Phosphoinositide 3-kinase (PI3K) allosteric chromone inhibitors for treatment of disease

Abstract

The present invention relates to Compounds (A), pharmaceutically acceptable salts thereof, processes for their preparation and their use, optionally in combination with one or more additional therapeutic agents, for the treatment of disease. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Applications 63 / 421,716 (filed November 2, 2022, Attorney Docket No. 30461_US_PRI), 63 / 382,999 (filed November 9, 2022, Attorney Docket No. 30461A_US_PRI), 63 / 383,206 (filed November 10, 2022, Attorney Docket No. 30461B_US_PRI), and 63 / 488,875 (filed March 7, 2023, Attorney Docket No. 30461C_US_PRI); the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid ("Compound A"), its pharmaceutically acceptable salts, and its use, optionally in combination with one or more additional therapeutic agents, for treating diseases.

[0004] background

[0005] The PIK3CA gene, encoding the catalytic isoform of phosphoinositide 3-kinase (PI3K), p110α, is the most commonly mutated gene in solid tumors and the most common genetic variant in the PI3K pathway. PIK3CA mutations are most commonly found in endometrial, breast, and head and neck cancers. Approximately 40% of patients with HR+ / HER2- breast cancer harbor activating PIK3CA mutations, which activate p110α and the PI3K / AKT / mTOR signaling network. H1047R is the most common missense mutation in PIK3CA.

[0006] Activating mutations in PIK3CA are associated with resistance to endocrine therapy and disease progression. Emerging driver mutations in PIK3CA may also represent a mechanism of resistance to CDK4 / 6 inhibitors. In preclinical models, paclitaxel resistance has also been associated with activation of the PI3K / mTOR pathway.

[0007] Several PI3K-targeted agents have been tested in patients with breast cancer. In a randomized phase III clinical trial (SOLAR-1; NCT02437318), the PI3Kα-specific inhibitor alpelisib combined with fulvestrant increased progression-free survival to 11.0 months, compared with 5.7 months with fulvestrant alone, leading to the FDA approval of alpelisib combined with fulvestrant for the treatment of patients with HR+ / HER2-PIK3CA-mutated advanced or metastatic breast cancer. While this approval represents a major therapeutic advance for PIK3CA-mutated breast cancer, alpelisib, along with other investigational PI3Kα inhibitors, inhibits both wild-type (WT) and mutant PI3Kα with approximately equal potency. As a result, their efficacy may be limited by toxicities mediated by targeting WT PI3Kα, including dose-limiting hyperglycemia and skin and GI toxicities, which has, to some extent, limited the widespread clinical application of PI3Kα inhibitors. For example, in the SOLAR-1 trial, adverse events that occurred in at least 35% of participants in the alpelisib / fulvestrant group or the placebo / fulvestrant group, respectively, included hyperglycemia (63.7% vs 9.8%), diarrhea (57.7% vs 15.7%), nausea (44.7% vs 22.3%), decreased appetite (35.6% vs 10.5%), and rash (35.6% vs 5.9%) (André F, Ciruelos E, Rubovszky G, et al., SOLAR-1 Study Group, Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer, N Engl J Med, 2019 May 16;380(20):1929-1940). In addition, hyperglycemia and rash were the most common adverse events leading to discontinuation of alpelisib. The proportion of participants who discontinued apellisin and placebo due to adverse events was 25.0% and 4.2%, respectively (Andre et al. 2019).

[0008] There is a need for PI3Kα inhibitors with improved therapeutic index and combination therapies including such PI3Kα inhibitors for the treatment of diseases associated with mutant PI3K, including PIK3CA mutant cancers. There is also a need for PI3Kα inhibitors and combination therapies that overcome resistance to approved therapies. There is also a need for doses and dosing regimens that achieve effective disease treatment, maximize patient compliance, convenience, and tolerability, while limiting dose interruptions and discontinuations, and minimize the risk of adverse events (e.g., hyperglycemia, diarrhea, nausea, decreased appetite, and rash). There is also a need for solid forms of PI3Kα inhibitors with favorable physical stability, chemical stability, solubility, or pharmacokinetic properties. SUMMARY OF THE INVENTION

[0010] In one aspect, a solid form of Compound A is provided.

