Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors
The invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof and/or stereoisomers thereof. The compounds of the invention are useful in therapy.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof and/or stereoisomers thereof, wherein:
W is selected from the group consisting of O, N—H, N—(C 1 -C 10 alkyl), and S(O) ww , wherein ww is 0, 1 or 2;
each X is independently selected from CH or N;
X 1 is selected from the group consisting of —CH 2 —CH 2 —, —CH═CH—, and —CH 2 —C(O)—wherein C(O) is attached to NH;
v is selected from 0, 1, 2 and 3;
R 1 is a 5 to 7-membered heterocycle containing at least 1 heteroatom selected from N or O;
R 2 is -L-Y;
L is selected from the group consisting of a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene, and C 2 -C 10 alkynylene;
Y is a 4- to 8-membered heterocycle containing at least one nitrogen atom and at least one sulfur atom, or —N(R 5 )-A-S(O q )R 6 ;
R 5 is independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 3 -C 10 alkynyl;
R 6 is independently selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 10 alkynyl, fluoro C 1 -C 10 alkyl, —O—C 1 —C 10 alkyl, —NH—C 1 -C 10 alkyl, —O—fluoro C 1 -C 10 alkyl, —NH-acyl, —NH—C(O)—NH—C 1 -C 10 alkyl, —C(O)—NH—C 1 -C 10 alkyl, aryl, and heteroaryl;
A is selected from the group consisting of C 1 -C 10 alkylene, C 2 -C 10 alkenylene, and C 3 -C 10 alkynylene;
q is selected from 0, 1, and 2;
each R 3 is independently selected from the group consisting of H, C 1 -C 10 alkyl, halogen, —CN, —CO 2 H, fluoro C 1 -C 10 alkyl, —O-C 1 -C 10 alkyl, —NH-C 1 -C 10 alkyl, —NH 2 , —S-C 1 -C 10 alkyl, —O-fluoro C 1 -C 10 alkyl, —NH-acyl, —NH-C(O)-NH-C 1 -C 10 alkyl, —C(O)-NH-C 1 -C 10 alkyl, aryl and heteroaryl; and
each alkyl, alkenyl, alkylene, alkenylene, alkynylene, acyl, heterocycle or heteroaryl is optionally substituted by C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, fluoro C 1 -C 3 alkyl, amino, C 1 -C 3 mono alkylamino, C 1 -C 3 bis alkylamino, C 1 -C 3 acylamino, C 1 -C 3 aminoalkyl, mono (C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, bis (C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, C 1 -C 3 -acylamino, C 1 -C 3 alkyl sulfonylamino, acyl, halo, nitro, cyano, carboxy, C 1 -C 3 alkoxycarbonyl, aminocarbonyl, mono C 1 -C 3 alkyl aminocarbonyl, bis C 1 -C 3 alkyl aminocarbonyl, —SO 3 H, C 1 -C 3 alkylsulfonyl, aminosulfonyl, mono C 1 -C 3 alkyl aminosulfonyl or bis C 1 -C 3 -alkyl aminosulfonyl.
2. The compound according to claim 1 , wherein R 2 is -L-Y; wherein
L is selected from the group consisting of a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene; and
Y is a 4- to 7-membered heterocycle containing at least one nitrogen atom and at least one sulfur atom, or —N(R 5 )-A-S(O q )R 6 , wherein R 5 , R 6 , A and q are as defined in claim 1 .
3. The compound according to claim 1 , wherein X 1 is —CH═CH—.
4. The compound according to claim 1 , wherein R 3 is independently selected from the group consisting of H, C 1 -C 10 alkyl, halogen, and fluoro C 1 -C 10 alkyl.
5. The compound according to claim 1 , wherein R 1 is represented by any of the following structures:
6. The compound according to claim 1 , wherein R 1 is morpholine.
7. The compound according to claim 1 , wherein W is O or S; and/or X is CH.
8. The compound according to claim 1 , wherein L is C 1 -C 10 alkylene.
9. The compound according to claim 1 , wherein q is 2; and/or R 5 is C 1 -C 10 alkyl.
10. The compound according to claim 1 , wherein A is C 1 -C 10 alkylene; and/or R 6 is independently selected from the group consisting of C 1 -C 10 alkyl, fluoro C 1 -C 10 alkyl, —O—C 1 -C 10 alkyl, —NH—C 1 -C 10 alkyl, aryl, and heteroaryl.
11. The compound according to claim 1 , wherein Y is selected from Formula (III) or Formula (IV):
wherein:
Z is selected from the group consisting of O, S, and CH 2 ;
K is selected from the group consisting of —S-, —S=O,—SO 2 , and
each a is independently selected from 1, 2, and 3;
each b is independently selected from 0, 1, and 2;
n is 0, 1, or 2; and
c is 0 or 1.
