Carbocyclic and heterocyclic arylsulfones as γ-secretase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) or to their pharmaceutically acceptable salts, in which X is selected from group, consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-; each R1 is independently selected from group consisting of H and alkyl; each of R2, R3 and R4 is independently selected from group consisting of (1) H, (2) alkyl, (3) -OR5, (4) alkylene-OR5, (5) -alkylene-R6, (6) -C(O)O-alkyl, (7) - alkylene-C(O)O-alkyl, (8) -alkylene-R8, (9) -NHR5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylene-O-alkyleneR6, (14)-NHCH(C(O)O(C1-C6)aalkyl)-alkylene-OH, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or R2 and R3 or R2 and R4 or R3 and R4 together with atoms with which they are bound, form condensed 3-7-member cycloalkyl or heterocycloalkyl ring, which represents non-aromatic monocyclic ring system, which contains in ring from about 5 to about 7 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen or oxygen, and said condensed cycloalkyl or heterocycloalkyl ring is not substituted or is substituted with one or several groups L3 ; and on condition that if X represents -O-, and m equals 1, then, at least, one of R2, R3 or R4 is not H; each R5 is independently selected from group consisting of (1) H, (2) (C1-C6)alkyl, (3) hydroxy-substituted alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenalkyl, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenalkyl, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylene-C(O)-(C1-C6)alkyl, (18) -alkylene-C(O)-(C1-C6)halogen-alkyl, (19) -alkylene-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylene-S(O)2-(C1-C6)alkyl, (22) -alkylene-S(O)2-(C1-C6)halogenalkyl, (23) -alkylene-S(O)2-R6, (24) -alkylene-S(O)2-R7, (25) -alkylene-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenalkyl, (28) alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylene-NHS(O)2-(C1-C6)alkyl, (31) -alkylene-NHS(O)2-(C1-C6)halogenalkyl, (32) -alkylene-NHS(O)2-R6, (33) -alkylene-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenalkyl, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-Ce)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40)-alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylene-C(O)-NH-(C1-C6)alkyl, (43) -alkylene-C(O)-NHR6, (44) -alkylene-C(O)-NHR7, (45) -alkylene-S(O)2NH-(C1-C6)alkyl, (46) -alkylene-S(O)2NH-R6, (47) -alkylene-S(O)2NH-R7 , (48) -alkylene-C(O)-N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (49) -alkylene-C(O)-N(alkyl)-R6, (50) -alkylene-C(O)-N(alkylene)-R7, (51) -alkylene-S(O)2N((C1-C6)alkyl)2, in which each alkyl group is selected independently, (52) -alkylene-S(O)2N(alkyl)-R6, (53) -alkylene-S(O)2N(alkyl)-R7, (54) -alkylene-OH, (55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8, (57) -alkylene-CN, (58) -R8, (59) -alkylene-SH, (60) -alkylene-S(O)2-NH-R8, (61) -alkylene-S(O)2-alkylene-R6, (62) substituted with halogen alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylene-O-(C1-C6)alkyl, (67) -C(O)NH2, (68) -alkylene-O-(C1-C6)alkyl, (69) -alkylene-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) hydroxy-substituted halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylene-O-C(O)-(C1-C6)alkyl, (77) -alkylene-O-S(O)2-(C1-C6)alkyl, (78) -alkylene-R6 , (79) -alkylene-R7, (80) -alkylene-NH-C(O)NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2 halogen(C1-C6)alkyl)2, and each -S(O)2 halogen(C1-C6)alkyl fragment is selected independently, (82) -alkylene-N((C1-C6)alkyl)S(O)2-R8 , (83) -alkylene-OC(O)-N(alkyl)2, and each alkyl is selected independently, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-alkylene-R6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2, and each -S(O)2(C1-C6)alkyl fragment is elected independently, (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylene-O-R6, (100) -alkylene-R7, (101) -C(O)OH, (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylene-C(O)-O-(C1-C6)alkyl, (104) halogenalkyl, (105) halogen, (106) -alkylene-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) -N-O-R6, (111) =N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116)-CN, R6 is selected from group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted with one or several groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which represents aromatic monocyclic or bicyclic system, which contains in ring from about 5 to about 9 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen or sulphur, one or in combination, substituted with one or several groups L1; R7 is selected from group consisting of unsubstituted heterocycloalkyl and heterocycloalkyl which represents non-aromatic monocyclic system, which contains in ring from about 4 to about 6 atoms, and one or several atoms in ring system represent atom of element, different from carbon, for instance, nitrogen, oxygen substituted with one or several groups L2; R8 is selected from group consisting of unsubstituted cycloalkyl and cycloalkyl substituted with one or several groups L2; A8 is selected from group consisting of (a) unsubstituted aryl, (b) aryl substituted with one or several groups L1; each group L1 is independently selected fron group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halogen(C1-C6)alkyl), -alkylen-OH (-CH2OH); each group L2 is independently selected from group consisting of (a) -OH, (b) alkyl, (c) alkyl substituted with one or several groups -OH and (d) piperidyl; each group L3 is independently selected from group consisting of -CN, =O, R5 , -OR5 ; =N-R5 and -N(R5)2; n equals 0, 1, 2 or 3; and m equals 0, 1 or 2; and on condition that in composition of substituent -OR5 fragment R5 and oxygen atom, which it is bound with, do not form group -O-O-; and on condition that in composition of substituents -OR5, =N-R5 and -NHR5 R5 are not -CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or -C(O)OH. Invention also relates to pharmaceutical composition, as well as to application of one or several compounds by one of ii. 1-125.

EFFECT: obtaining novel biologically active compounds possessing properties of γ-secretase inhibitor.

127 cl, 447 ex, 94 tbl

 

The text descriptions are given in facsimile form.