[0011] In another aspect, provided are pharmaceutically acceptable salts of Compound A and solid forms thereof.

[0012] In another aspect, provided is a therapy comprising Compound A or a pharmaceutically acceptable salt thereof for treating a disease, such as a PIK3CA mutant cancer.

[0013] In another aspect, provided are dosages and dosing regimens comprising Compound A or a pharmaceutically acceptable salt thereof for treating a disease, such as a PIK3CA mutant cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is an XRPD pattern of crystalline Compound A Form A.

[0016] Figure 2 is the XRPD spectrum of crystalline Compound A Form B.

[0017] Figure 3 is an XRPD pattern of crystalline Compound A Form C.

[0018] Figure 4 is an XRPD pattern of crystalline Compound A tromethamine salt Form A.

[0019] Figure 5 is an XRPD pattern of crystalline Compound A tromethamine salt Form C.

[0020] Figure 6 is an XRPD pattern of crystalline Compound A tromethamine salt Form D.

[0021] Figure 7 is the XRPD spectrum of the crystalline erbumine salt of Compound A.

[0022] Detailed description

[0023] Compound 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid ("Compound A") is a potent and mutation-selective PI3Kα H1047R inhibitor.

[0024]

[0025] In one aspect, provided herein is a solid form of Compound A.

[0026] Compound A Form A

[0027] In one aspect, provided is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form A, also referred to as Compound A Form A. In one embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.8°±0.2°, 12.1°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 24.1°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2°, in combination with at least one peak selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2°, in combination with at least two peaks selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2°, in combination with at least three peaks selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2°, in combination with peaks at 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angles 2-θ of 7.8°±0.2°, 12.1°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 24.1°±0.2°.

[0028] Compound A Form B

[0029] In another aspect, provided is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form B, also referred to as Compound A Form B. In one embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2°, and 17.4°±0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7°±0.2°, in combination with at least one peak selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2°, and 7.0°±0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7°±0.2°, in combination with at least two peaks selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2°, and 7.0°±0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7°±0.2°, in combination with at least three peaks selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2°, and 7.0°±0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2°, and 17.4°±0.2°.

[0030] Compound A Form C

[0031] In another aspect, provided is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form C, also referred to as Compound A Form C. In one embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 13.4°±0.2°, in combination with at least one peak selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2°, and 7.4°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 13.4°±0.2°, in combination with at least two peaks selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2°, and 7.4°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4°±0.2°, in combination with at least three peaks selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2°, and 7.4°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2°.

[0032] In another aspect, provided herein are tromethamine salts of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain tromethamine salts of Compound A may have favorable physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain tromethamine salts of Compound A may have processability or other manufacturing advantages. Certain tromethamine salts of Compound A may provide enhanced chirality of Compound A upon crystallization of the tromethamine salt.

[0033] Compound A Tromethamine Salt Form A

[0034] In another aspect, a crystalline tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, designated Compound A tromethamine Salt Form A. In one embodiment, Compound A tromethamine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°. In another embodiment, Compound A tromethamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least one peak selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°. In another embodiment, Compound A tromethamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least two peaks selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°. In another embodiment, Compound A tromethamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least three peaks selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°. In another embodiment, Compound A tromethamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with peaks at 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°. In another embodiment, Compound A tromethamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has peaks at diffraction angles 2-θ of 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

[0035] In another embodiment, Compound A tromethamine salt Form A is prepared by13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm). In another embodiment, Compound A tromethamine salt Form A is prepared by 13 C solid-state NMR (100.6 MHz) spectrum characterized by at least one peak selected from the group consisting of 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm, respectively) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A tromethamine salt Form A is prepared by 13 The sample was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks referenced to glycine (external reference at 176.5 ppm) at 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

[0036] Compound A Tromethamine Salt Form C

[0037] In another aspect, provided is a crystalline tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid, designated Compound A tromethamine Salt Form C. In one embodiment, Compound A tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°. In another embodiment, Compound A tromethamine salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 15.9°±0.2°, in combination with at least one peak selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°. In another embodiment, Compound A tromethamine salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 15.9°±0.2°, in combination with at least two peaks selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°. In another embodiment, Compound A tromethamine salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 15.9°±0.2°, in combination with at least three peaks selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°. In one embodiment, Compound A tromethamine salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks with diffraction angles 2-θ of 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°.