12. The compound according to claim 1 , wherein Y is a heterocycloalkyl represented by:
wherein
m is selected from 0, 1 and 2,
n is selected from 0, 1 and 2,
p is selected from 0 and 1,
R 4 is independently selected from the group consisting of H, C 1 -C 10 alkyl, halogen, fluoro C 1 -C 10 alkyl, —O— C 1 -C 10 alkyl, —NH—C 1 -C 10 alkyl, —NH 2 , —S—C 1 -C 10 alkyl, —O-flouro C 1 -C 10 alkyl, —NH-acyl, —NH—C(O)—NH—C 1 -C 10 alkyl, —C(O)—NH—C 1 -C 10 alkyl, aryl and heteroaryl.
13. The compound according to claim 12 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable excipient.
15. A compound of formula II:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of O, N—H, N—(C 1 -C 10 alkyl) and S;
each X is independently selected from CH or N;
v is selected from 0, 1, 2 and 3;
R 1 is a 5 to 7-membered heterocycle containing at least 1 heteroatom selected from N or O;
R 2 is -L-Y;
L is selected from the group consisting of a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene;
Y is a 4- to 7-membered heterocycle containing at least one nitrogen atom and at least one sulfur atom, or —N(R 5 )-A-S(O q )R 6 ;
R 5 is independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 3 -C 10 alkynyl;
R 6 is independently selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 10 alkynyl, fluoro C 1 -C 10 alkyl, —O—C 1 -C 10 alkyl, —NH—C 1 -C 10 alkyl, —O-flouro C 1 -C 10 alkyl, —NH-acyl, —NH—C(O)—NH—C 1 -C 10 alkyl, —C(O)—NH—C 1 -C 10 alkyl, aryl and heteroaryl;
A is selected from the group consisting of C 1 -C 10 alkylene, C 2 -C 10 alkenylene and C 3 -C 10 alkynylene;
q is selected from 0, 1 and 2; and
each R 3 is independently selected from the group consisting of H, C 1 -C 10 alkyl, halogen, fluoro C 1 -C 10 alkyl, —O—C 1 -C 10 alkyl, —NH—C 1 -C 10 alkyl, —NH 2 , —S—C 1 -C 10 alkyl, —O-flouro C 1 -C 10 alkyl, —NH-acyl, —NH—C(O)—NH—C 1 -C 10 alkyl, —C(O)—NH—C 1 -C 10 alkyl, aryl or heteroaryl; and
each alkyl, alkenyl, alkylene, alkenylene, alkynylene, acyl, heterocycle or heteroaryl is optionally substituted by C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, fluoro C 1 -C 3 alkyl, amino, C 1 -C 3 mono alkylamino, C 1 -C 3 bis alkylamino, C 1 -C 3 acylamino, C 1 -C 3 aminoalkyl, mono (C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, bis (C 1 -C 3 alkyl) amino C 1 -C 3 alkyl, C 1 -C 3 -acylamino, C 1 -C 3 alkyl sulfonylamino, acyl, halo, nitro, cyano, carboxy, C 1 -C 3 alkoxycarbonyl, aminocarbonyl, mono C 1 -C 3 alkyl aminocarbonyl, bis C 1 -C 3 alkyl aminocarbonyl, —SO 3 H, C 1 -C 3 alkylsulfonyl, aminosulfonyl, mono C 1 -C 3 alkyl aminosulfonyl or bis C 1 -C 3 -alkyl aminosulfonyl.
16. The compound according to claim 15 , wherein R 1 is morpholine.
17. The compound according to claim 15 , wherein W is O or S; and/or X is CH.
18. The compound according to claim 15 , wherein R 3 is independently selected from H, C 1 -C 10 alkyl, halogen, and fluoro C 1 -C 10 alkyl.
19. The compound according to claim 15 , wherein L is C 1 -C 10 alkylene.
20. The compound according to claim 15 , wherein Y is a heterocycloalkyl represented by:
wherein
m is selected from 0, 1 and 2,
n is selected from 0, 1 and 2,
p is selected from 0 and 1,
R 4 is independently selected from the group consisting of H, C 1 -C 10 alkyl, halogen, fluoro C 1 -C 10 alkyl, —O— C 1 -C 10 alkyl, —NH—C 1 -C 10 alkyl, —NH 2 , —S—C 1 -C 10 alkyl, —O-flouro C 1 -C 10 alkyl, —NH-acyl, —NH—C(O)—NH—C 1 -C 10 alkyl, —C(O)—NH—C 1 -C 10 alkyl, aryl and heteroaryl.