Compositions comprising phosphoinositide 3-kinase inhibitors and a second antiproliferative agent

1. A pharmaceutical composition comprising a combination 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 and O;

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 a fused, bridged or spirocyclic non-aromatic 5-12 membered heterocycle containing up to 4 heteroatoms selected from N or O;

wherein any aforementioned heterocycle may be optionally substituted with up to three substituents 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, 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; 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, 0-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; and

at least one second agent selected from the group consisting of poly (ADP-ribose) polymerase (PARP) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, anti-PD-1 agents, and anti-PD-L1 agents.

2. The pharmaceutical composition of claim 1 , wherein R 1 is represented by any of the following structures:

3. The pharmaceutical composition of claim 1 , wherein R 1 is morpholine.

4. The pharmaceutical composition of claim 1 , wherein W is O or S.

5. The pharmaceutical composition of claim 1 , wherein W is O.

6. The pharmaceutical composition of claim 1 , wherein X is CH.

7. The pharmaceutical composition of claim 1 , wherein R 3 is H.

8. The pharmaceutical composition of claim 1 , wherein L is C 1 -C 10 alkylene.

9. The pharmaceutical composition of claim 1 , wherein Y contains one or two heteroatoms.

10. The pharmaceutical composition of claim 1 , wherein 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;

B 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 aforementioned C 1 -C 3 alkylene, C 2 -C 3 alkenylene, C 2 -C 3 alkynylene, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl may be optionally substituted with up to three substituents 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, 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 selected from 0 and 1;

each m is independently selected from 0, 1, and 2; and

each n is independently selected from 1, 2, and 3.

11. The pharmaceutical composition of claim 10 , wherein A is O or C 1 -C 3 alkylene.

12. The pharmaceutical composition of claim 10 , wherein B is O or CH 2 .

13. The pharmaceutical composition of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 1 , wherein the poly (ADP-ribose) polymerase (PARP) inhibitors are selected from the group consisting of Olaparib, Veliparib, Rucaparib, lnipararib, Talazoparib, G007-LK, NU1025, AG-14361, INO-1001, UPF-1069, AZD-2461, PJ34, ME0328, and A-966492.

15. The pharmaceutical composition of claim 1 , wherein the Bruton's tyrosine kinase (BTK) inhibitors are selected from the group consisting of Ibrutinib, CC-292, CNX-774, CGI1746, LFM-A13, and RN486.

16. The pharmaceutical composition of claim 1 , wherein the anti-PD-1 agents are selected from the group consisting of Pembrolizumab, Nivolumab, Pidilizumab, and AMP-224.

17. The pharmaceutical composition of claim 1 , wherein the anti-PD-L1 agents are selected from the group consisting of MSB0010718C, Atezolizumab, MEDI4736, and MPDL3280A.