Solid dispersions of 6-chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-YL)-4-OXO-chromen-8-YL]ethoxy]pyridine-2-carboxamide

Abstract

The present invention relates to solid dispersions of Compound A, methods of making, and use thereof for the treatment of disease.

Description

[0001] SOLID DISPERSIONS OF 6-CHLORO-3-[(1R)-1-[3,6-DIMETHYL-2-(2- METHYLINDAZOL-5-YL)-4-OXO-CHROMEN-8-YL]ETHOXY]PYRIDINE-2- CARBOXAMIDE TECHNICAL FIELD [1] The present invention relates to solid dispersions of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, methods of making, and use thereof for the treatment of disease. BACKGROUND [2] The PIK3CA gene encoding the PI3K catalytic isoform p110α is the most frequently mutated gene in solid tumors and is also the most frequent site of genetic alteration within the PI3K pathway. PIK3CA mutations are most frequently found in endometrial, breast, and head and neck cancers. Approximately 40% of patients with HR+ / HER2- breast cancer harbor activating mutations in PIK3CA, which activates p110α and the PI3K / AKT / mTOR signaling network. H1047R is the most common missense mutation in PIK3CA. [3] Several PI3K-targeting agents have been tested in breast cancer patients. Approved and other investigational PI3Kα inhibitors in the clinic inhibit both wild-type (WT) and mutated PI3Kα with approximate equal potency. On-target WT PI3Kα mediated toxicity can include dose-limiting hyperglycemia as well as cutaneous and GI toxicity. [4] There is a need for PI3Kα inhibitors with improved therapeutic indices for the treatment of diseases associated with mutant PI3K, including PIK3CA-mutant cancers. There is also a need for formulations of PI3Kα inhibitors having advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. SUMMARY [5] In one aspect, provided are solid dispersions including 6-Chloro-3-[(1R)-1-[3,6-dimethyl- 2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and a pharmaceutically acceptable polymer. [6] In another aspect, provided are therapies including the solid dispersions for the treatment of disease, such as PIK3CA-mutated cancer. DETAILED DESCRIPTION [7] The compound 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide (“Compound A”), alternatively referred to as (R)-6-Chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-chromen-8- yl)ethoxy)picolinamide, is a potent and mutant-selective inhibitor of PI3Kα H1047R. [8] The present invention provides solid dispersions including Compound A and a pharmaceutically acceptable polymer. The solid dispersions may have one or more of advantageous physical stability, advantageous chemical stability, advantageous solubility, or advantageous pharmacokinetic properties. [9] In certain embodiments, the 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)- 4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide is amorphous.

[0010] In certain embodiments, the pharmaceutically acceptable polymer is selected from a cellulose ether; a cellulose ester; a polyalkylene oxide; polyvinyl alcohol; a polyacrylate or polymethacrylate; a homopolymer or copolymer of an N-vinyl lactam; polyacrylamide; a homopolymer or copolymer of a vinyl acetate; a graft copolymer of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; an oligosaccharide; and a polysaccharide; or a combination thereof.

[0011] Exemplary cellulose ethers include, but are not limited to, methyl cellulose, ethyl cellulose, (hydroxyalkyl)cellulose (e.g., hydroxyethyl cellulose (“HEC”) or hydroxypropyl cellulose (“HPC”)), and (hydroxyalkyl)alkyl-cellulose (e.g., hydroxypropylmethyl cellulose (“HPMC” or “hypromellose”)). Exemplary cellulose esters include, but are not limited to, cellulose phthalate (e.g., cellulose acetate phthalate or hypromellose phthalate (“HPMCP”)) and cellulose succinate (e.g., hypromellose succinate (“HPMCS”) or hypromellose acetate succinate (“HPMCAS”)). Cellulose polymers described herein may be further defined by a particular grade. For example, an HPMC polymer may be HPMC E3, HPMC E5, HPMC E6, HPMC E5, HPMC K3, HPMC A4, or HPMC A 15. An HPMCAS polymer may be, for example, HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LG, HPMCAS-MG, or HPMCAS-HG. An HPMCP polymer may be HPMCP 50 or HPMCP 55.

[0012] Exemplary polyalkylene oxide polymers include, but are not limited to, polyethylene oxide (also referred to as polyethylene glycol (“PEG”)) and copolymers of ethylene oxide and propylene oxide (“poloxamers”). Exemplary PEGs include, but are not limited to, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and mixtures thereof. Exemplary poloxamers include, but are not limited to, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof.

[0013] Exemplary polyacrylate or polymethacrylate polymers include, but are not limited to, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates). Suitable polyacrylate or polymethacrylate polymers include, without limitation, those sold under the Eudragit™ trademark of Rohm GmbH as Eudragit RS 100, Eudragit L 100, Eudragit L 100-55, and Eudragit S 100.

[0014] Exemplary homopolymers or copolymers of an N-vinyl lactam include, but are not limited to, polyvinylpyrrolidone (PVP or povidone) or a copolymer comprising monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl propionate. In certain embodiments, the polymer is polyvinylpyrrolidone K30. In some embodiments, the polymer is poly(1-vinylpyrrolidone-co-vinyl acetate).

[0015] Exemplary vinyl acetate polymers include, but are not limited to, copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, or partially hydrolyzed polyvinyl acetate.

[0016] Exemplary graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate include Soluplus® of BASF or equivalent product.

[0017] Exemplary oligo- or polysaccharide polymers include carrageenans, galactomannans, and xanthan gum.

[0018] In certain embodiments, the solid dispersion includes 6-Chloro-3-[(1R)-1-[3,6-dimethyl- 2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide, and a pharmaceutically acceptable polymer selected from methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate (CAP), hypromellose (HPMC), hydroxypropyl cellulose, hypromellose phthalate (HPMCP), hypromellose acetate succinate (HPMCAS), polyvinyl caprolactam-polyvinyl acetate-poly- ethylene glycol graft copolymer (e.g., Soluplus®), polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2: 0.1 (e.g., Eudragit® RS 100), methyl methacrylate copolymer (1:2) (e.g., Eudragit® S 100), polyvinyl acetate phthalate (e.g., Sureteric®), polyoxyethylene-polyoxypropylene block copolymer (e.g., Pluronic® F-68), and polyoxyethylene (20) sorbitan monooleate (e.g., Tween® 80).

[0019] The solid dispersions may include any suitable drug loading. In certain embodiments, the solid dispersion includes 5 wt% to 95 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 20 wt% to 80 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 30 wt% to 70 wt% 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 30 wt% to 50 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 30 wt% 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 29 wt% to 31 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 49 wt% to 51 wt% 6-Chloro-3-[(1R)-1- [3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 30 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 40 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion. In certain embodiments, the solid dispersion includes 50 wt% 6- Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide based on total weight of the dispersion.

[0020] The solid dispersions may include any suitable pharmaceutically acceptable polymer content. In certain embodiments, the solid dispersion includes 5 wt% to 95 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 20 wt% to 80 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 30 wt% to 70 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 50 wt% to 70 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 49 wt% to 51 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 69 wt% to 71 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 50 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 60 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion. In certain embodiments, the solid dispersion includes 70 wt% pharmaceutically acceptable polymer content based on total weight of the solid dispersion.

[0021] The solid dispersions may include any suitable weight ratio of drug load to pharmaceutically acceptable polymer. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen- 8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 5:95 to 95:5. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 25:75 to 55:45. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)- 4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 30:70 to 50:50. In certain embodiments, the solid dispersion has a weight ratio of 6- Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 29:71 to 31:69. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 49:51 to 51:49. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)- 4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 30:70. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide to pharmaceutically acceptable polymer of 40:60. In certain embodiments, the solid dispersion has a weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol- 5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer of 50:50.