1. The compound of formula (I)

or its pharmaceutically acceptable salt,
in which X is selected from the group consisting of-C(R1)2-, -O-, -S-, -S(O2)-, -NR1-;
each R1independently selected from the group consisting of H and alkyl;
each of R2, R3and R4independently selected from the group consisting of (1) H, (2) alkyl, (3) -OR5(4) alkylen-OR5, (5) -alkylen-R6, (6) -C(O)O-alkyl, (7) -alkylen-C(O)O-alkyl, (8) -alkylen-R8, (9) -other5, (10) -N(R5)2, (11) alkenyl, (12) -NH-R8, (13) -NH-CH(C(O)O(C1-C6)alkyl)-alkylen-O-alkylene-R6, (14) -NHCH(C(O)O(C1-C6)alkyl)-alkylene-HE, (15) -NH-C(O)-alkenyl and (16) -N(C1-C6alkyl)C(O)-alkenyl; or
R2and R3or R2and R4or R3and R4together with the atoms to which they are linked, education is the comfort condensed 3-7-membered cycloalkyl or geteroseksualnoe ring, which means non-aromatic monocyclic ring system containing ring from about 5 to about 7 atoms, where one or more atoms in the ring system represents an atom of an element other than carbon, for example nitrogen or oxygen, with the specified condensed cycloalkyl or geteroseksualnoe ring is not substituted or is substituted by one or more groups L3;
provided that when X represents-O-, a m equals 1, then at least one of R2, R3or R4is not H;
each R5independently selected from the group consisting of (1) H, (2) (C1-C6)alkyl, (3) replacement of alkyl, (4) R6, (5) R7, (6) -C(O)-(C1-C6)alkyl, (7) -C(O)-(C1-C6)halogenoalkane, (8) -C(O)-R6, (9) -C(O)-R7, (10) -C(O)NH-(C1-C6)alkyl, (11) -C(O)N((C1-C6)alkyl)2in which each alkyl group is independently selected, (12) -S(O)2-(C1-C6)alkyl, (13) -S(O)2-(C1-C6)halogenoalkane, (14) -S(O)2-R6, (15) -S(O)2-R7, (16) -S(O)2-R8, (17) -alkylen-C(O)-(C1-C6)alkyl, (18) -alkylen-C(O)-(C1-C6)halogen-alkyl, (19) -alkylen-C(O)-R6, (20) -alkylene-C(O)-R7, (21) -alkylen-S(O)2-(C1-C6)alkyl, (22) -alkylen-S(O)2-(C1-C6)ha is hogenakkal, (23) -alkylen-S(O)2-R6, (24) -alkylen-S(O)2-R7, (25) -alkylen-S(O)2-R8, (26) -alkylene-NHC(O)-(C1-C6)alkyl, (27) -alkylene-NHC(O)-(C1-C6)halogenoalkane, (28) -alkylene-NHC(O)-R6, (29) -alkylene-NHC(O)-R7, (30) -alkylen-NHS(O)2-(C1-C6)alkyl, (31) -alkylen-NHS(O)2-(C1-C6)halogenoalkane, (32) -alkylen-NHS(O)2-R6, (33) -alkylen-NHS(O)2-R7, (34) -alkylene-N(alkyl)C(O)-(C1-C6)alkyl, (35) -alkylene-N(alkyl)C(O)-(C1-C6)halogenoalkane, (36) -alkylene-N(alkyl)C(O)-R6, (37) -alkylene-N(alkyl)C(O)-R7, (38) -alkylene-N(alkyl)S(O)2-(C1-C6)alkyl, (39) -alkylene-N(alkyl)S(O)2-(C1-C6)halogen-alkyl, (40) -alkylene-N(alkyl)S(O)2-R6, (41) -alkylene-N(alkyl)S(O)2-R7, (42) -alkylen-C(O)-NH-(C1-C6)alkyl, (43) -alkylen-C(O)-other6, (44) -alkylen-C(O)-other7, (45) -alkylen-S(O)2NH-(C1-C6)alkyl, (46) -alkylen-S(O)2NH-R6, (47) -alkylen-S(O)2NH-R7, (48) -alkylen-C(O)-N((C1-C6)alkyl)2in which each alkyl group is independently selected, (49) -alkylen-C(O)-N(alkyl)-R6, (50) -alkylen-C(O)-N(alkyl)-R7,
(51) -alkylen-S(O)2N((C1-C6)alkyl)2in which each alkyl group is independently selected, (52) -alkylen-S(O)2N(alkyl)-R6, (53) -alkylen-S(O 2N(alkyl)-R7,
(54) -alkylene-(55) -alkylene-OC(O)-NH-alkyl, (56) -alkylene-OC(O)NH-R8,
(57) -alkylen-CN, (58) -R8, (59) -alkylen-SH, (60) -alkylen-S(O)2-NH-R8, (61) -alkylen-S(O)2-alkylen-R6, (62) substituted with halogen of alkylene, (63) -C(O)OR8, (64) -C(O)O(C1-C6)alkyl, (65) -C(O)R8, (66) -C(O)-alkylen-O-(C1-C6)alkyl, (67) -C(O)NH2,
(68) -alkylen-O-(C1-C6)alkyl, (69) -alkylen-R8, (70) -S(O)2-halogen(C1-C6)alkyl, (71) replacement halogen(C1-C6)alkyl, (72) -alkylene-NH2, (73) -alkylene-NH-S(O)2-R8, (74) -alkylene-NH-C(O)-R8, (75) -alkylene-NH-C(O)O-(C1-C6)alkyl, (76) -alkylen-O-C(O)-(C1-C6)alkyl, (77) -alkylen-O-S(O)2-(C1-C6)alkyl, (78) -alkylen-R6, (79) -alkylen-R7, (80) -alkylene-NH-C(O)-NH-(C1-C6)alkyl, (81) -alkylene-N(S(O)2halogen(C1-C6)alkyl)2and each-S(O)2halogen(C1-C6)alkyl fragment chosen independently (82) -alkylene-N((C1-C6)alkyl)S(O)2R8, (83) -alkylene-OC(O)-N(alkyl)2and each alkyl independently selected, (84) -alkylene-NH-(C1-C6)alkyl, (85) -C(O)-alkylene-C(O)O-(C1-C6)alkyl, (86) -C(O)-C(O)-O-(C1-C6)alkyl, (87) -C(O)-alkylene-R6, (88) -C(O)-NH-R8, (89) -C(O)-NH-R6, (90) -C(O)-NH-Alki the EN-R 6, (91) -C(O)-alkylene-NH-S(O)2-halogen(C1-C6)alkyl, (92) -C(O)-alkylene-NH-C(O)-O-(C1-C6)alkyl, (93) -C(O)-alkylene-NH2, (94) -C(O)-alkylene-NH-S(O)2-R8, (95) -C(O)-alkylene-NH-S(O)2-(C1-C6)alkyl, (96) -C(O)-alkylene-NH-C(O)-(C1-C6)alkyl, (97) -C(O)-alkylene-N(S(O)2(C1-C6)alkyl)2and each-S(O)2(C1-C6)alkyl fragment chosen independently (98) -C(O)-alkylene-NH-C(O)-NH-(C1-C6)alkyl, (99) -alkylen-O-R6, (100) -alkylen-R7, (101) -C(O), (102) -alkylene-N(S(O)2(C1-C6)alkyl)2, (103) -alkylen-C(O)-O-(C1-C6)alkyl, (104) halogenoalkane, (105) halogen, (106) -alkylen-C(O)-NH2, (107) =N-O-(C1-C6)alkyl, (108) =N-O-alkylene-R6, (109) =N-O-alkenyl, (110) =N-O-R6, (111) -N-NH-S(O)2-R6, (112) alkenyl, (113) =R8, (114) -O-C(O)-R9, (115) -O-C(O)-(C1-C6)alkyl, (116) -CN;
