Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors
Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein: W is O, N—H, N—(C 1 -C 10 alkyl) or S; each X is independently CH or N; R 1 is a 5 to 7-membered saturated or unsaturated, optionally substituted heterocycle containing at least 1 heteroatom selected from N or O; R 2 is (LQ) m Y; and each R 3 is independently H, C 1 -C 10 alkyl, aryl or heteroaryl, are surprisingly found to be inhibitors of PI3K-p110δ, and therefore have utility in therapy.
1. A pharmaceutical composition comprising a compound represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
W is O;
X is CH;
R 2 is (LQ) m Y;
m is 0, 1, or 2;
L is C 1 alkylene;
Q is selected from the group consisting of: heteroarylene, —NR 3 —, —C(O)—, —NR 4 R 5 —, and —C(O)NR 4 R 5 , where R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker;
Y is selected from the group consisting of: H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, —OR 3 , —N(R 3 ) 2 , —SO 2 —R 3 , —SO 2 —N(R 3 ) 2 , halogen, —CN, and —C(halogen) b R 3 (3-b) ,
b is from 1 to 3; and
R 3 is independently selected for each occurrence from H or C 1 -C 10 alkyl; and
a pharmaceutically acceptable excipient.
2. The composition of claim 1 , wherein both of the R 3 groups that are attached to the 6,5-ring system in formula I are H.
3. The composition of claim 1 , wherein Y is H.
4. The composition of claim 1 , wherein Q is selected from —NR 3 — and —NR 4 R 5 —.
5. The composition of claim 1 , wherein Q is —NR 4 R 5 wherein R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7-membered heterocycle linker having an additional heteroatom 0; and Y is H.
6. A method of treating lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by:
or a pharmaceutically acceptable salt thereof, wherein:
W is O;
X is CH;
R 2 is (LQ) m Y;
m is 0, 1, or 2;
L is C 1 alkylene:
Q is a heterocyclic linker;
Y is selected from the group consisting of: H, C 1-10 alkyl, —OR 3 , and —C(O)N(R 3 ) 2 ; and
R 3 is H.
7. The method of claim 6 , wherein Y is H.