[0022] The solid dispersions may include one or more pharmaceutically acceptable excipients. Exemplary pharmaceutically acceptable excipients include solubilizers, diluents, binders, disintegrants, fillers, lubricants, glidants, surfactants, stabilizers, antioxidants, colors, flavors, and preservatives.

[0023] In certain embodiments, the solid dispersions include a surfactant. Exemplary surfactants include sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS), dioctyl sodium sulfosuccinate (Docusate), dioxycholic acid sodium salt (DOSS), sorbitan monostearate, sorbitan tristearate, hexadecyltrimethyl ammonium bromide (HTAB), sodium N-lauroylsarcosine, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, ethylenediamine tetraacetic acid (EDTA), vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), lecithin, glutanic acid monosodium monohydrate, PEG 8 caprylic / capric glycerides (e.g., Labrasol®), diethylene glycol monoethyl ether (e.g., Transcutol®), polyethylene glycol / hydroxystearate (e.g., Kolliphor® HS 15), polyoxyethylene-polyoxypropylene co-polymers (e.g., Pluronics®), saturated polyoxylglycerides (e.g., Gelucirs®, such as Gelucire® 44 / 14), polyethoxylated castor oil (e.g., Kolliphor® EL), citric acid, and poloxamer (e.g, Kolliphor® P 407). In certain embodiments, the solid dispersion includes 0.1 wt% to 5 wt% surfactant, based on total weight of the solid dispersion.

[0024] In a preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS, preferably HPMCAS-H or HPMCAS-M, more preferably HPMCAS-M.

[0025] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-H in a weight ratio of 50:50 (w / w).

[0026] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-H in a weight ratio of 40:60 (w / w).

[0027] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-H in a weight ratio of 30:70 (w / w).

[0028] In another preferred embodiment, the solid dispersions include 50 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 50 wt% HPMCAS-H, based on total weight of the solid dispersion.

[0029] In another preferred embodiment, the solid dispersions include 40 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 60 wt% HPMCAS-H, based on total weight of the solid dispersion.

[0030] In another preferred embodiment, the solid dispersions include 30 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 70 wt% HPMCAS-H, based on total weight of the solid dispersion.

[0031] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-M in a weight ratio of 50:50 (w / w).

[0032] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-M in a weight ratio of 40:60 (w / w).

[0033] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and HPMCAS-M in a weight ratio of 30:70 (w / w).

[0034] In another preferred embodiment, the solid dispersions include 50 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 50 wt% HPMCAS-M, based on total weight of the solid dispersion.

[0035] In another preferred embodiment, the solid dispersions include 40 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 60 wt% HPMCAS-M, based on total weight of the solid dispersion.

[0036] In another preferred embodiment, the solid dispersions include 30 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 70 wt% HPMCAS-M, based on total weight of the solid dispersion.

[0037] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and polyvinylpyrrolidone vinyl acetate (PVP- VA).

[0038] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and PVP-VA in a weight ratio of 50:50 (w / w).

[0039] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and PVP-VA in a weight ratio of 40:60 (w / w).

[0040] In another preferred embodiment, the solid dispersions include 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide, and PVP-VA in a weight ratio of 30:70 (w / w).

[0041] In another preferred embodiment, the solid dispersions include 50 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 50 wt% PVP-VA, based on total weight of the solid dispersion.

[0042] In another preferred embodiment, the solid dispersions include 40 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 60 wt% PVP-VA, based on total weight of the solid dispersion.

[0043] In another preferred embodiment, the solid dispersions include 30 wt% 6-Chloro-3- [(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide, preferably amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, and 70 wt% PVP-VA, based on total weight of the solid dispersion. Processes

[0044] Further provided are processes to prepare solid dispersions of the present disclosure. The solid dispersions may be prepared using various techniques known to those skilled in the art. Exemplary processes for preparing solid dispersions include solvent evaporation methods (e.g., rotary evaporation, electrospraying, or spray-drying), and melt methods (e.g, hot melt extrusion). In certain embodiments, secondary drying processes may be used (e.g., fluidized bed drying or vacuum drying) to reduce residual solvent levels.

[0045] In certain embodiments, a process for preparing a solid dispersion of the present disclosure includes dissolving 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and a pharmaceutically acceptable polymer in a solvent to provide a solution, and spray-drying the solution to provide a solid dispersion. In certain embodiments, the pharmaceutically acceptable polymer is polyvinylpyrrolidone vinyl acetate (PVP-VA). In certain embodiments, the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS), preferably HPMCAS-H or HPMCAS-M, more preferably HPMCAS-M.

[0046] Useful solvents for spray-drying include any solvent that partially dissolves or completely dissolves the components to be spray dried. Suitable solvents for spray-drying include acetone, chloroform, dichloromethane, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, methyl ethyl ketone, and mixtures thereof. In certain embodiments, the solvent is acetone, dichloromethane, methanol, or a mixture thereof. Therapeutic Uses

[0047] Also provided herein are therapies including a solid dispersion of the present disclosure for the treatment of patients with a disease, including PIK3CA-mutated cancer, such as PIK3CA-mutated advanced or metastatic breast cancer, or other solid tumors with a PIK3CA mutation. A solid dispersion of the present disclosure may be used in monotherapy or in combination with one or more additional therapeutic agents. The therapies may provide new treatment options for patients, and may provide an enhanced and / or unexpected beneficial therapeutic effect in some patients over known therapies.

[0048] The efficacy of a cancer treatment can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, best overall response, disease control rate, clinical benefit rate, time to response, and quality of life. Therapeutic agents may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Novel approaches to determining efficacy of any particular mono- or combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and / or cell cycle activity, tissue-based biomarkers for angiogenesis and / or cell cycle activity, and measurement of response through radiological imaging.

[0049] In one aspect, provided is a method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0050] In another aspect, provided is a method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0051] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0052] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0053] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0054] In another aspect, provided is a method of treating a patient with CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS), comprising administering to the patient an effective amount of a solid dispersion of the present disclosure.

[0055] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0056] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of PIK3CA-mutated cancer.

[0057] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of a PIK3CA-mutated solid tumor.

[0058] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of PIK3CA-mutated breast cancer.

[0059] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0060] In another aspect, provided is a solid dispersion of the present disclosure, for use in the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0061] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0062] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer.

[0063] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor.

[0064] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer.

[0065] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0066] In another aspect, provided is the use of a solid dispersion of the present disclosure, in the manufacture of a medicament for the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0067] In certain embodiments, the PIK3CA-mutated cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0068] In certain embodiments, the PIK3CA-mutated cancer is endometrial cancer, breast cancer, oesophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ- cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0069] In certain embodiments, the PIK3CA-mutated cancer is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0070] In certain embodiments, the PIK3CA-mutated cancer is breast cancer, prostate cancer, or brain cancer. In certain embodiments, the PIK3CA-mutated cancer is breast cancer. In certain embodiments, the PIK3CA-mutated cancer is prostate cancer. In certain embodiments, the PIK3CA-mutated cancer is brain cancer.

[0071] In certain embodiments, the PIK3CA-mutated cancer is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a breast neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a thyroid neoplasm. In certain embodiments, the PIK3CA-mutated cancer is an ovarian neoplasm. In certain embodiments, the PIK3CA-mutated cancer is non-small-cell lung carcinoma. In certain embodiments, the PIK3CA-mutated cancer is an endometrial neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a pancreatic neoplasm.