R6selected from the group consisting of unsubstituted (C6-C14)aryl, (C6-C14)aryl, substituted by one or more groups L1, unsubstituted (C5-C14)heteroaryl and (C5-C14)heteroaryl, which means an aromatic monocyclic or bicyclic system containing ring from about 5 to about 9 atoms, where one or more atoms in the ring system are and what Ohm element, other than carbon, for example nitrogen, oxygen or sulfur, single or in combination, substituted by one or more groups L1;
R7selected from the group consisting of unsubstituted geterotsiklicheskie and geterotsiklicheskie, which means non-aromatic monocyclic system containing ring of from about 4 to about 6 atoms, and one or more atoms in the ring system represents an atom of an element other than carbon, for example nitrogen or oxygen, substituted by one or more groups L2;
R8selected from the group consisting of unsubstituted cycloalkyl and cycloalkyl substituted by one or more groups L3;
Ar is selected from the group consisting of (a) unsubstituted aryl, (b) aryl, substituted by one or more groups L1, (C) unsubstituted pyridyl and (d) pyridyl substituted by one or more groups L1;
each group of L1independently selected from the group consisting of halogen, alkyl, -CN, -CF3, -O-(C1-C6)alkyl, -O-(halo(C1-C6)alkyl), -alkylene-HE(-CH2OH);
each group of L2independently selected from the group consisting of (a) HE, (b) alkyl, (C) alkyl substituted by one or more groups-HE, and (d) of piperidine;
each group of L3independently selected from the group consisting of-CN, =O, R 5, -OR5; =N-R5and-N(R5)2;
n is 0, 1, 2 or 3; and
m is 0, 1 or 2; and
provided that the Deputy OR5the fragment of R5and the oxygen atom to which it is attached, do not form a group-O-O-; and
provided that the substituents OR5, =N-R5and-other5R5is not
-CH2OH, -CH2NH2, -CH2NH-alkyl, -CH2NH-aryl or-C(O)HE.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, in which R1selected from the group consisting of H and (C1-C6)alkyl;
R2selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkylen-OR5-(C1-C6)alkylene-R6-(C1-C6)alkylen-C(O)O-(C1-C6)alkyl, -(C1-C6)alkylene-R8-C(O)O-(C1-C6)alkyl and -(C2-C6)alkenyl;
R3selected from the group consisting of H, -(C1-C6)alkyl, -(C1-C6)alkylen-OR5-(C2-C6)alkenyl, -C(O)O-(C1-C6)alkyl and -(C1-C6)alkylen-C(O)O-(C1-C6)alkyl; or
R2and R3or R2and R4or R3and R4together with the carbon atoms to which they are linked, form a condensed (C3-C7)cycloalkyl ring or (C3-C7)heterocyclyl the second ring, having specified in claim 1 value, and the specified condensed cycloalkyl or geteroseksualnoe ring is not substituted or is substituted by one or more groups L3;
each R4independently selected from the group consisting of H, -(C1-C6)alkyl and -(C1-C6)alkylene-R6; and provided that when X represents-O - or-S-, a m is 1, at least one of R2, R3or R4is not H;
each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6-C(O)-(C1-C6)alkyl, -C(O)-R6and-C(O)-R7;
R6selected from the group consisting of unsubstituted (C6-C14)aryl and (C6-C14)aryl, substituted by one or more groups L1;
R7selected from the group consisting of unsubstituted (C3-C10)geterotsiklicheskie and (C3-C10)geterotsiklicheskie substituted by one or more groups L2and the specified heteroseksualci has specified in claim 1 is,
R8selected from the group consisting of unsubstituted (C3-C10)cycloalkyl and (C3-C10)cycloalkyl substituted by one or more groups L3;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1;
each of the group L 1independently selected from the group consisting of halogen, (C1-C6)alkyl, -CN, and-CF3;
each group of L2independently selected from the group consisting of HE, (C1-C6)alkyl, (C1-C6)alkyl, substituted by one or more groups-HE, and piperidyl.

