y is N or-CH-;
R2represents H, halogen or C1-C6alkyl;
each R' independently represents H or C1-C6alkyl, or two groups R' on the same carbon atom form an oxo group (=O); or when Y is N, the two groups R' on different carbon atoms together form a bridge-CH2-;
each R" independently represents N or C1-C6alkyl, or two groups R on the same carbon atom form an oxo group (=O);
Z is an R10or-NR11R12;
R10represents H, C3-C6cycloalkyl group, C1-C6alkyl, which is unsubstituted or CF3;
R11and R12each independently selected from H, C1-C6of alkyl, which is unsubstituted, and -(alk)q-OR, or R11and R12together form with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatom selected from O and N;
q is 0 or 1;
r is 0 or 1;
alk represents a C1-C6alkylen; and
R3chosen from:
(a) a group of the following formula:

where a represents a phenyl ring which is unsubstituted or replacement of the military, and Z is selected from H, -OR, -SR, CH2OR, -(CH2)qOR, -C(O)N(R)2, -NR2, -NRC(O)R, -S(O)mN(R)2, -NRS(O)mR, halogen, where each R is independently selected from N and C1-C6of alkyl, m is 1 or 2 and q is 0, 1 or 2;
(b) a heteroaryl group which contains 1, 2 or 3 ring nitrogen atom, where this group is monocyclic or bicyclic and is unsubstituted or substituted with halogen, =O, C1-C6by alkyl, -or, or-N(R)2;
and
(C) groups containing a benzene ring, which is condensed with a heteroaryl group, as defined above;
or its pharmaceutically acceptable salt;
under the following conditions:
(i) R3is other than indole or 3-hydroxyproline group when X represents S;
(ii) Z is other than a group selected from Me, -(alk)q-NMe2and-alk-morpholino, when satisfied of the following: Y is N, each of R' and R" is H, R2represents N, and R3is indazol-4-yl;
(iii) Z is other than Me, when satisfied of the following: Y is-CH -; each of R' and R" is H, R2represents N, and R3is indazol-4-yl.

3. The compound according to claim 1, which is a condensed pyrimidine of the formula (Ib'):
< / br> where X represents O or S;
Y is N or-CH-;
R2represents H, halogen or C1-C6alkyl;
each R' independently represents H or C1-C6alkyl;
each R" independently represents N or C1-C6alkyl;
Z is an R10or-NR11R12;
R10represents H, C3-C6cycloalkyl group or a C1-C6alkyl, which is unsubstituted;
R11and R12each independently selected from H and C1-C6of alkyl, which is unsubstituted;
q is 0 or 1;
r is 0 or 1;
alk represents a C1-C6alkylen; and
R3chosen from:
(a) a group of the following formula:

where a represents a phenyl ring which is unsubstituted or substituted, and Z is selected from H, -OR, -SR, CH2OR, -(CH2)qOR, -C(O)N(R)2, -NR2, -NRC(O)R, -S(O)mN(R)2, -NRS(O)mR, halogen, where each R is independently selected from N and C1-C6of alkyl, m is 1 or 2 and q is 0, 1 or 2;
(b) a heteroaryl group which contains 1, 2 or 3 ring nitrogen atom, where this group is monocyclic or bicyclic and is unsubstituted or substituted with halogen, =O, C1-C6by alkyl, -or, or-N(R)2;
br/> (C) groups containing a benzene ring, which is condensed with a heteroaryl group, as defined above;
or its pharmaceutically acceptable salt.

4. The compound according to claim 1, which is a condensed pyrimidine of formula (Ia) or (Ib"):


where X represents O or S;
R2represents H, halogen or C1-C6alkyl;
R4represents a C1-C6alkyl, -alk-heterocycle or -(alk)q-OR;
R5is a group of piperazine, piperidine, pyrrolidine, sulfonylureas or -(alk)q-heterocyclyl where the specified group, piperazine, piperidine, pyrrolidine, sulfonylureas or heterocyclyl is unsubstituted or substituted C1-C6by alkyl, -(alk)q-Or, or-S(O)2R10;
R represents H or C1-C6alkyl, which is unsubstituted;
R10represents H, C3-C6cycloalkyl group, C1-C6alkyl, which is unsubstituted or CF3;
heterocyclyl represents a 5 - or 6-membered saturated N-containing heterocyclic group containing 0 or 1 additional heteroatom selected from O, N;
q is 0 or 1;
alk represents a C1-C6alkylen; and
R3chosen from:
(a) is the group of the following formula:

where a represents a phenyl ring which is unsubstituted or substituted, and Z is selected from H, -OR, -SR, CH2OR, -(CH2)qOR, -C(O)N(R)2, -NR2, -NRC(O)R, -S(O)mN(R)2, -NRS(O)mR, halogen, where each R is independently selected from N and C1-C6of alkyl, m is 1 or 2 and q is 0, 1 or 2;
(b) a heteroaryl group which contains 1, 2 or 3 ring nitrogen atom, where this group is monocyclic or bicyclic and is unsubstituted or substituted with halogen, =O, C1-C6by alkyl, -or, or-N(R)2;
and
(C) groups containing a benzene ring, which is condensed with a heteroaryl group, as defined above;
or its pharmaceutically acceptable salt;
under the following conditions:
(i) when X in the formula (Ia") is S, then R3is other than indole or 3-hydroxyproline group; and
(ii) when X in the formula (Ib") is S, then R3is other than indole group.

5. The compound according to any one of claims 1 to 4, where R1represents (4-methylsulfonylmethane-1-yl)methyl.

6. The compound according to any one of claims 1 to 4, where R2represents N.

7. The compound according to any one of claims 1 to 4, where R3chosen from:

where W is prex which is a CR 10or N; each R10independently selected from N and C1-C6the alkyl.