[0072] In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0073] In certain embodiments, the PIK3CA-mutated solid tumor is a PIK3CA-mutated advanced solid tumor. In certain embodiments, the PIK3CA-mutated advanced solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is gynecological cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is head and neck cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is triple negative breast cancer. Pharmaceutical Compositions

[0074] Further provided are pharmaceutical compositions including the solid dispersions of the present disclosure. The pharmaceutical compositions can include one or more pharmaceutically acceptable carriers or excipients.

[0075] A solid dispersion of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.

[0076] A solid dispersion of the present disclosure may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action). Synthetic Methods

[0077] Compound A can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compound A can be synthesized by following the steps outlined in General Schemes 1-5. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. Scheme 1

[0078] Scheme 1 depicts an exemplary preparation of Compound A. Ketone (1) can be reduced to hydroxy compound (2) with a chiral catalyst such as the Noyori catalyst. Hydroxy compound (2) can undergo Mitsunobu reaction with hydroxypicolinonitrile (3) to provide heteroaryl ether (4). The nitrile of (4) can be converted to the amide (e.g., with Ghaffar- Parkins catalyst) to give Compound A.

[0002] Scheme 2 O O F Cl

[0079] Scheme 2 depicts an alternative exemplary preparation of Compound A. Ketone (1) can be reduced to hydroxy compound (5) with a chiral catalyst such as the Noyori catalyst. Hydroxy compound (5) can undergo reaction with picolinamide (6) to give Compound A.

[0003] Scheme 3

[0080] to the acyl chloride (8) with, for example, oxaylyl chloride. Addition of aryl halide (9) to acyl chloride (8) can be performed in the presence of a base (e.g., lithium bis(trimethylsilyl)amide) to give diketone (10). Acidic conditions can be used to affect cyclization of diketone (10) to chromenone (11). Bromide (11) can be acylated via palladium catalysis to generate ketone (1). Exemplary palladium catalysis conditions may include bromide (11), tributyl(1-ethoxyethenyl)stannane, and catalytic PdCl2(Ph3)2 in 1,4-dioxane. Scheme 4

[0081] . Chloropyridine (12) can be iodinated (e.g., I2, Na2CO3, H2O) to provide iodopyridine (13). Iodopyridine (13) can be converted to hydroxypicolinonitrile (3), for example, with copper cyanide in DMF. Scheme 5

[0082] Scheme 5 depicts an exemplary preparation of picolinamide (6). Acid (14) can be converted to the acyl chloride (15) with, for example, oxaylyl chloride. Acyl chloride (15) can be transformed into amide (6) with, for example, aqueous ammonia. Definitions

[0083] As used herein, the term “advanced" or "metastatic” means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.

[0084] As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.

[0085] As used herein, the term “effective amount” refers to the amount or dose of a therapeutic agent, a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment.

[0086] As used herein, the term “effective response” of a patient or a patient’s “responsiveness” to treatment with a therapeutic agent, or a pharmaceutically acceptable salt thereof, refers to the clinical or therapeutic benefit imparted to a patient upon administration of the therapeutic agent, or pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof.

[0087] As used herein, the term “in combination with” refers to the administration of a therapeutic agent, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, either separately, simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.

[0088] As used herein, the term “patient” refers to a mammal, preferably, a human.

[0089] As used herein, the terms “treating”, “to treat”, or “treatment” refer to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. Exemplary Aspects

[0090] Various aspects of the invention are set forth in the following numbered clauses.

[0091] Clause 1. A solid dispersion including 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and a pharmaceutically acceptable polymer.

[0092] Clause 2. The solid dispersion of clause 1, wherein the 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide is amorphous.

[0093] Clause 3. The solid dispersion of clause 1 or clause 2, wherein the pharmaceutically acceptable polymer is a cellulose ether; a cellulose ester; a polyalkylene oxide; polyvinyl alcohol; a polyacrylate or polymethacrylate; a homopolymer or copolymer of an N-vinyl lactam; polyacrylamide; a homopolymer or copolymer of a vinyl acetate; a graft copolymer of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate; an oligosaccharide; a polysaccharide; or a mixture thereof.

[0094] Clause 4. The solid dispersion of any one of clauses 1-3, wherein the pharmaceutically acceptable polymer is a cellulose ester.

[0095] Clause 5. The solid dispersion of any one of clauses 1-4, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS).

[0096] Clause 6. The solid dispersion of any one of clauses 1-5, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS), wherein the HPMCAS comprises 10-14% acetyl content, 4-8% succinoyl content, 22-26% methoxyl content, and 6- 10% hydroxypropoxy content (referred to as HPMCAS-H).

[0097] Clause 7. The solid dispersion of any one of clauses 1-5, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS), wherein the HPMCAS comprises 7-11% acetyl content, 10-14% succinoyl content, 21-25% methoxyl content, and 5-9% hydroxypropoxy content (referred to as HPMCAS-M).

[0098] Clause 8. The solid dispersion of any one of clauses 1-3, wherein the pharmaceutically acceptable polymer is a homopolymers or copolymers of an N-vinyl lactam.

[0099] Clause 9. The solid dispersion of any of clauses 1-3 or 8, wherein the pharmaceutically acceptable polymer is polyvinylpyrrolidone vinyl acetate (PVP-VA).

[0100] Clause 10. The solid dispersion of any one of clauses 1-9, wherein the solid dispersion includes 5 wt% to 95 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, based on total weight of the solid dispersion.

[0101] Clause 11. The solid dispersion of any one of clauses 1-10, wherein the solid dispersion includes 20 wt% to 80 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, based on total weight of the dispersion.

[0102] Clause 12. The solid dispersion of any one of clauses 1-11, wherein the solid dispersion includes 30 wt% to 70 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, based on total weight of the dispersion.

[0103] Clause 13. The solid dispersion of any one of clauses 1-12, wherein the solid dispersion includes 30 wt% to 50 wt% 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, based on total weight of the dispersion.

[0104] Clause 14. The solid dispersion of any one of clauses 1-13, wherein the solid dispersion includes 5 wt% to 95 wt% pharmaceutically acceptable polymer content, based on total weight of the solid dispersion.

[0105] Clause 15. The solid dispersion of any one of clauses 1-14, wherein the solid dispersion includes 20 wt% to 80 wt% pharmaceutically acceptable polymer content, based on total weight of the solid dispersion.

[0106] Clause 16. The solid dispersion of any one of clauses 1-15, wherein the solid dispersion includes 30 wt% to 70 wt% pharmaceutically acceptable polymer content, based on total weight of the solid dispersion.

[0107] Clause 17. The solid dispersion of any one of clauses 1-16, wherein the solid dispersion includes 50 wt% to 70 wt% pharmaceutically acceptable polymer content, based on total weight of the solid dispersion.

[0108] Clause 18. The solid dispersion of any one of clauses 1-17, wherein the weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer is 5:95 to 95:5.

[0109] Clause 19. The solid dispersion of any one of clauses 1-18, wherein the weight ratio of of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer is 30:70.

[0110] Clause 20. The solid dispersion of any one of clauses 1-19, wherein the weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer is 40:60.

[0111] Clause 21. The solid dispersion of any one of clauses 1-20, wherein the weight ratio of 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide to pharmaceutically acceptable polymer is 50:50.

[0112] Clause 22. The solid dispersion of any one of clauses 1-21, further comprising a surfactant.