3. The compound according to claim 1, in which each group of L3independently selected from the group consisting of =O, R5, -OR5and-other5.

4. The compound according to claim 1, in which each group of L3represents the same or different group-other5and each R5independently selected from the group consisting of-S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7and-S(O)2R8.

5. The compound according to claim 1, in which each group of L3represents the same or different group OR5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7, -C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

6. The compound according to claim 1, in which each group of L3represents the same or different group, R5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7, S(O)2 1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane,
-S(O)2R6, -S(O)2R7, -S(O)2R8, -C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

7. The compound according to claim 1, characterized by the following formula (IA):

or its pharmaceutically acceptable salt,
and R1-R4, Ar, L1and n are specified in claim 1 values.

8. The compound according to claim 1, characterized by the following formula (IB):

or its pharmaceutically acceptable salt,
and R2-R4, Ar, L1and n are specified in claim 1 values.

9. The compound according to claim 1, characterized by the following formula (1C):

or its pharmaceutically acceptable salt,
and R1-R3, Ar, L1and n are specified in claim 1 values.

10. The compound according to claim 1, characterized by the following formula (ID):

or its pharmaceutically acceptable salt,
and R1-R4, Ar, L1and n are specified in claim 1 values.

11. The compound according to claim 1, characterized by the following formula (IE):

or its pharmaceutically acceptable salt,
and R2-R4, Ar, L1and n are specified in claim 1 values.

12. The connection according to claim 7, the which
R1represents H or alkyl;
R2selected from the group consisting of H, alkyl, alkylen-OR5-alkylen-R6-alkylen-C(O)O-alkyl, -C(O)O-alkyl and alkenyl;
R3selected from the group consisting of H, alkyl, alkylen-OR5and-alkylen-C(O)O-alkyl;
R4independently represents H or alkyl;
each R5independently represents H or-C(O)-R7;
R6selected from the group consisting of unsubstituted (C6-C14)aryl and (C6-C14)aryl, substituted by one or more groups L1;
R7selected from the group consisting of unsubstituted geterotsiklicheskie and geterotsiklicheskie substituted by one or more groups L2;
moreover, the specified heteroseksualci has specified in claim 1;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1;
each group of L1independently represents halogen or alkyl;
each group of L2independently represents-HE or piperidyl; and
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

13. The connection according to claim 7, in which
R1represents H or-CH3;
R2selected from the group consisting of H, -CH(CH3)2, -CH3, -CH2CH3, -(CH2)3CH3, -CH2-R6,-CH 2CH2-OH, -CH2-C(O)O-CH2CH3-C(O)O-CH2CH3, -CH2CH2-O-C(O)-pyrrolidinyl substituted by one or more groups L2, -CH2CH2-O-C(O)-piperidine substituted by one or more groups L2, -CH2CH=CH2;
R3selected from the group consisting of H, -CH3, -CH2CH3, -CH2-OH, -CH2-O-C(O)-piperidine substituted by one or more groups L2, -CH2-O-C(O)-pyrrolidinyl substituted by one or more groups L2, -CH2-C(O)O-CH3, -CH2-C(O)O-CH2CH3;
R4represents H or-CH3;
R6selected from the group consisting of unsubstituted phenyl and phenyl substituted by one or more groups L1;
Ar represents unsubstituted phenyl or phenyl substituted by one or more groups L1;
each group of L1independently represents F, Cl or-CH3;
each group of L2independently represents-HE or piperidyl; and
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

14. The connection according to claim 7, selected from the group consisting of


or its pharmaceutically acceptable salt.

15. The connection of claim 8, in which
R2selected from a group is s, consisting of H, alkyl, alkylen-OR5-alkylen-R6-alkylen-C(O)O-alkyl, -alkylene-R8and alkenyl;
R3selected from the group consisting of H, alkyl and alkylene-OR5; or
R2and R3together with the carbon atoms to which they are linked, form a condensed 3-7-membered cycloalkyl ring or have a specified in claim 1 is geteroseksualnoe ring, and condensed specified cycloalkyl or geteroseksualnoe ring is not substituted or is substituted by one or more groups L3;
R4selected from the group consisting of H, alkyl and-alkylen-R6;
each R5independently selected from the group consisting of H, alkyl and-C(O)-R7;
R6selected from the group consisting of unsubstituted (C6-C14)aryl and (C6-C14)aryl, substituted by one or more groups L1;
R7selected from the group consisting of unsubstituted geterotsiklicheskie and geterotsiklicheskie substituted by one or more groups L2and the specified heteroseksualci has specified in claim 1;
R8selected from the group consisting of unsubstituted cycloalkyl and cycloalkyl substituted by one or more groups L3;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1 ;
each group of L1independently represents halogen or alkyl;
each group of L2independently selected from the group consisting of HE, alkyl, alkyl substituted by one or more groups-HE, and piperidyl;
each group of L3represents-OR5;
n is an integer from 0 to 3,
or its pharmaceutically acceptable salt.

16. The connection of claim 8, in which
R2selected from the group consisting of H, -CH2-C(O)O-CH3, -CH3, -CH2CH3, -CH(CH3)2, -CH2-R6, -CH2-R8, -CH2CH2-OR5, -CH2CH=CH2and-CH(CH3)CH2CH2-HE;
R3selected from the group consisting of H, -CH3, -CH2-OH and-CH2-O-CH3; or
R2and R3together with the carbon atoms, to which they are bound, form a condensed cyclopropylidene, tsiklogeksilnogo, cycloheptyl or tetrahydropyranyl ring, and condensed specified cyclopropylidene, tsiklogeksilnogo, cycloheptyl or tetrahydropyranyl ring is not substituted or is substituted by one or more groups L3;
R4selected from the group consisting of H, -CH3, -CH2CH3and-CH2-R6;
each R5independently selected from H or-C(O)-R7;
R6selected from the group consisting whom her from unsubstituted phenyl and phenyl, substituted by one or more groups L1;
R7selected from the group consisting of unsubstituted of piperidyl, piperidino substituted by one or more groups L2, unsubstituted piperazinil, piperazinil substituted by one or more groups L2, unsubstituted pyrrolidinyl, pyrrolidinyl substituted by one or more groups L2;
R8selected from the group consisting of the unsubstituted cyclopropyl and cyclopropyl substituted by one or more groups L3;
Ar represents unsubstituted phenyl or phenyl substituted by one or more groups L1;
each group of L1independently represents F, Cl or-CH3;
each group of L2independently selected from the group consisting of-OH, -CH2CH2HE, piperidyl and- (CH3)3;
each group of L3independently represents-IT or-C(O)-R7;
n is 0, 1, 2 or 3,
or its pharmaceutically acceptable salt.

