Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors
A compound 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 LY; each L is a direct bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene or C 2 -C 10 alkynylene; Y is an optionally substituted fused, bridged or spirocyclic non-aromatic 5-12 membered heterocycle containing up to 4 heteroatoms selected from N or O; and each R 3 is independently 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, 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 or heteroaryl, are useful as inhibitors of the class IA phosphoinositide 3-kinase enzyme, PI3K-p110δ, and therefore have potential utility in the therapy of cancer, immune and inflammatory diseases.
1. A pharmaceutical composition comprising a compound represented by:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein:
R 33 is independently selected for each occurrence from the group consisting of H, halogen, NH—C 1-3 alkyl, NH 2 , C 1-6 alkyl and —O—C 1-6 alkyl, wherein C 1-6 alkyl for each occurrence is optionally substituted by one, two or three substituents selected from halogen or hydroxyl;
R 34 is selected from H or C 1-3 alkyl; and
R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-10 membered bicyclic spirocycle or bridged heterocycle each having an additional heteroatom selected from the group consisting of O, S, and NR 55 , wherein R 55 is H or C 1-3 alkyl.
2. The pharmaceutical composition of claim 1 , wherein R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-8 membered bicyclic bridged heterocycle represented by:
wherein:
D is selected from the group consisting of O, S and NR 55 ;
E is (CH 2 ) r , wherein r is 1 or 2,
V is O or NR 55 , and
R 55 is H or C 1-3 alkyl.
3. The pharmaceutical composition of claim 1 , wherein R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-10 membered spirocycle having one additional heteroatom selected from O or NR 55 , wherein R 55 is H or C 1-3 alkyl.
4. A compound represented by:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising the compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
6. A method of treating a cancer in a patient in need thereof, wherein the cancer is selected from the group consisting of a leukaemia, lymphoma, solid tumour, and PTEN-negative tumour, the method comprising administering to the patient a therapeutically effective amount of a compound represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R 33 is independently selected for each occurrence from the group consisting of H, halogen, NH—C 1-3 alkyl, NH 2 , C 1-6 alkyl and —O—C 1-6 alkyl, wherein C 1-6 alkyl for each occurrence is optionally substituted by one, two or three substituents selected from halogen or hydroxyl;
R 34 is selected from H or C 1-3 alkyl; and
R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-10 membered bicyclic spirocycle or bridged heterocycle each having an additional heteroatom selected from the group consisting of O, S, and NR 55 , wherein R 55 is H or C 1-3 alkyl.
7. The method of claim 6 , wherein R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-8 membered bicyclic bridged heterocycle represented by:
wherein:
D is selected from the group consisting of O, S and NR 55 ;
E is (CH 2 ) r , wherein r is 1 or 2,
V is O or NR 55 , and
R 55 is H or C 1-3 alkyl.
8. The method of claim 6 , wherein R 44 and R 45 , when taken together with the nitrogen to which they are attached form a 7-10 membered spirocycle having one additional heteroatom selected from O or NR 55 , wherein R 55 is H or C 1-3 alkyl.
9. The method of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 6 , wherein the PTEN-negative tumor is selected from the group consisting of PTEN-negative haematological, breast, lung, endometrial, skin, brain and prostate cancers.
11. The method of claim 6 , wherein the cancer is leukaemia or lymphoma.