[0113] Clause 23. The solid dispersion of clause 22, wherein the solid dispersion includes 0.1 wt% to 5 wt% surfactant, based on total weight of the solid dispersion.

[0114] Clause 24. A pharmaceutical composition comprising a solid dispersion of any one of clauses 1-23, and a pharmaceutically acceptable carrier.

[0115] Clause 25. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24.

[0116] Clause 26. A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24.

[0117] Clause 27. The method of clause 25 or clause 26, wherein the PI3K is PI3Kα.

[0118] Clause 28. The method of any one of clauses 25-27, wherein the PI3K has a H1047R mutation.

[0119] Clause 29. The method of any one of clauses 26-28, wherein the disease is a cancer.

[0120] Clause 30. The method of clause 29, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0121] Clause 31. The method of clause 29, wherein the cancer is breast cancer.

[0122] Clause 32. The method of clause 29, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0123] Clause 33. The method of any one of clauses 26-28, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0124] Clause 34. A method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a solid dispersion of any one of clauses 1- 23, or a pharmaceutical composition of clause 24.

[0125] Clause 35. A method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24.

[0126] Clause 36. A method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24.

[0127] Clause 37. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24.

[0128] Clause 38. The method of clause 34, wherein the PIK3CA-mutated cancer is PIK3CA H1047R-mutant cancer.

[0129] Clause 39. The method of clause 35, wherein the PIK3CA-mutated solid tumor is a PIK3CA H1047R-mutant solid tumor.

[0130] Clause 40. The method of clause 35, wherein the PIK3CA-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0131] Clause 41. The method of clause 40, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0132] Clause 42. The method of clause 40, wherein the PIK3CA-mutated solid tumor is head and neck cancer.

[0133] Clause 43. The method of clause 40, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0134] Clause 44. The method of clause 36, wherein the PIK3CA-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0135] Clause 45. The method of clause 37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

[0136] Clause 46. The method of clause 37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0137] Clause 47. The method of clause 37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0138] Clause 48. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in therapy.

[0139] Clause 49. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0140] Clause 50. The solid dispersion, or pharmaceutical composition, for use according to clause 49, wherein the PI3K is PI3Kα.

[0141] Clause 51. The solid dispersion, or pharmaceutical composition, for use according to clause 49 or clause 50, wherein the PI3K has a H1047R mutation.

[0142] Clause 52. The solid dispersion, or pharmaceutical composition, for use according to any one of clauses 49-51, wherein the disease is a cancer.

[0143] Clause 53. The solid dispersion, or pharmaceutical composition, for use according to clause 52, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0144] Clause 54. The solid dispersion, or pharmaceutical composition, for use according to clause 52, wherein the cancer is breast cancer.

[0145] Clause 55. The solid dispersion, or pharmaceutical composition, for use according to clause 52, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0146] Clause 56. The solid dispersion, or pharmaceutical composition, for use according to any one of clauses 49-51, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0147] Clause 57. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in the treatment of PIK3CA-mutated cancer.

[0148] Clause 58. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in the treatment of a PIK3CA-mutated solid tumor.

[0149] Clause 59. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in the treatment of PIK3CA-mutated breast cancer.

[0150] Clause 60. A solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0151] Clause 61. The solid dispersion or pharmaceutical composition for use according to clause 57, wherein the PIK3CA-mutated cancer is PIK3CA H1047R-mutant cancer.

[0152] Clause 62. The solid dispersion or pharmaceutical composition for use according to clause 58, wherein the PIK3CA-mutated solid tumor is a PIK3CA H1047R-mutant solid tumor.

[0153] Clause 63. The solid dispersion or pharmaceutical composition for use according to clause 58, wherein the PIK3CA-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0154] Clause 64. The solid dispersion or pharmaceutical composition for use according to clause 63, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0155] Clause 65. The solid dispersion or pharmaceutical composition for use according to clause 63, wherein the PIK3CA-mutated solid tumor is head and neck cancer.

[0156] Clause 66. The solid dispersion or pharmaceutical composition for use according to clause 63, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0157] Clause 67. The solid dispersion or pharmaceutical composition for use according to clause 59, wherein the PIK3CA-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0158] Clause 68. The solid dispersion or pharmaceutical composition for use according to clause 60, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

[0159] Clause 69. The solid dispersion or pharmaceutical composition for use according to clause 60, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0160] Clause 70. The solid dispersion or pharmaceutical composition for use according to clause 60, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0161] Clause 71. The use of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, in the manufacture of a medicament for the treatment of PIK3CA- mutated cancer.

[0162] Clause 72. The use of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor.

[0163] Clause 73. The use of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, in the manufacture of a medicament for the treatment of PIK3CA- mutated breast cancer.

[0164] Clause 74. The use of a solid dispersion of any one of clauses 1-23, or a pharmaceutical composition of clause 24, in the manufacture of a medicament for the treatment of PIK3CA- mutated, advanced or metastatic breast cancer.

[0165] Clause 75. Amorphous 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4- oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide.

[0166] Clause 76. A solid dispersion comprising amorphous 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide. Examples

[0167] Nuclear magnetic resonance (NMR) spectra are recorded at 400 MHz or 300 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (δ) are reported in parts per million (ppm). Spectra are recorded using a Bruker or Varian instrument with 8, 16 or 32 scans.

[0168] LC-MS chromatograms and spectra are recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C182.0x30 mm or Xbridge Shield RPC182.1x50 mm. Injection volumes were 0.7 – 8.0 µl and the flow rates were typically 0.8 or 1.2 ml / min. Detection methods are diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range is 100 - 1000 Da. Solvents are gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate.

[0169] Differential scanning calorimetry (DSC) analysis is conducted using a TA Q2000 DSC run by TA Thermal Advantage Software v5.2.6 and data analyzed by Universal Analysis 2000 v4.5a. Samples are equilibrated at 25 °C in crimped aluminum pans, then pierced prior to being heated to 300 °C at 10 °C / min with a 50 mL / min nitrogen purge. The temperature and heat flow is calibrated against indium melting.

[0170] Thermogravimetric analysis is collected using a TA Instruments Q5000 TGA (run by TA Thermal Advantage Software v5.2.6 and data analyzed by Universal Analysis 2000 v4.5a. Samples (3-10 mg) are heated from ambient temperature (approximately 25 °C) to 200 °C at a rate of 10 °C / min. N2 is the carrier (10 mL / min) and purge (50 mL / min) gas. Temperature is calibrated by Curie temperature determination with nickel and alumel standards. The weight calibration is performed with manufacturer-supplied standards.

[0171] Abbreviations: ACN Acetonitrile AcOH Acetic Acid ADP Adenosine diphosphate ATP Adenosine triphosphate CDCl3Chloroform-d DCM Dichloromethane DMF N,N-dimethylformamide DMSO Dimethylsulfoxide DMSO-d6Hexadeuterodimethylsulfoxide DSC Differential Scanning Calorimetry eq equivalents EtOAc Ethyl Acetate EtOH Ethanol h hour(s)1H NMR Proton nuclear magnetic resonance spectroscopy IPA Isopropanol Kg Kilograms L Liters LC-MS Liquid Chromatography – Mass Spectrometry MeOH Methanol MPa Megapascal 2-MeTHF 2-Methyltetrahydrfuran min minute(s) MS ES Mass Spectroscopy Electro Spray ppm parts per million rt room temperature SFC Supercritical Fluid Chromatography SGF Simulated Gastric Fluid SIF Simulated Intestinal Fluid THF Tetrahydrofuran TGA Thermogravimetric Analysis XRD X-ray Diffraction XRPD X-ray Powder Diffraction Example 1 (R)-6-Chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-chromen-8- yl)ethoxy)picolinamide (“Compound A”)

[0172] Preparation 1: 6-Chloro-2-iodopyridin-3-ol

[0173] 6-Chloropyridin-3-ol (1.0 kg, (10 L) were added to a 30 L reactor and stirred at 20 – 25 ℃ for 30 min. Sodium carbonate (1.64 kg, 15.44 mol) was slowly added giving a clear solution which was slowly treated with iodine (1.96 kg, 7.72 mol) at 10 – 15 ℃. After addition was complete, the reaction was allowed to stir at rt for 17 h. The pH of the reaction was adjusted to 7 with 2M aqueous HCl giving the title compound (1.75 kg, 89%) as an off-white solid that was removed by filtration and dried at 60 ℃. ESI / MS (m / z): 256 (M+H).