8. The compound according to any one of claims 1 to 4, where R3represents 1H-indazol-4-yl.

9. A compound selected from:
(1S,4S)-2-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-a]pyrimidine-6-yl)methyl)-5-methylsulphonyl-2,5-diazabicyclo[2.2.1]heptane;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-(N-morpholino)sulfanilimide-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((3S,5R)-3-methyl-4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholino-2-(pyrimidine-5-yl)thieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((3S,5R) - for 3,5-dimethyl-4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
6-(((2R,6S)-4-methylsulphonyl-2,6-dimethylpiperazine-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine;
6-(((2R,6S)-4-isopropylphenyl-2,6-dimethylpiperazine-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine;
6-(((2R,6S)-4-trifloromethyl-2,6-dimethylpiperazine-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine;
6-(((R)-4-methylsulphonyl-3-methylpiperazin-1-yl)methyl)-2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine;
3-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)benzosulfimide;
(4-(6-((4-what ethylsulfonylimidazo-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenyl)methanol;
3-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)benzamide;
1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-4-methylsulfonylmethane-2-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-amino-2-methylpropan-1-he;
2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
(3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine-2-yl)phenyl)methanol;
2-(1H-indazol-4-yl)-6-((4-N-methyl-N-methoxyaminomethyl-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N,N-dimethylaminomethylene-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N,N-dimethylaminomethylene-1-yl)methyl)-7-methyl-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-methylaminoacetaldehyde-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-7-methyl-6-((4-(methylsulphonyl)piperidine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-4-methyldiphenylphosphine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-imidazol-1-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-benzo[d]imidazol-1-yl)-6-((4-methylsulfone the piperazine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidin;
2-(1H-indazol-4-yl)-6-((4-N,N-dimethylaminomethylene-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-N-morpholinosydnonimine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-7-methyl-6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-1-methylsulphonyl-N-(2-morpholinoethyl)piperidine-4-amine;
2-(1H-indazol-4-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
(1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)pyrrolidin-2-yl)-N-methylsulfonylmethane;
2-chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenol;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-(2-methoxyethyl)-1-methylsulfonylmethane-4-amine;
4-fluoro-3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenol;
2,3-debtor-5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenol;
5-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)pyridine-3-ol;
2-(1H-indazol-4-yl)-6-((1-methylpiperidin-4-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
6-((4-methylpiperazin-1-yl)methyl)-4-morpholino-2-(1H-pyrazole-4-yl)thieno[3,2-d]pyrimidine;
(3-(6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenyl)methanol;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[,2-d]pyrimidine-6-yl)methyl)-tetrahydro-N-methyl-2H-sulfonylureas-4-amine;
2-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-methylpropanamide;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-1-(2-methoxyethyl)-N-methylpiperidin-4-amine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N,1-dimethylpiperidin-4-amine;
1-(2-hydroxyethyl)-4-((2-(3-hydroxyphenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-2-he;
4-((2-(3-hydroxyphenyl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-(2-methoxyethyl)-N-methylpiperazin-1-carboxamide;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)(cyclopropyl)methanon;
2-(1H-indazol-4-yl)-6-((3-(methylsulphonyl)pyrrolidin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(((S)-2-methyl-4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
(3-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)phenyl)methanol;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2,2-DIMETHYLPROPANE-1-he;
4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-carbaldehyde;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)Etalon;
ethyl 4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-carboxylate;
methyl 4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)PIP the Razin-1-carboxylate;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-methyl-N-methylsulfinylpropyl-3-amine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-methyl(1-methylsulfinylpropyl-2-yl)methanamine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-methyl-(1-methylsulfonylbenzoyl)-3-amine;
1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperidine-4-ol;
1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)pyrrolidin-3-ol;
1-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperidine-3-ol;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxypropan-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-(dimethylamino)Etalon;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminoethane;
2-(1H-indazol-6-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)-N-(2-methoxyethyl)-1-methylpiperidin-4-amine;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-1-methylsulfonylmethane-2-yl)-N,N-dimethylethanamine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N,1-methylsulfone the piperidine-4-amine;
3-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)benzoylmethylecgonine;
6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholino-2-(pyrimidine-5-yl)thieno[3,2-d]pyrimidine;
2-(6-herperidin-3-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
N-methyl-3-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)benzamide;
2-(3-forfinal)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(2-herperidin-3-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-2-(2-methoxypyridine-5-yl)-4-morpholine-4-illiano[2,3-d]pyrimidine;
{5-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[2,3-d]pyrimidine-2-yl]-pyrimidine-2-yl}-dimethylamine;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-yl-2-pyridin-3-yl-thieno[3,2-d]pyrimidine;
N-{4-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine-2-yl]-phenyl}-methanesulfonamide;
N-{4-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine-2-yl]-phenyl}-ndimethylacetamide;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-yl-2-pyridin-3-yl-thieno[2,3-d]pyrimidine;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-2-(2-Mei-1-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
3-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]Piri is one-2-yl]-healin;
4-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine-2-yl]-isoquinoline;
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
4-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-yl-thieno[2,3-d]pyrimidine-2-yl]-isoquinoline;
3-[6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-yl-thieno[2,3-d]pyrimidine-2-yl]-quinoline;