17. The compound of claim 8 selected from the group consisting of


or its pharmaceutically acceptable salt.

18. The connection according to claim 9, in which
R1selected from the group consisting of H and alkyl;
R2represents H;
R3represents H;
Ar represents the t an unsubstituted aryl or aryl, substituted by one or more groups L1;
each group of L1independently selected from the group consisting of halogen, alkyl, -CN, and-CF3;
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

19. The connection according to claim 9, in which
R1selected from the group consisting of H and CH3;
R2represents H;
R3represents H;
Ar represents unsubstituted phenyl or phenyl substituted by one or more groups L1;
each group of L1independently represents F or Cl; and
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

20. The connection according to claim 9 or its pharmaceutically acceptable salt selected from the group consisting of

21. The connection of claim 10, in which
R1represents H;
R2selected from the group consisting of H, alkyl and alkenyl;
R3selected from the group consisting of H, alkyl and alkenyl;
each R4represents H;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1;
each group of L1independently selected from the group consisting of halogen, alkyl, -CN, and-CF3;
n is 0, 1, 2 or 3,
or its pharmaceutically acceptable salt.

22. The connection of claim 10, in which
R1represents H;
2selected from the group consisting of H, -CH3, -CH(CH3)2and CH2CH=CH2;
R3selected from the group consisting of H, -CH3and CH2CH=CH2;
each R4represents H;
Ar represents unsubstituted phenyl or phenyl substituted by one or more groups L1;
each group of L1independently represents F or Cl; and
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

23. The compound of claim 10 selected from the group consisting of

or its pharmaceutically acceptable salt.

24. Connection by claim 11, in which
R2represents H or alkyl;
R3represents H or alkyl;
each R4represents H;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1;
each group of L1independently selected from the group consisting of halogen, alkyl, -CN, and-CF3;
n is 0, 1, 2 or 3,
or its pharmaceutically acceptable salt.

25. Connection by claim 11, in which
R2represents H or-CH3;
R3represents H or-CH3;
each R4represents H;
Ar represents unsubstituted phenyl or phenyl substituted by one or more groups L1;
each group of L1/sup> independently represents F or Cl; and
n is 0, 1 or 2,
or its pharmaceutically acceptable salt.

26. Connection claim 11, selected from the group consisting of

or its pharmaceutically acceptable salt.

27. The compound according to claim 1, in which
R2and R3or R2and R4or R3and R4together with the atoms to which they are linked, form a condensed 3-7-membered cycloalkyl ring or geteroseksualnoe ring which is not substituted or is substituted by one or more groups L3and these heteroseksualci and group L3have specified in claim 1 values;
or its pharmaceutically acceptable salt.

28. Connection item 27, which
X represents-O-;
R3selected from the group consisting of H, alkyl, alkylen-OR5alkenyl, -C(O)O-alkyl and-alkylen-C(O)O-alkyl; or
R2and R3or R2and R4or R3and R4together with the atoms to which they are linked, form a condensed 3-7-membered cycloalkyl ring which is not substituted or is substituted by one or more groups L3;
each R5independently selected from the group consisting of H, alkyl, R6-C(O)-alkyl, -C(O)-R6and-C(O)-R7;
R6selected from the group consisting of unsubstituted aryl and aryl substituted one the th or more groups L 1;
R7selected from the group consisting of unsubstituted geterotsiklicheskie and geterotsiklicheskie substituted by one or more groups L2and the specified heteroseksualci has specified in claim 1;
Ar is an unsubstituted aryl or aryl substituted by one or more groups L1;
each group of L1independently selected from the group consisting of halogen, alkyl, -CN, and-CF3;
each group of L2independently selected from the group consisting of HE, alkyl, alkyl substituted by one or more groups-HE, and piperidyl;
L3represents-OR5;
n is 0, 1, 2 or 3; and
m is 1,
or its pharmaceutically acceptable salt.

29. Connection p selected from the group consisting of

or its pharmaceutically acceptable salt.

30. The compound according to claim 1, characterized by formula (IF)

where Q represents a condensed ring consisting of unsubstituted 3-7-membered cycloalkyl substituted by one or more groups L33-7-membered cycloalkyl, unsubstituted geterotsiklicheskie or substituted by one or more groups L3geterotsiklicheskie, and these heteroseksualci and group L3have specified in claim 1 values.

31. The connection p is item 30, in which each group of L3represents the same or different group-other5and each R5independently selected from the group consisting of-S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7and-S(O)2R8.

32. Connection item 30, in which each group of L3represents the same or different group OR5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7-C(O)-(C1-C6)alkyl, -C(O)-C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

33. Connection item 30, in which each group of L3represents the same or different group, R5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7, S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7, -S(O)2R8-C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

34. Connection item 30, in which Q represents a condensed 3-7-membered cycloalkyl ring.

35. Connection item 30, in which m is 1.

36. Connection item 30, in which R4represents N.

37. Connect the s on item 30, in which X represents O.

38. Connection item 30, in which L1represents a halogen.

39. Connection item 30, in which L1is a halogen, where each halogen is independently selected from the group consisting of Cl and F.

40. Connection item 30, in which the Deputy Ar represents an aryl fragment that is substituted by one or more groups L1and these groups L1have specified in claim 1 value.