[0174] Preparation 1A: 6-Chloro-3-fluoropicolinoyl chloride

[0175] A solution of 6-chloro-3- g, 1.42 mol) and DMF (10.41 g, 142.4 mmol) in DCM (1.5 L) was an and treated dropwise with oxalyl chloride (361.5 g, 2.85 mol) maintaining the internal temperature below 10 ℃. After addition was complete, allowed the reaction to warm to rt and stirred for 2 h. The reaction was concentrated under reduced pressure to give the title compound (253.24 g, 91%) as a yellow semi-solid. This intermediate was used without further purification or characterization.

[0176] Preparation 2: 6-Chloro-3-hydroxypicolinonitrile

[0177] 6-Chloro-2-iodopyridin-3-ol and DMF (3.0 L) were added to a 20 L reactor and stirred at 20 – 25 ℃ for 30 min. Copper(I) cyanide (439.7 g, 4.70 mol) was slowly added and the reaction stirred at 90 – 95 ℃ for 2 h. The reaction was cooled to below 10 ℃ and poured into ice water (10 L). The mixture was stirred for 30 min and filtered. The solids were washed with 2-methyltetrahydrofuran (2 X 2 L). The filtrate was extracted with fresh 2-methyltetrahydrofuran (3 X 5 L). The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure at 35 – 40 ℃. The residue was triturated with water (5 L) at 0 – 5 ℃ for 1 hour to give the title compound (342.6 g, 57%) as a yellow solid on filtration. ESI / MS (m / z): 153 (M-H).

[0178] Preparation 2A: 6-Chloro-3-fluoropicolinamide

[0179] A solution of aqueous in an ice bath and treated portionwise with 6-chloro-3-fluoropicolinoyl chloride (250 g, 1.29 mol) maintaining the internal temperature below 15 ℃. After addition was complete, allowed the reaction to warm to rt and stirred for 0.5 h. The suspension was filtered and the solids washed with water (2X) and dried at 50 ℃ for 12 h to give the title compound (218.3 g, 97%) as an off-white solid. ESI / MS (m / z) (35Cl / 37Cl): 175 / 177 (M+H).

[0180] Preparation 3: 2-Bromo-4-methylphenyl propionate

[0181] A solution of 2-bromo-4- 53.5 mmol) in EtOAc (3.5 L) at 0 ℃ was treated with pyridine (355.25 g, . chloride (380.91 g, 4.12 mol) was added dropwise keeping the temperature below 10 ℃. The reaction was allowed to warm to 22 ℃ and stirred for 2 h. The reaction was diluted with water (1.4 L) and the organic layer separated. The organic layer was washed with saturated aqueous NaCl (2.0 L), dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound as a light yellow liquid (872.00 g, 96% yield). ESI / MS (m / z) (79Br / 81Br): 265 / 267 (M+Na).

[0182] Preparation 4: 1-(3-Bromo-2-hydroxy-5-methylphenyl)propan-1-one

[0183] A solution of L) was treated with 2-bromo-4- methylphenyl propionate (870.0 g, 3.58 mol) at 0 – 15 ℃ and maintaining the internal temperature below 10 ℃. The reaction was allowed to warm to 60 ℃ and stirred for 2 h. The reaction was cooled to 10 ℃ and poured into 8 kg of ice water. The mixture was stirred for 0.5 h and filtered. The solid was rinsed with water (1 L). The solid was slurried in water (3 L) for 30 min, filtered, and dried to give the title compound (865.0 g, 99%). ESI / MS (m / z) (79Br / 81Br): 241 / 243 (M-H).

[0184] Preparation 5: 1-(3-Bromo-2-hydroxy-5-methylphenyl)-2-methyl-3-(2-methyl-2H- indazol-5-yl)propane-1,3-dione

[0185] A solution of 1-(3-brom propan-1-one (300.0 g, 1.23 mol) in THF (2.7 L) was cooled to -78 ℃ under nitrogen protection. LiHMDS (1M in THF, 4.32 mol) was added dropwise keeping the internal temperature below -70 ℃. After 1 h, a solution of 2-methyl-2H-indazole-5-carbonyl chloride (288.21 g, 1.48 mol) in THF was added dropwise keeping the internal temperature below -78 ℃. The reaction was stirred at -78 ℃ for 1 h and then allowed to warm to rt to stir for 12 h. The reaction was cooled to 0 – 10 ℃ and quenched dropwise with glacial acetic acid (1050 mL) and water (1050 mL). The reaction was concentrated under reduced pressure to give the title compound (503.26 g, 102%) as a yellow liquid. This compound was taken to the next synthetic step without further workup or purification.

[0186] Preparation 6: 8-Bromo-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4- one O

[0187] A solution of 1-(3- -2-methyl-3-(2-methyl-2H- indazol-5-yl)propane-1,3-dione (501.0 g, 1.25 mol) in acetic acid (1.5 L) was treated with concentrated hydrochloric acid (60 mL). The reaction was stirred at 100 ℃ for 2 h. The reaction was cooled to 20 ℃, diluted with water (2505 mL), stirred for 30 min, and filtered. The solid was sequentially slurried in water (2 x 2505 mL), EtOAc (2004 mL), and ACN (1503 mL) to give the title compound (321.34 g, 67%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.09 (s, 2H), 8.01(d, 1H), 7.96-7.84(d, 1H), 7.75(s, 1H), 7.68(d, 1H), 4.31(s, 3H), 2.48(s, 3H), 2.28(s, 3H).

[0188] Preparation 7: 8-acetyl-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4-one

[0189] A solution of 8-bromo-3, -indazol-5-yl)-4H-chromen-4-one (300.0 g, 782.80 mmol), tributyl(1-ethoxyethenyl)stannane (310.98 g, 861.08 mmol), and bis(triphenylphosphine)palladium(II) dichloride (21.98 g, 31.31 mmol) in 1,4-dioxane (1.5 L) was degassed with nitrogen for 30 min and stirred at 90 ℃ for 16 h. The reaction was cooled to 20 ℃ and treated with 2 M aqueous HCl (500 mL). The resulting slurry was stirred at 20 ℃ for 30 min and filtered. The solid was dissolved in DCM / MeOH (10:1) and washed with water (1.2 L). The organic layer was removed and stirred with saturated aqueous KF for 1 h. The slurry was filtered through diatomaceous earth and the filtrate dried over MgSO4and concentrated under reduced pressure. The residue was slurried with DCM:petroleum ether (600 mL; 1:5) for 2 h and filtered to give the title compound (241.09 g, 89%) as a white solid. ESI / MS (m / z): 347 (M+H).

