PHARMACEUTICAL COMPOUNDS
The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J 1 -J 2 is CH═CH, N═CH, CH═N, HN—C(O) or CH 2 CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
1 - 111 . (canceled)
112 . A compound of the formula (I):
or salts, solvates, tautomers or N-oxides thereof, wherein
(1) GP is a group GP1:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 20 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; n is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH; or
(2) GP is a group GP2:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 21 is selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and methyl; T is N; and J 1 -J 2 is CH═CH; or
(2A) GP is a group GP2A:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 21 is selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and methyl; R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH; or
(3) GP is a group GP3:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH; or
(3A) GP is a group GP3A:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH, CH═N or CH 2 CO; or
(3B) GP is a group GP3B:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH, CH═N or CH 2 CO; or
(3C) GP is a group GP3C:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is CH; and J 1 -J 2 is CH 2 CO; or
(4) GP is a group GP4:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy;
difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O); or
(5) GP is a group GP5:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O); or
(6) GP is a group GP6:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2; t is 0 or 1; T is N; and J 1 -J 2 is HN—C(O); provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; and provided also that when t is 1, r is 1 and R 23 is other than a 4-chloro substituent; or
(7) GP is a group GP7:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is N; and J 1 -J 2 is CH═N; or
(8) GP is a group GP8:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is CH; and J 1 -J 2 is CH 2 —C(O); or
(9) GP is a group GP9:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy;
difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O); and A is selected from:
(i)
wherein the letter “a” denotes the point of attachment to the neighbouring benzene rings;
(ii) CH—CH 2 —NHCH 3 ;
(iii) CH—CH 2 —CH 2 —NH 2 ; and
(iv) C(OH)—CH 2 —CH 2 —NH 2 .
(10) GP is a group GP10:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 25 is selected from hydrogen, fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; and C 1-4 alkyl; T is CH or N; and J 1 -J 2 is CH 2 CO or CH═N; or
(11)GP is a group GP11:
wherein (a) g is 0; d is 1; R w is hydrogen or methyl; T is N; J 1 -J 2 is N═CH, CH 2 CO or CH═N; or (b) g is 1; d is 0 or 1; R w is hydrogen; T is N; and J 1 -J 2 is CH═CH; or
(12) GP is a group GP12:
wherein T is N and J 1 -J 2 is CH═CH; or
(13) GP is a group GP13:
wherein T is N and J 1 -J 2 is CH═CH; and (a) R 24 is methoxy and R 25 is hydrogen or chlorine; or (b) R 24 is methanesulphonyl or cyano and R 25 is hydrogen or
(14) GP is a group GP14:
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH.
113 . A compound according to claim 112 having the formula (IA):
or salts, solvates, tautomers or N-oxides thereof, wherein
(iv) GP is a group GP1:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 20 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; n is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH; or
(2) GP is a group GP2:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 21 is selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and methyl; T is N; and J 1 -J 2 is CH═CH; or
(3) GP is a group GP3:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH; or
(4) GP is a group GP4:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O); or
(5) GP is a group GP5:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O); or
(6) GP is a group GP6:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy, difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2; t is 0 or 1; T is N; and J 1 -J 2 is HN—C(O); provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; and provided also that when t is 1, r is 1 and R 23 is other than a 4-chloro substituent; or
(7) GP is a group GP7:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is N; and J 1 -J 2 is CH═N; or
(8) GP is a group GP8:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is CH; and J 1 -J 2 is CH 2 —C(O); or
(9) GP is a group GP9:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; t is 0 or 1; T is N; and J 1 -J 2 is HN—C(O); and A is selected from:
(i)
wherein the letter “a” denotes the point of attachment to the neighbouring benzene rings;
(ii) CH—CH 2 —NHCH 3 ;
(iii) CH—CH 2 —CH 2 —NH 2 ; and
(iv) C(OH)—CH 2 —CH 2 —NH 2 .
114 . A compound according to claim 112 wherein the moiety GP is a group GP1:
or salts, solvates, tautomers or N-oxides thereof,
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 20 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; n is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH.
115 . A compound according to claim 112 wherein the moiety GP is a group GP2:
or salts, solvates, tautomers or N-oxides thereof, wherein
the point of attachment to the bicyclic group is denoted by the asterisk;
R 21 is selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and methyl; T is N; and J 1 -J 2 is CH═CH.
116 . A compound according to claim 112 wherein GP is a group GP2A:
or salts, solvates, tautomers or N-oxides thereof,
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 21 is selected from fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and methyl; R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH.
117 . A compound according to claim 112 wherein the moiety GP is a group GP3:
or salts, solvates, tautomers or N-oxides thereof,
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is CH═CH.
118 . A compound according to claim 112 wherein GP is a group GP3A:
or salts, solvates, tautomers or N-oxides thereof,
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH, CH═N or CH 2 CO.
119 . A compound according to claim 112 wherein the moiety GP is a group GP4:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O).
120 . A compound according to claim 112 wherein the moiety GP is a group GP5:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2, provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; T is N; and J 1 -J 2 is HN—C(O).
121 . A compound according to claim 112 wherein the moiety GP is a group GP6:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 23 is selected from fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; C 1-4 alkyl; and phenyl optionally substituted by fluorine, chlorine, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy or methyl; r is 0, 1 or 2; t is 0 or 1; T is N; and J 1 -J 2 is HN—C(O); provided that when r is 2, no more than 1 substituent R 23 can be an optionally substituted phenyl group; and provided also that when t is 1, r is 1 and R 23 is other than a 4-chloro substituent.
122 . A compound according to claim 112 wherein the moiety GP is a group GP7:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
T is N; and J 1 -J 2 is CH═N.
123 . A compound according to claim 112 wherein GP is a group GP10:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 25 is selected from hydrogen, fluorine; chlorine; C 1-4 alkoxy; trifluoromethyl; trifluoromethoxy; difluoromethoxy; and C 1-4 alkyl; T is CH or N; and J 1 -J 2 is CH 2 CO or CH═N.
124 . A compound according to claim 112 wherein GP is a group GP11:
wherein (a) g is 0; d is 1; R w is hydrogen or methyl; T is N; J 1 -J 2 is N═CH, CH 2 CO or CH═N; or (b) g is 1; d is 0 or 1; R w is hydrogen; T is N; and J 1 -J 2 is CH═CH.
125 . A compound according to claim 112 wherein GP is a group GP13:
wherein T is N and J 1 -J 2 is CH═CH; and (a) R 24 is methoxy and R 25 is hydrogen or chlorine; or (b) R 24 is methanesulphonyl or cyano and R 25 is hydrogen.
126 . A compound according to claim 112 wherein GP is a group GP14:
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH.
127 . A compound according to claim 112 wherein GP is a group GP3B:
wherein the point of attachment to the bicyclic group is denoted by the asterisk;
R 22 is selected from fluorine, chlorine, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy and C 1-4 alkyl; p is 0, 1 or 2; T is N; and J 1 -J 2 is N═CH, CH═N or CH 2 CO.
128 . A compound as defined in claim 112 in the form of a salt, solvate or N-oxide.
129 . A method for the prophylaxis or treatment of a disease state or condition mediated by protein kinase A or protein kinase B, which method comprises administering to a subject in need thereof a compound as defined in claim 112 .
130 . A method for treating a disease or condition comprising or arising from abnormal cell growth or abnormally arrested cell death in a mammal, which method comprises administering to the mammal a compound as defined in claim 112 in an amount effective in inhibiting abnormal cell growth.
131 . A pharmaceutical composition comprising a compound as defined in claim 112 and a pharmaceutically acceptable carrier.