41. Connection item 30, in which the Deputy Ar represents phenyl substituted by one or more groups L1and these groups L1have specified in claim 1 value.

42. Connection item 30, in which the Deputy Ar represents phenyl substituted by a group of L1and the L1represents a halogen.

43. Connection item 30, in which the Deputy Ar represents phenyl substituted by a group of L1and the L1represents Cl or-CF3.

44. Connection item 30, in which n is 1 or 2.

45. Connection item 30, in which n is 1.

46. Connection item 30, in which n is 2.

47. Connection item 30, in which the group L1is a halogen, where each halogen is independently selected from the group consisting of Cl and Br, a n is 2.

48. Connection item 30, in which the group is and L 1represents F, and n is 2.

49. Connection item 30, in which m is 1, and X represents O.

50. Connection item 30, in which m is 1, X represents Oh, a R4represents N.

51. Connection item 30, in which m is 1, X represents Oh, R4represents H, n is 2, and the group L1selected from the group consisting of Cl and F.

52. Connection item 30, in which m is 1, X represents Oh, R4represents H, n is 2, the group L1selected from the group consisting of Cl and F, and Ar is a phenyl, substituted Cl.

53. Connection item 30, in which m is 1, X represents Oh, R4represents H, n is 2, and the group L1is a F.

54. Connection item 30, in which m is 1, X represents Oh, R4represents H, n is 2, the group L1represents F, and Ar is a phenyl, substituted Cl.

55. Connection item 30, and the compound of formula (IF) is a compound of formula (IF.1)

and Ar, R4L1, X and m are specified in claim 1 values, a Q has the meaning specified in article 30.

56. Connection § 55, in which m is 1, X represents Oh, R4represents H, a group of L1represents F, and Ar is a phenyl, substituted Cl.

57. Connect the s on any of PP, 55 or 56, in which Q represents a

58. The compound according to any one of p, 55 or 56, in which Q represents a

59. The compound according to any one of p, 55 or 56, in which Q represents a

moreover, the group L3selected from the group consisting of =O, -OR5-The other5, -SO2R6, -SO2R7and-SO2R8and R5selected from the group consisting of-SO2-(C1-C6)halogenoalkane, -C(O)-(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -SO2-(C1-C6)alkyl and -(C1-C6)alkyl, R6represents unsubstituted (C5-C14)heteroaryl, R7represents unsubstituted geteroseksualnoe ring having specified in claim 1 value, and R8represents unsubstituted cycloalkyl ring.

60. Connection p, in which the group L3selected from the group consisting of =O, -OH, -NH2, -NHSO2CF3, -NHC(O)CH3, -NHC(O)NHCH2CH3, -NHSO2CH3, -NHSO2CH2CH3, -NHSO2CH2CH2CH3, -OCH3,

61. Connection item 30 or 55, in which Q represents a

62. Connection item 30 or 55, in which Q represents Soboh the

63. Connection item 30 or 55, in which Q represents a

moreover, the group L3selected from the group consisting of-OR5and-other5.

64. Connection item 30 or 55, in which Q represents a

moreover, the group L3selected from the group consisting of-HE-NHSO2CF3.

65. Connection item 30, in which Q represents an unsubstituted geteroseksualnoe ring containing one heteroatom selected from the group consisting of-O - and-NH-, and geteroseksualnoe ring has specified in claim 1 value.

66. Connection item 30, in which Q represents geteroseksualnoe ring, substituted by one or more groups L3and specified geteroseksualnoe ring contains at least one heteroatom selected from the group consisting of-O-, -NH - and-N(L3), and moreover, these geteroseksualnoe ring and band L3have specified in claim 1 values.

67. Connection item 30, in which Q represents a

68. Connection item 30 or 55, in which Q represents a

69. Connection item 30 or 55, in which Q represents a

70. Connection p, in which the group L3depict is to place a C 1-C6alkyl group.

71. Connection item 30 or 55, in which Q represents a

72. Connection item 30 or 55, in which Q represents a

73. Connection item 30 or 55, in which Q represents a

where the group L3associated with the N atom represents the same or different group relative to the group L3associated with the carbon atom in the composition of the rings.

74. Connection item 30 or 55, in which Q represents a

75. Connection p, where L3represents-C(O)-alkyl group.

76. Connection on item 75, in which L3represents-C(O)CH3.

77. The compound according to claim 1, characterized by formula (IG)

where Q represents a condensed ring consisting of unsubstituted 3-7-membered cycloalkyl substituted by one or more groups L33-7-membered cycloalkyl, unsubstituted geterotsiklicheskie or substituted by one or more groups L3geterotsiklicheskie, and these heteroseksualci and group L3have specified in claim 1 values.

78. Connection p, in which each group of L3represents the same or different group-other5, and each R5independently selected from the group consisting of-S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7and-S(O)2R8.

79. Connection p, in which each group of L3represents the same or different group OR5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7-C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

80. Connection p, in which each group of L3represents the same or different group, R5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7, S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7, -S(O)2R8-C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

81. Connection p, in which Q represents a condensed 3-7-membered cycloalkyl ring.

82. The compound according to claim 1, characterized by formula (IH)

where Q represents a condensed ring consisting of unsubstituted 3-7-membered cycloalkyl substituted one or bore alkemi groups L 33-7-membered cycloalkyl, unsubstituted geterotsiklicheskie or substituted by one or more groups L3geterotsiklicheskie, and these heteroseksualci and group L3have specified in claim 1 values.

83. Connection p, in which each group of L3represents the same or different group-other5and each R5independently selected from the group consisting of-S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7and-S(O)2R8.

84. Connection p, in which each group of L3represents the same or different group OR5with each group , R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7-C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)halogenoalkane, -C(O)-R6and-C(O)-R7.

85. Connection p, in which each group of L3represents the same or different group, R5and each R5independently selected from the group consisting of H, (C1-C6)alkyl, R6, R7, S(O)2-(C1-C6)alkyl, -S(O)2-(C1-C6)halogenoalkane, -S(O)2R6, -S(O)2R7, -S(O)2R8-C(O)-(C1-C6)alkyl, -C(O)-(C1-C6)the halogen is of Lila, -C(O)-R6and-C(O)-R7.