[0190] Preparation 8: (S)-8-(1-hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one

[0191] A solution of DBU (2.3 L) was treated slowly with formic acid (92.48 g, 2.01 mol) and 8-acetyl-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one (232.0 g, 669.79 mmol) below 30 ℃ followed by RuCl(p-cymene)[S,S-Ts- DPEN] (12.78 g, 20.09 mmol). The reaction was allowed to stir under nitrogen at 25 ℃ for 16 h. The reaction was quenched with 2M aquoues HCl (1.2 L) below 30 ℃, stirred for 15 min, and the layers separated. The organic layer was concentrated under reduced pressure and the residue slurried in ACN (300 mL) and filtered. The solid was slurried in ACN until the %ee was upgraded to >98% to give the title compound (203.16 g, 87%) as a light yellow solid. ESI / MS (m / z): 349 (M+H).

[0192] Preparation 8A: (R)-8-(1-Hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)- 4H-chromen-4-one

[0193] A 3 L 4-neck round thermocouple, addition funnel, and nitrogen inlet was 2-(2-methyl-2H-indazol-5- yl)-4H-chromen-4-one (150 g, 433 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (8.27 g, 12.99 mmol). Added chloroform (1.5 L) and stirred the mixture at 0 ℃ until fully suspended. When the temperature of the suspension was below 5 ℃, DBU (197.8 g, 194 mL, 1.30 mol) was transferred to the addition funnel and added dropwise over 30 min maintaining the internal temperature below 30 ℃. After addition was complete and the internal temperature was below 5 ℃, added formic acid dropwise (59.80 g, 49 mL, 1.30 mol) via the addition funnel maintaining the internal temperature below 30 ℃. When addition was complete, allowed the reaction to warm to rt and stir for 16 h under N2. The complete reaction was treated with 2 M aqueous HCl (750 mL) over 10 min and allowed to stir for 15 min. Stirring was stopped and the layers allowed to separate. The organic layer was transferred to a fresh vessel and concentrated under reduced pressure to 900 mL. Added 1.5 L of ACN and concentrated under reduced pressure to 900 mL (3X). Warmed the reaction to 60 ℃ and stirred for 1 h and then at rt overnight. The resulting solids were removed by filtration and the solids washed with ACN (2 x 300 mL). The solids were dried in a vacuum oven at 45 ℃ until constant weight was achieved to give the title compound (136.9 g, 91%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.36 Hz, 3H), 2.10 (s, 3H), 2.43 (s, 3H), 4.23 (s, 3H), 5.28 (br d, J=5.87 Hz, 1H), 5.38 (br s, 1H), 7.56 (d, J=8.88 Hz, 1H), 7.70 - 7.74 (m, 1H), 7.76 (s, 1H), 7.77 (d, J=8.49 Hz, 1H), 8.14 (s, 1H), 8.53 (s, 1H).

[0194] Preparation 9: (R)-6-Chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo- 4H-chromen-8-yl)ethoxy)picolinonitrile

[0004]

[0195] A solution of (S)-8-(1-hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one (200.51 g, 575.53 mmol) in THF (1.6 L) was cooled to 0 ℃ and treated with triphenylphosphine (226.43 g, 863.29 mmol) and 6-chloro-3-hydroxypicolinonitrile (97.84 g, 633.08 mmol) under nitrogen. DIAD (217.63 g, 1.08 mol) was added dropwise keeping the internal temperature below 5 ℃. The reaction was allowed to warm to 22 ℃ and stirred for 2 h. The reaction was concentrated under reduced pressure onto silica gel and eluted with 100% DCM. After concentrating under reduced pressure, the residue was slurried in MeOH (400 mL) and filtered to give the title compound (160.40 g, 57%) as a white solid. ESI / MS (m / z): 485 (M+H).

[0196] Compound A: (R)-6-chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo- 4H-chromen-8-yl)ethoxy)picolinamide

[0197] Preparation A: A solution of (R)-6-chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H-indazol- 5-yl)-4-oxo-4H-chromen-8-yl)ethoxy)picolinonitrile (120.0 g,247.46 mmol) and Ghaffar- Parkins catalyst (10.67 g, 24.75 mmol, CAS#: 173416-05-2) in EtOH (960 mL) was stirred at 80 ℃ for 16 h. The reaction was cooled to 25 ℃ and diluted with water (500 mL) and EtOAc (1 L). The organic layer was removed and the aqueous layer re-extracted with EtOAc (2 X 600 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (118.69 g, 95%) as an off-white solid. ESI / MS (m / z): 503 (M+H).

[0198] Preparation B: A 5L reactor outfitted with a Huber chiller, mechanical stirrer, temperature probe, condenser, and N2 inlet was charged with (R)-8-(1-hydroxyethyl)-3,6- dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4-one (135 g, 387.5 mmol), 6-chloro-3- fluoropicolinamide L(87.93 g, 503.7 mmol), lithium tert-butoxide (49.63 g, 620 mmol), and THF (675 mL). The reaction was stirred at 40 ℃ overnight. The reaction was allowed to cool (jacket set to 20 ℃) and when internal temperature was below 30 ℃, added water (2L) and stirred at 55 ℃ for 1 h. The jacket was set to 20 ℃ and when the internal temperature was below 25 ℃, the reaction was seeded with title compound (0.68 g, 0.5%) and allowed to stir at rt for 36 h. The resulting solids were removed by filtration and the solids washed with water (4 X 100 mL). The solid was dried at 45 ℃ until constant weight was achieved to give the title compound (167.4 g, 81%).1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (d, J=6.36 Hz, 3H), 2.10 (s, 3H), 2.40 (s, 3H), 3.35 (s, 1H), 4.23 (s, 3H), 5.98-6.05 (m, 1H), 7.36 (d, J=8.80 Hz, 1H), 7.51 (d, J=9.05 Hz, 1H), 7.58 (d, J=9.05 Hz, 1H), 7.67 (br s, 1H), 7.71 - 7.77 (m, 1H), 7.82 (s, 1H), 7.88 (br s, 1H), 8.16 (s, 1H), 8.52 (s, 1H).

[0199] Crystalline Form A: A 5 L jacketed reactor outfitted with overhead stirring, temperature probe, Huber unistat 410 dynamic temperature control system, distillation head, and nitrogen inlet was charged with (R)-6-chloro-3-(1-(3,6-dimethyl-2-(2-methyl-2H- indazol-5-yl)-4-oxo-4H-chromen-8-yl)ethoxy)picolinamide (hydrate form, 200 g, 374.98 mmol) and THF (3.0 L). The mixture was stirred at rt for 15 min and filtered through GF / F filter paper. The filtrate was added back to the reactor and the jacket set to 55 ℃. Removed solvent by distillation until volume reduced from 3.0 L to 800 mL. Added MeOH (200 mL) and re-warmed the mixture to 55 ℃. Added heptane (600 mL) over no more than 15 min and then added Form A seed crystals (1.0 g) and stirred the mixture at 55 ℃ for 3.5 h. Added heptane (1.0 L) over 1 h and aged the mixture at 55 ℃ for 1 h before slowly ramping down the temperature of the mixture to rt over 4 h. Once the slurry was at rt, allowed to age for 16 h. Filtered the slurry over PPE cloth and washed the cake with 600 mL of a mixture of THF in heptane (1:2). The cake was then washed with heptane (2 X 1.0 L) and then dried at 45 ℃ until constant weight was achieved to give the title compound (163.17 g, 86%).1H NMR (400 MHz, CDCl3) δ ppm 1.83 (d, J=6.36 Hz, 3H), 2.20 (s, 3H), 2.43 (s, 3H), 4.29 (s, 3H), 5.96 (d, J=6.48 Hz, 1H), 7.17 (d, J=1.96 Hz, 2H), 7.41 (br s, 1H), 7.48 (d, J=9.07 Hz, 1H), 7.72 (s, 1H), 7.83 (d, J=8.93 Hz, 1H), 7.92 (s, 1H), 7.99 (s, 1H), 8.10 (s, 1H). Example 2 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide Amorphous Form

