Tricyclic heterocyclic compounds as phosphoinositide 3-kinase inhibitors

1. 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 of formula I:

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 CH or N;

R 1 is a 5 to 7-membered saturated or unsaturated heterocycle containing at least 1 heteroatom selected from N or O, wherein the 5 to 7-membered heterocycle is optionally substituted up to three substituents independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, 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, halo, nitro, cyano, carboxy, C 1 -C 3 -haloalkyl, 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 and bis C 1 -C 3 -alkyl aminosulfonyl;

R 2 is LY;

each 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 selected from:

wherein:

A is selected from the group consisting of O, S, NR 4 , C 1 -C 3 alkylene, C 2 -C 3 alkenylene, and C 2 -C 3 alkynylene, wherein the C 1 -C 3 alkylene, C 2 -C 3 alkenylene, and C 2 -C 3 alkynylene are each independently optionally substituted with up to three substituents independently selected from the group of C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, 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 (e.g. fluoro), nitro, cyano, trifluoromethyl, 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 and bis C 1 -C 3 -alkyl aminosulfonyl;

W is selected from the group consisting of NR 4 , O and CH 2 ;

wherein R 4 is selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl, wherein the C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl are each independently optionally substituted with up to three substituents independently selected from the group of C 1 -C 6 alkyl, hydroxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, 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, trifluoromethyl, 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 and bis C 1 -C 3 -alkyl aminosulfonyl;

p is 1;

each m is independently selected from the group consisting of 0, 1 and 2; and

each n is independently selected from the group consisting of 1, 2 and 3;

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, 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.

2. The method according to claim 1 , wherein R 1 is represented by any of the following structures:

3. The method according to claim 1 , wherein R 1 is morpholine.

4. The method according to claim 1 , wherein W is O or S.

5. The method according to claim 1 , wherein W is O.

6. The method according to claim 1 , wherein X is CH.

7. The method according to claim 1 , wherein R 3 is H.

8. The method according to claim 1 , wherein L is C 1 -C 10 alkylene.

9. The method according to claim 1 , wherein Y contains one or two heteroatoms.

10. The method according to claim 1 , wherein A is O or C 1 -C 3 alkylene.

11. The method according to claim 1 , wherein W at Y is O or CH 2 .

12. The method according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein L is methylene.

14. The method of claim 1 , wherein Y contains two heteroatoms.

15. The method of claim 1 , wherein A is methylene.

16. The method of claim 1 , wherein W at Y is O.

17. The method of claim 1 , wherein the leukaemia is chronic myelogenous leukaemia or acute myeloid leukaemia.

18. The method of claim 1 , wherein the PTEN-negative tumor is selected from the group consisting of PTEN-negative haematological, breast, lung, endometrial, skin, brain and prostate cancers.

19. A method of treating leukaemia or lymphoma in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.