86. The compound according to claim 1, characterized by formula (IF.1A)

where Q represents a condensed ring consisting of unsubstituted 3-7-membered cycloalkyl substituted by one or more groups L33-7-membered cycloalkyl, unsubstituted geterotsiklicheskie or substituted by one or more groups L3geterotsiklicheskie, and these heteroseksualci and group L3have specified in claim 1 values, and Y is linked to the carbon atom common to two condensed rings and is selected from the group consisting of-other5That is-HE-OR5where R5has specified in claim 1 value.

87. Connection item 30 or 55, in which the ring Q represents a

88. Connection item 30 or 55, in which the ring Q represents a

89. Connection item 30, in which the ring Q represents a substituted tsiklogeksilnogo ring

where the group L3selected from the group consisting of-alkylene-C(O)NH(C1-C6)alkyl and alkylene-C(O)N(C1-C6)alkyl)2and each alkyl independently selected.

90. Connection p, where L3selected from the group consisting of-CH2C(O)NHC2H5and CH2C(O)NHCH3.

91. Soy is inania on item 30, in which Q represents a substituted tsiklogeksilnogo ring

where the group L3selected from the group consisting of-alkylene-NHS(O)2-(C1-C6)alkyl and-alkylen-NHS(O)2-(C1-C6)halogenoalkane.

92. Connection p, where L3selected from the group consisting of-CH2NHS(O)2C2H5, -CH2NHS(O)2CH3and-CHNHS(O)2CH2CF3.

93. Connection item 30, in which Q represents a substituted tsiklogeksilnogo ring

where the group L3selected from the group consisting of replacement of Akilov.

94. Connection p, in which the group L3selected from the group consisting of-CH2CH(OH)CH2CH3and CH2CH2CH(OH)CH2OH.

95. Connection item 30, in which Q represents a substituted tsiklogeksilnogo ring

where the group L3selected from the group consisting of-alkylene-S(O)2-(C1-C6)alkyl.

96. Connection p, in which the group L3represents-CH2CH2SO2CH2CH3or-CH2CH2SO2CH3.

97. Connection item 30, in which Q represents a substituted tsiklogeksilnogo ring

where the group L3select the and of the group, consisting of-alkylene-C(O)-(C1-C6)alkyl.

98. Connection p, where L3represents-CH2CH2-C(O)-CH3.

99. The compound according to any one of p, 91, 93, 95 or 97, and the compound is a compound according to § 55, in which m is 1, X represents Oh, R4represents H, a group of L1represents F, and Ar is a phenyl, substituted Cl.

100. Connection item 30, in which Q represents a substituted geteroseksualnoe ring

where the group L3selected from the group consisting of-alkylene-C(O)NH(C1-C6)alkyl and-alkylen-C(O)N((C1-C6)alkyl)2and each alkyl independently selected.

101. Connection item 100, in which the group L3selected from the group consisting of-CH2C(O)NHC2H5and CH2C(O)NHCH3.

102. Connection item 30, in which Q represents a substituted geteroseksualnoe ring

where the group L3selected from the group consisting of-alkylene-NHS(O)2-(C1-C6)alkyl and-alkylen-NHS(O)2-(C1-C6)halogenoalkane.

103. The connection 102, in which the group L3selected from the group consisting of-CH2NHS(O)2CH2CH3and-CH2NHS(O)2CF3.

104. Connection item 30 in which Q represents a substituted geteroseksualnoe ring

where the group L3selected from the group consisting of replacement of Akilov.

105. Connection p, in which the group L3selected from the group consisting of-CH2CH(OH)CH2CH3and-CH2CH3CH(OH)CH2HE.

106. Connection item 30, in which Q represents a substituted geteroseksualnoe ring

where the group L is selected from the group consisting of-alkylene-S(O)2-(C1-C6)alkyl.

107. Connection p, in which the group L3represents-CH2CH2SO2CH2CH3or-CH2CH2SO2CH3.

108. Connection item 30, in which Q represents a substituted geteroseksualnoe ring

where the group L3selected from the group consisting of-alkylene-C(O)-(C1-C6)alkyl.

109. Connection p, where L3represents-CH2CH2-C(O)-CH3.

110. The compound according to any one of p, 102, 104, 106 or 108, which is a compound according to § 55, in which m is 1, X represents Oh, R4represents H, L1represents F, and Ar is a phenyl, substituted Cl.

111. The compound according to claim 1, selected from the group consisting of compounds of the following formulas:



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to azabenzothiophenyl compounds of formula I

and salts thereof, where: Z1 denotes CR1; Z2 denotes N; Z3 denotes CR3; Z4 denotes CR4; R1, R3 and R4 are independently selected from H or halogen; W denotes , R5 and R6 denote H; X1 denotes -OR11; X2 denotes phenyl which is optionally substituted with one or two groups selected from halogen or (C1-C3)alkylsulphanyl; R11 denotes (C1-C12) alkyl, substituted by one or two groups independently selected from - (CR19R20)nOR16; n equals 0; R16 denotes H, (C1-C12) alkyl or (C2-C8) alkenyl. The invention also relates to a pharmaceutical composition based on said compounds, which can be used in medicine for treating hyperproliferative disorders.

EFFECT: high efficiency of using said compounds.

11 cl, 12 ex

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

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: agriculture.

SUBSTANCE: improvement of effectiveness of insecticidal preparation is achieved through the use in sublethal doses of a mixture of fluorinated usnic acid (FUA) of the formula and II obtained by the reaction of (+)-usnic acid with perfluoropropene as a synergist of such insecticides. The decline of the latent period of the disease and increased mortality rate of larvae of Colorado potato beetle is marked using FUA and entomopathogenic microorganisms of Beauveria bassiana, Metarhizium anisopliae and Bacillus thuringiensis. The mixed composition of FUA at a concentration of 0.03% with a suspension of conidia of the fungus Bauveria bassiana with a titer of 3×106 conidia/ml (in vitro) and 5×106 conidia/ml (in the field) has proved to be the best in all respects.