[0200] A stock solution of Compound A was prepared by dissolving 25.207 mg in 1.260 mL of MeOH (~20mg / mL). The mixture was vortexed for approximately 10 seconds and bath sonicated for approximately 5 minutes until a clear solution was obtained. Dispensed 113 μL of the stock solution (2.25mg) into an 8 mL vial and immediately placed in a pre-heated vacuum oven set to 50 °C to quickly draw vacuum and flash evaporate the solvent from the sample. The sample was dried in the vacuum oven for 20 hours then removed and cooled to room temperature. The process resulted in a clear film that was visually inspected and determined to be amorphous Compound A. Example 3 Solubility Testing of Crystalline Compound A and Amorphous Compound A

[0201] Aqueous solubility was measured across a range of pH conditions (pH 1-7.5) and in simulated gastric and intestinal fluids. A small amount of material, typically 1-3 mg, was weighed into vials and weights recorded. Media was added to obtain a concentration of 2 mg / mL. Media includes water, 0.01N HCl (~pH 2), 0.1N HCl (~pH 1), pH 4.5 (USP) buffer, pH 6.0 (USP) buffer, pH 7.5 (USP) buffer, simulated gastric fluid (SGF), simulated intestinal fluid-fasted (SIF-fasted), and simulated intestinal fluid-fed (SIF-fed). The vials were tightly capped and agitated by rotating at least 180 degrees to ensure all material contacts the media. Samples agitated overnight for approximately 24 hours at ambient, room temperature conditions (23 ± 3°C). Samples were filtered through a 0.22 µm PVDF centrifugal filter. The pH of the filtrate was recorded and then analyzed by HPLC (High Performance Liquid Chromatography) to determine free base drug concentration. Table 1 Condition Equilibrium Solubility (mg / mL) 24 hrs Room Temp Compound A Compound A Amorphous Crystalline Solubility Media 0.1 N HCl (pH 1) 0.019 0.008 0.01 N HCl (pH 2) 0.016 0.003 pH 4.5 0.017 0.003 pH 6.0 0.018 0.002 pH 7.5 0.016 0.002 water 0.033 (pH=6.27) 0.003 (pH=6.68) SGF 0.065 0.058 SIF-fasted 0.174 0.008 SIF-fed 1.931 0.043 (DSC / microscopy) Amorphous Crystalline (MP=198°C)

[0202] Solubility of the amorphous form was higher in all aqueous media (pH 1-7.5) relative to the crystalline free base. In addition, solubility of the amorphous form was higher in simulated intestinal fluids (SIF-fasted and SIF-fed) relative to the crystalline free base. Example 4 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide Solid Dispersions

[0203] Preparation of solid dispersion films at 30% drug load.

[0204] Polymer stock solutions were prepared at 40mg / mL in either Acetone:MeOH (1:1) or DCM:MeOH (1:1). Dispensed 131uL of each polymer stock solution into separate 8 mL vials. A stock solution of the compound was prepared by dissolving 25.207 mg in 1.260 mL of MeOH (~20mg / mL). The mixture was vortexed for approximately 10 seconds and bath sonicated for approximately 5 minutes until a clear solution was obtained. Dispensed 113 μL of the stock solution (2.25mg) into each of the 8 mL vials containing the polymers. Samples were mixed by vortex and placed in a pre-heated vacuum oven set to 50 °C to quickly draw vacuum and flash evaporate the solvent from the sample. The samples were dried in the vacuum oven for 20 hours then removed and cooled to room temperature. The process resulted in a clear films that were visually inspected and determined to be amorphous solid dispersions.

[0205] Preparation of solid dispersion films at 50% drug load.

[0206] Polymer stock solutions were prepared at 40mg / mL in either Acetone:MeOH (1:1) or DCM:MeOH (1:1). Dispensed 56uL of each polymer stock solution (2.25mg) into separate 8 mL vials. A 20 mg / mL stock solution of the compound was prepared by dissolving 31.531 mg in 1.577 mL of DCM:MeOH (1:1). The mixture was vortexed for approximately 10 seconds and bath sonicated for approximately 5 minutes until a clear solution was obtained. Dispensed 113 μL of the stock solution (2.25mg) into the 8 mL vial containing the polymer. Samples were mixed by vortex and placed in a pre-heated vacuum oven set to 50 °C to quickly draw vacuum and flash evaporate the solvent from the sample. The samples were dried in the vacuum oven for 20 hours then removed and cooled to room temperature. The process resulted in a clear films that were visually inspected and determined to be amorphous solid dispersions. Solubility Study of Solid Dispersions

[0207] Gastric Phase: Placed vials into a Vortemp mixer at 37 °C and allowed to equilibrate for approximately 10 - 15 minutes. Added 1.5 mL of 0.001N HCl (warmed to ~37 °C) to the samples. The samples were briefly vortex-mixed externally. After 15 minutes, 170 μL was removed via pipette and filtered through a 0.22 μm centrifuge filter, with centrifuge set to 37 °C at 10,000 RPM. Sampled 100 μL of filtrate and diluted with 400 μL of (MeOH) directly into vials for HPLC analysis.

[0208] Intestinal Phase: After 20 minutes, exactly 3.0 mL of SIF-Fasted was then added to the vials. Samples were thoroughly vortex mixed. Time points were then sampled at 15, 30, 60, and 120 minutes after dilution with SIF-fasted. At each time point ~200 μL of sample was filtered through 0.22 μm centrifuge filter at 37°C.100 μL of filtrate was sampled and diluted with 400 μL of (MeOH) directly into vials for HPLC analysis. Table 2 Phase Timepoint API Concentration (mg / mL) (min)PVP- HPMC- Soluplus HPMC- HPMC- HPMC- Amorphous VA CP15 AS-L AS-M AS-H -5 0.052 0.030 0.021 0.017 0.015 0.014 0.023 cirtsaG 15 0.082 0.059 0.024 0.024 0.018 0.022 0.030 lani30 0.089 0.065 0.028 0.072 0.028 0.027 0.040 tsetn 60 0.090 0.056 0.039 0.072 0.075 0.051 0.059 I 120 0.091 0.062 0.051 0.061 0.059 0.071 0.071 Example 5 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide PVP-VA Solid Dispersion

[0209] Preparation of a Compound A PVP-VA spray dried dispersion was performed by weighing 30.00g Compound A into a bottle and then diluting with 550mL of Acetone / MeOH / DCM at a ratio of 2.5 / 2.5 / 1 (v / v) and mixed until completely dissolved (50mg / mL). Next, added PVP-VA (30.00g) to the bottle and mixed until completely dissolved resulting in 50% (w / w) drug load spray solution. Spray solution was sprayed in a Buchi 290 spray dryer with the following parameters: Inlet temp: 110°C; Aspiration %: 100; Pump %: 50; Outlet Temp.72°C.

