US 12,257,254 B2
Compositions comprising phosphoinositide 3-kinase inhibitors and a second antiproliferative agent
Stephen Joseph Shuttleworth, Oxfordshire (GB); and Andrew David Whale, Oxfordshire (GB)
Assigned to Convalife (Shanghai) Co. Limited, Shanghai (CN)
Filed by Convalife (Shanghai) Co. Limited, Shanghai (CN)
Filed on Mar. 1, 2022, as Appl. No. 17/684,020.
Application 17/684,020 is a continuation of application No. 16/855,758, filed on Apr. 22, 2020, granted, now 11,291,669.
Application 16/855,758 is a continuation of application No. 15/753,353, granted, now 10,668,077, issued on Jun. 2, 2020, previously published as PCT/GB2016/052575, filed on Aug. 19, 2016.
Claims priority of application No. 1514760 (GB), filed on Aug. 19, 2015.
Prior Publication US 2023/0066999 A1, Mar. 2, 2023
Int. Cl. A61K 31/5377 (2006.01); A61K 31/4184 (2006.01); A61K 31/51 (2006.01); A61K 31/519 (2006.01); A61K 31/5386 (2006.01); A61K 31/58 (2006.01); A61K 31/69 (2006.01); A61K 38/05 (2006.01); A61K 45/06 (2006.01); C07D 471/14 (2006.01)
CPC A61K 31/5377 (2013.01) [A61K 31/4184 (2013.01); A61K 31/519 (2013.01); A61K 31/5386 (2013.01); A61K 31/69 (2013.01); A61K 38/05 (2013.01); A61K 45/06 (2013.01)] 17 Claims
 
1. A pharmaceutical composition comprising a combination of a compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from the group consisting of O, N—H, N—(C1-C10 alkyl) and S;
each X is independently CH or N;
R1 is a 5 to 7-membered saturated or unsaturated heterocycle containing at least 1 heteroatom selected from N and O;
R2 is LY;
each L is selected from the group consisting of a direct bond, C1-C10 alkylene, C2-C10 alkenylene, and C2-C10 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 C1-C6 alkyl, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 mono alkylamino, C1-C3 bis alkylamino, C1-C3 acylamino, C1-C3 aminoalkyl, mono (C1-C3 alkyl) amino C1-C3 alkyl, bis (C1-C3 alkyl) amino C1-C3 alkyl, C1-C3-acylamino, C1-C3 alkyl sulfonylamino, acyl, halo, nitro, cyano, trifluoromethyl, carboxy, C1-C3 alkoxycarbonyl, aminocarbonyl, mono C1-C3 alkyl aminocarbonyl, bis C1-C3 alkyl aminocarbonyl, —SO3H, C1-C3 alkylsulfonyl, aminosulfonyl, mono C1-C3 alkyl aminosulfonyl, and bis C1-C3-alkyl aminosulfonyl; and
each R3 is independently selected from the group consisting of H, C1-C10 alkyl, halogen, fluoro C1-C10 alkyl, O—C1-C10 alkyl, NH—C1-C10 alkyl, S—C1-C10 alkyl, O-fluoro C1-C10 alkyl, NH-acyl, NH—C(O)—NH—C1-C10 alkyl, C(O)—NH—C1-C10 alkyl, aryl, and heteroaryl; and
at least one second agent selected from the group consisting of signal transduction pathway inhibitors, tumour immunotherapeutics, agents inhibiting the BCL2 family of proteins, agents inhibiting Mcl-1, proteasome inhibitors, aromatase inhibitors, conventional cytotoxic agents or a miscellaneous agent selected from abiraterone, ARN-509 and MYC inhibitors; wherein;
the signal transduction pathway inhibitor is a spleen tyrosine kinase (SYK) inhibitor, a BMX non-receptor tyrosine kinase inhibitor, an anaplastic lymphoma kinase (ALK) inhibitors, small molecule inhibitors of or a biological agent targeting tyrosine kinases, vascular endothelial growth factor (VEGF) inhibitors, small molecule inhibitors of the ribosomal protein S6 kinase, p-70S6K, inhibitors of mammalian target of rapamycin (mTOR), RAF kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, BCR-ABL inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, JAK-STAT signalling inhibitors or NF-KB-inducing kinase (NIK) inhibitors;
the tumour immunotherapeutic is an HDAC inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, an immunomodulator or a CTLA-4-targeted agent;
the agent inhibiting the BCL2 family of proteins is ABT-737, ABT-263, Obatoclax, Venetoclax, Sabutoclax, AT101, HA14-1 or BAM 7; and
the conventional cytotoxic agent is cisplatin, carboplatin, mitoxantrone, vincristine, vinblastine, daunorubicin, doxorubicin, chlorambucil, melphalan, paclitaxel, methotrexate, tomudex, etoposide, camptothecins, irinotecan or a DNA methylation inhibitor.