EFFECT: increased biological efficiency of insecticides based on entomopathogenic fungi and bacteria.

1 cl, 4 tbl,5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing an optically active chromene oxide compound of formula or formula where R5, R6, R7, R8, R9, R10 and A are as described in the claim, and the absolute configuration of carbon atoms, denoted by *, denotes (R) or (S), which includes asymmetric epoxidation of a chromene compound of formula or formula with an oxidant in a solvent using optically active titanium complexes of formula formula formula and formula where R1, R2, R3 and R4 are defined in the claim, as a catalyst for asymmetric oxidation of the optically active chromene compound with high enantioselectivity and high chemical output.

EFFECT: efficient method of producing an optically active chromene oxide compound, which is an important intermediate compound used to produce a benzopyran compound, which is effective in treating arrhythmia.

18 cl, 26 ex

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R1 independently represents H or halogen; R2 represents H or --R10-NR11R12 where R10 represents C1-C6 alkylene; R11 and R12 independently represent H, C1-C4 alkyl; and R3 independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.

EFFECT: new compounds which can find application for preparing the compounds applicable for treatment or prevention of cardiac arrhythmia.

6 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or stereoisomer thereof, or salt thereof, as well as synthesis method thereof and intermediate compounds of formulae (II) and (III) used in this method.

EFFECT: novel compound which can be used to produce HIV protease inhibitors.

23 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing diastereoismerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol (6), as well as a novel intermediate compound (3aR,4S,6aS)-4-methoxytetrahydrofuro [3,4-b]furan-2-one (4) for use in said methods. More specifically, the invention relates to a stereo-selective method of producing diastereoisomerically pure (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol, as well as methods for crystallisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one and epimerisation of (3aR,4S,6aS)-4-methoxytetrahydrofuro[3,4-b]furan-2-one to (3aR,4S,6aS)-4- methoxytetrahydrofuro[3,4-b]furan-2-one.

EFFECT: improved method.

25 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.

EFFECT: disclosed are products of oxidative decomposition of an atorvastatin salt, which can be used to identify impurities or a product of decomposition of an atorvastatin salt in accordance with approved analytical procedures.

15 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: sesamin or sesamin-containing composition undergoes epimerisation in such a way that a portion of the sesamin converts to episesamin. Episesamin is crystallised through recrystallisation. The device for producing sesamin has an isomerisation unit which has a mixing reservoir for mixing oil or fat containing sesamin or a sesamin-containing composition with an acid catalyst; a crystallisation unit having a crystallisation reservoir for carrying out recrystallisation; a liquid supply line which connects the mixing reservoir with the crystallisation reservoir.

EFFECT: high output of product.

21 cl, 2 dwg, 5 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4β-amino-4'-demetyl-4-desoxypodophyllotoxin of formula (1), involving the following steps: a) reaction of thiourea and 4β-halogenoacetamido-4'-demethyl-4-desoxypodophyllotoxin in a medium of a weak pure acid or mixture of acid, water an organic solvent without using any other solvent at temperature higher than ambient temperature; b) extraction of 4β-amino-4'-demethyl-4- desoxypodophyllotoxin.

EFFECT: compound is an intermediate product in synthesis of anti-cancer compounds.

22 cl, 1 tbl, 1 ex

Pest control agent // 2405310

FIELD: chemistry.

SUBSTANCE: invention describes compositions for use as a pest control agents containing a compound of formula (I), or a salt of the said compound, acceptable in agriculture or horticulture, as an active ingredient or carrier which is acceptable in agriculture or horticulture: [chemical formula 1] , where Het1 denotes an optionally substituted pyridyl, R1 denotes hydroxyl, optionally substituted C1-6alkylcarbonyloxy, optionally substituted C1-6alkyloxy, or oxo, in the absence of a hydrogen atom in position 13, or the bond between position 5 and position 13 is a double bond in the presence of R1 and a hydrogen atom in position 5, R2 denotes hydroxyl, optionally substituted C1-18alkylcarbonyloxy, benzoyloxy or C1-6alkylsulphonyloxy, R3 denotes a hydrogen atom, hydroxyl, optionally substituted C1-18alkylcarbonyloxy, benzoyloxy, C1-6alkylsulphonyloxy, benzoylsulphonyloxy, imidazolylthiocarbonyloxy, R4 denotes a hydrogen atom, hydroxyl, optionally substituted C1-18alkylcarbonyloxy, C2-6alkenylcarbonyloxy, C2-6alkynylcarbonyloxy, benzoyloxy, C1-6alkylsulphonyloxy, benzoylsulphonyloxy, benzyloxy, C1-6alkyloxy, C1-6alkyloxy-C1-6alkyloxy, C1-6alkylthio-C1-6alkyloxy, C1-6alkyloxy-C1-6alkyloxy-C1-6alkyloxy, C1-6alkyloxycarbonyloxy, C1-6alkylaminocarbonyloxy, tetrahydropyranyloxy, a saturated or unsaturated five- or six-member heterocyclic carbonyloxy, where the said heterocyclic part is selected from a group comprising pyridyl, thienyl, thiazolylpyrazinyl and imidazolyl, optionally substituted tieno[3,2-b]pyridylcarbonyloxy, 1H-indolylcarbonyloxy, imidazolylthiocarbonyloxy, or oxo, in the absence of a hydrogen atom in position 7, provided that the compound, where Het1 denotes 3-pyridyl, R1 denotes hydroxyl and each of R2, R3 and R4 is acetyloxy, is excluded. Disclosed composition is also used in hemipterous pest control.

EFFECT: synthesis of a novel pyripyropen having significant insecticide activity.

22 cl, 29 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

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