2-(1H-indazol-4-yl)-6-((S)-4-methanesulfonyl-3-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(propane-2-sulfonyl)-piperazine-1-ylmethyl]thieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((R)-4-methanesulfonyl-3-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-2,2-dimethylpiperazine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-3,3-dimethylpiperidin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-2-(2-methylbenzimidazole-1-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((2S,6R)-4-methanesulfonyl-2,6-dimethylpiperazine-1-ylmethyl)-4-morpholine-4-illiano[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-illiano[2,3-d]pyrimidine-6-ylmethyl]-methyl-(1-methylpiperidin-4-yl)-amine;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[2,3-d]pyrimidine-6-ylmethyl]-piperazine-1-yl}-N,N-dimethylacetamide;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-ilti is but[2,3-d]pyrimidine-6-ylmethyl]-piperazine-1-yl}-N-methylisoleucine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-5-methyl-4-morpholine-4-illiano[2,3-d]pyrimidine;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxypropan-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxy-2-methylpropan-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxyethane;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-methoxyethanol;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)(tetrahydrofuran-2-yl)methanon;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)(1-aminocyclopropane)methanon;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminopropan-1-he;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminopropan-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-(methylsulphonyl)Etalon;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxypropan-1-he;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxypropan-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxy-2-methylprop the n-1-he;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxyethane;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-methoxyethanol;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)(tetrahydrofuran-2-yl)methanon;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-amino-2-methylpropan-1-he;
(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)(1-aminocyclopropane)methanon;
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminoethane;
(S)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminopropan-1-he;
(R)-1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-aminopropan-1-it; and
1-(4-((2-(1H-indazol-4-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-(methylsulphonyl)Etalon;
2-(1H-indol-4-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-cyclopropanesulfonyl-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-N-methylpiperidin-4-amine;
(S)-1-(4-((2-(1H-indazol-4-yl)-7-methyl-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)-2-hydroxypropan-1-he;
N-((2-(1H-indazol-4-yl)-7-methyl-4-morpho is inotera[3,2-d]pyrimidine-6-yl)methyl)-N,1-dimethylpiperidin-4-amine;
6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-d]pyridin-5-yl)thieno[3,2-d]pyrimidine;
(S)-1-((S)-4-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-3-methylpiperazin-1-yl)-2-hydroxypropan-1-he;
2-(1H-benzo[d]imidazol-5-yl)-6-((4-methylpiperazin-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
2-(1H-indazol-5-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
5-(6-((4-methylsulfonylmethane)1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)-1H-benzo[d]imidazol-2(3H)-he;
2-(1H-benzo[d]imidazol-4-yl)-6-((4-methylsulfonylmethane)1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine;
6-((4-methylsulfonylmethane)1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridine)5-yl)thieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
6-((4-methylsulfonylmethane)1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridine)5-yl)furo[3,2-d]pyrimidine;
N-((2-(1H-indazol-4-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)-1-isopropyl-N-methylpiperidin-4-amine;
6-(6-((4-methylsulfonylmethane)1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)-3H-imidazo[4,5-b]pyridine;
6-((4-isopropylpiperazine-1-yl)methyl)-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-d]pyrimidine;
6-(6-((4-methylsulfone the piperazine)1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine-2-yl)-3H-imidazo[4,5-b]pyridine;
(S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-(1H-pyrrolo[2,3-d]pyridin-5-yl)thieno[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he;
(S)-2-hydroxy-1-(4-((4-morpholino-2-(1H-pyrrolo[2,3-b]pyridine-5-yl)thieno[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he;
(S)-2-hydroxy-1-(4-((7-methyl-4-morpholino-2-(quinoline-3-yl)thieno[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he;
(S)-2-hydroxy-1-(4-((4-morpholino-2-(quinoline-3-yl)thieno[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he;
2-methyl-6-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine-2-yl)-3H-imidazo[4,5-b]pyridine;
(S)-2-hydroxy-1-(4-((2-(2-methyl-3H-imidazo[4,5-b]pyridine-6-yl)-4-morpholinothio[2,3-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he;
6-(6-((4-methylsulfonylmethane-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine-2-yl)imidazo[1,2-a]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholine-4-yl-thieno[2,3-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
6-(4-methanesulfonylaminoethyl-1-ylmethyl)-2-(2-methyl-1H-benzoimidazol-5-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-5-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-benzo[d]imidazol-5-yl)-6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
2-(2-methyl-1H-benzo[d]imidazol-5-yl)-6-((4-(methylsulphonyl)Pipa is Azin-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine;
4-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-4-morpholinothio[2,3-d]pyrimidine-2-yl)benzene-1,2-diamine; 4-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(pyrido[2,3-b]pyrazin-7-yl)thieno[2,3-d]pyrimidine-4-yl)morpholine; 5-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)-1H-indazol-3-amine; 6-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-4-morpholinothio[3,2-d]pyrimidine-2-yl)-1H-indazol-3-amine; 4-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(1H-pyrazolo[3,4-b]pyridine-5-yl)thieno[2,3-d]pyrimidine-4-yl)morpholine; 4-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(1H-pyrazolo[3,4-c]pyridine-4-yl)thieno[2,3-d]pyrimidine-4-yl)morpholine; 4-(6-((4-(methylsulphonyl)piperazine-1-yl)methyl)-2-(5,6,7,8-tetrahydroquinolin-3-yl)thieno[2,3-d]pyrimidine-4-yl)morpholine; N,1-dimethyl-N-((4-morpholino-2-(quinoline-3-yl)thieno[2,3-d]pyrimidine-6-yl)methyl)piperidine-4-amine; and (S)-2-hydroxy-1-(4-((7-methyl-2-(2-methyl-1H-imidazo[4,5-b]pyridine-6-yl)-4-morpholinothio[3,2-d]pyrimidine-6-yl)methyl)piperazine-1-yl)propane-1-he and their pharmaceutically acceptable salts.

10. Pharmaceutical composition having activity of an inhibitor of phosphatidylinositol-3-kinase, which contains a pharmaceutically acceptable carrier or diluent and, as active ingredient the compound according to any one of claims 1 to 9.

11. The composition according to claim 10, which is prepared for oral administration.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound presented by formula (1), to its salt or hydrate where in formula R1 represents a methylene group, R2 represents a phenyl group which can contain a substitute(s), or a heterocyclic group which can contain a substitute(s), the cycle A represents a 6- or 7-members cycle (where cycle-making atoms of the cycle A different from a sulfur atom in position 6 are carbon atoms), and R3 represents a hydrogen atom, or 1-3 equal or different substitutes used to substitute the cycle A where the possible substitutes are specified in clause 1 of the patent claim. Also, the invention refers to a pharmaceutical composition exhibiting an anticancer activity, on the basis of the compound presented by formula (1).

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for cancer treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

EFFECT: invention refers to methods for producing pure olanzapine, intermediate products and acid-additive olanzapine salts which in turn can find application for producing pure olanzapine used for preparing a drug for treating mental disorders and conditions.

38 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

EFFECT: novel method of producing prasugrel with low content of impurities, specifically "ОХТР" by-product.

2 cl, 6 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

Up!