[0210] Material spray dried in approximately 1 hour with 56.3g solids recovered (93.8% yield) before vacuum drying. After vacuum drying at 50°C for 3 hours the final material amount was 55.3g (92.2% yield). The spray dried dispersion material was amorphous with particles in the range of 5-50um based on polarized light microscopy. The material was analyzed by HPLC and the result was 49.4% Compound A. Example 6 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide HPMCAS-M Solid Dispersion

[0211] Preparation of a Compound A HPMCAS-MG solid dispersion was performed by mixing 6.75g acetone and 6.75g methanol. 0.5g HPMCAS-MG was added and stirred until dissolved in the acetone: methanol mixture. 0.5g 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide was added to the mixture and stirred until dissolved. The solution was spray-dried with an SD-5 spray dryer at a rate of 1ml / min at inlet temperature of 71°C and exhaust temperature between 23 to 27°C. Gas pressure was controlled at 50psi. The collected spray-dried dispersion was dried in a high-vacuum oven overnight at 40°C.

[0212] The parameters used in the spray drying process are defined below. Table 3 Parameter Spray Dry Dispersion Formulation 50:50 Compound A / HPMCAS-MG Solvent 50:50 acetone: methanol Solids Loading (%) 6.89 Nozzle 1 / 4J-Spraying systems Solution Flow Rate 1 ml / min Gas Pressure (psig) 50 Inlet Temp. ˚C 71 Outlet Temp. ˚C 23 – 27 Wet Yield (%) 70 Secondary Dryer High-Vacuum Dryer Secondary Drying Conditions 40C / 12 hours Dry Yield (%) 66 Example 7 PI3K-Alpha kinase (PIK3CA) activity in vitro cell based assay

[0213] PI3K-Alpha kinase (PI3Kα) activity: wild-type PI3Kα, H1047R mutant PI3Kα, and E545K mutant PI3Kα in vitro cell based assays and determination of IC50 values for inhibitors.

[0214] The MDA-MB-453 (ATCC-HTB-131) cell line (PI3Kα H1047R) and MCF-7 (ATCC- HTB-22) cell line (PI3Kα E545K), MDA-MB-361 (ATCC-HTB-27) cell line (PI3Kα E545K), and SKBR3 (ATCC-HTB-30) cell line (wild type PI3Kα) were obtained from the American Type Culture Collection (Manassas, VA). MDA-MB-453 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), 1X non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and 1X Anti-Anti (Gibco 15240). MCF-7 cells were maintained in Minimum Essential Media (MEM) (Gibco 11095) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), 1X non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360), 1X Anti-Anti (Gibco 15240) and 10 µg / mL human insulin (Sigma I 9278). MDA-MB-361 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 20% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), 1X non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and 1X Anti-Anti (Gibco 15240). SKBR3 cells were maintained in McCoy’s 5A (Gibco 16600) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), and 1X Anti-Anti (Gibco 15240). Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0215] For compound testing in 0% FBS, MDA-MB-453, MCF-7 and SKBR3 cells were seeded at a density of 1.5×104, 1.0×104, and 1.0×104cells, respectively, per well in white 384- well plates in 20 µl of Minimum Essential Media (MEM) assay media with 1X NEAA, 1 mM sodium pyruvate, and 1 µg / mL human insulin (Sigma I9278) (Assay Medium); while MDA- MB-361 cells were seeded at a density of 1.5×104per well in white 384-well plates in 20 µl Assay Medium without insulin. After plating, cells were allowed to attach overnight. Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte). A 5X intermediate compound dilution plate in MEM with 1X NEAA and 1 mM sodium pyruvate (150 µM starting compound concentration in 1.5% DMSO) was then prepared. Five µl of the intermediate serially diluted compounds were added to the cell plate to final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO.0.3% DMSO alone was used to establish the maximum (MAX) signal and GDC-0032 at a final concentration of 1 µM was used as a reference compound for the minimum (MIN) signal. After 3 hours treatment, the medium was removed, and the cells were lysed in 10 µL of 1X SureFire Lysis buffer with shaking for 10 minutes at room temperature. The Acceptor Mix (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Acceptor Beads) was prepared by diluting Activation buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2. The Acceptor beads were diluted 50-fold in the combined Reaction Buffers. Five µL of Acceptor Mix was added to each well, the plate was sealed and covered with foil and incubated for 1 hour at room temperature. The Donor Mix (dilution buffer + SureFire Ultra Donor Beads) was prepared by diluting Donor Beads 50-fold in dilution buffer. Five µL of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1-2 hours at room temperature in the dark. The plates were read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings.

[0216] Compounds were tested in duplicate and the % inhibition at each compound concentration was used to generate two dose response curves. One IC50 was generated using average % inhibition at each compound concentration. The data were processed using the Genedata-Screener tool. Relative IC50values were determined using luminescence units by calculating percent inhibition with respect to the in-plate “MIN” (GDC-0032 reference control) and “MAX” (DMSO) controls. The data was analyzed using a 4-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve): Y = bottom + [(top - bottom) / 1+(X / IC50)slope], where Y = % inhibition, X = concentration of inhibitor, bottom = minimum value of y attained by curve-fit, top = maximum value of y attained by curve-fit and slope = steepness of curve at the IC50. % Inhibition = [(signal at X – median Min) / (median Max – median Min)] x 100 IC50: concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%. Relative IC50: concentration giving half the compound’s maximum response.

[0217] Compound selectivity was calculated by dividing IC50in SKBR3 by IC50in cell lines harboring mutant PI3Kα (MDA-MB-453: H1047R; MCF-7 and MDA-MB-361: E545K).

[0218] Compound A exhibited an IC50 value of 27.3 nM for the PI3Kα H1047R mutant.

[0219] Compound A exhibited 19.2 × fold-selectivity for PI3K-Alpha kinase H1047R mutant versus wild-type.

[0220] Compound A exhibited an IC50 value of 194.4 nM for the MDA-MB-361 PI3Kα E545K mutant.

Claims

WE CLAIM:

1. A solid dispersion comprising 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and a pharmaceutically acceptable polymer.

2. The solid dispersion of claim 1, wherein the 6-Chloro-3-[(1R)-1-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide is amorphous.

3. The solid dispersion of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer is hypromellose acetate succinate (HPMCAS).

4. The solid dispersion of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer is polyvinylpyrrolidone vinyl acetate (PVP-VA).

5. The solid dispersion of any one of claims 1-4, wherein the 6-Chloro-3-[(1R)-1-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and the pharmaceutically acceptable polymer are present in a weight ratio of 50:50 (w / w).

6. A pharmaceutical composition comprising a solid dispersion of any one of claims 1-5, and a pharmaceutically acceptable carrier.

7. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a solid dispersion of any one of claims 1-5, or a pharmaceutical composition of claim 6.

8. A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a solid dispersion of any one of claims 1-5, or a pharmaceuticalcomposition of claim 6.

9. The method of claim 7 or claim 8, wherein the PI3K is PI3Kα.

10. The method of any one of claims 7-9, wherein the PI3K has a H1047R mutation.

11. The method of any one of claims 8-10, wherein the disease is a cancer.

12. The method of claim 11, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

13. The method of claim 11, wherein the cancer is breast cancer.

14. The method of claim 11, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

15. A solid dispersion of any one of claims 1-5, or a pharmaceutical composition of claim 6, for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

16. The solid dispersion for use according to claim 15, wherein the PI3K is PI3Kα.

17. The solid dispersion for use according to claim 15 or 16, wherein the PI3K has a H1047R mutation.

18. The solid dispersion for use according to any one of claims 15-17, wherein the disease is a cancer.

19. The solid dispersion for use according to claim 18, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lungcancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

20. The solid dispersion for use according to claim 18, wherein the cancer is breast cancer.

21. The solid dispersion for use according to claim 18, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

Images