[0038] Compound A Tromethamine Salt Form D

[0039] In another aspect, provided is a crystalline tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid, designated Compound A tromethamine Salt Form D. In one embodiment, Compound A tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°. In another embodiment, Compound A tromethamine salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least one peak selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°. In another embodiment, Compound A tromethamine salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least two peaks selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°. In another embodiment, Compound A tromethamine salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least three peaks selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°. In one embodiment, Compound A tromethamine salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks with diffraction angles 2-θ of 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°.

[0040] In another aspect, provided herein are tert-butylamine salts of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain tert-butylamine salts of Compound A may have favorable physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain tert-butylamine salts of Compound A may have processability or other manufacturing advantages.

[0041] Compound A tert-butylamine salt form A

[0042] In another aspect, a crystalline tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, referred to as Compound A tert-butylamine Salt Form A. In one embodiment, Compound A tert-butylamine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.5°±0.2°, 10.5°±0.2°, 11.1°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 21.5°±0.2°, 22.2°±0.2°, 22.7°±0.2°, and 26.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least one peak selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least two peaks selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least three peaks selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak with a diffraction angle 2-θ of 11.1°±0.2°, in combination with peaks 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°. In one embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has peaks at diffraction angles 2-θ of 66.5°±0.2°, 10.5°±0.2°, 11.1°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 21.5°±0.2°, 22.2°±0.2°, 22.7°±0.2°, and 26.3°±0.2°.

[0043] In another embodiment, Compound A tert-butylamine salt Form A is prepared by 13 C solid-state NMR (100.6 MHz) spectrum characterized by at least one peak selected from the group consisting of 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm). In another embodiment, Compound A tert-butylamine salt Form A is prepared by 13 C solid-state NMR (100.6 MHz) spectrum characterized by at least one peak selected from 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (±0.2 ppm, respectively) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A tert-butylamine salt Form A is prepared by 13 The sample was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks referenced to glycine (external reference at 176.5 ppm) at 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm).

[0044] Therapeutic uses

[0045] Also provided herein are therapies comprising Compound A or a pharmaceutically acceptable salt thereof for treating patients with PIK3CA mutant cancers (e.g., advanced or metastatic breast cancer with PIK3CA mutations) or other solid tumors with PIK3CA mutations. Compound A or a pharmaceutically acceptable salt thereof can be used in monotherapy or in combination with one or more additional therapeutic agents. These therapies can provide new treatment options for patients and may provide enhanced and / or unexpected beneficial therapeutic effects that are superior to known therapies in certain patients.

[0046] The efficacy of cancer treatment can be measured by various common endpoints used to evaluate cancer treatment, including but not limited to tumor regression, reduction in tumor weight or size, 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 can result in inhibition of metastatic spread without shrinking the primary tumor, can induce shrinkage of the primary tumor, or can simply exert a tumor suppressive effect. Novel methods for determining the efficacy of any specific monotherapy or combination therapy of the present invention can optionally be employed, including, for example, measuring plasma or urine markers of angiogenesis and / or cell cycle activity, tissue-based biomarkers of angiogenesis and / or cell cycle activity, and measuring response by radiographic imaging.

[0047] In one aspect, provided is a method of treating a patient suffering from a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0048] In another aspect, provided is a method of treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, provided is a method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0050] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0051] In another aspect, provided is a method for treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0052] In another aspect, a method for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, a method is provided for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer previously treated with endocrine therapy, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0054] On the other hand, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents. In some embodiments, the combination of an effective amount of Compound A or a pharmaceutically acceptable salt thereof and an effective amount of one or more therapeutic agents can provide an additive or synergistic effect in the treatment of PIK3CA mutant cancer. In some embodiments, the effective amount of one or more therapeutic agents (e.g., taxanes, such as paclitaxel) in the combination therapy may be lower than the effective amount of the agent in the treatment of PIK3CA mutant cancer when Compound A or a pharmaceutically acceptable salt thereof is not administered in combination with one or more agents.

[0055] In another aspect, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of the following drugs: a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an anti-androgen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof.

[0056] In another aspect, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0057] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, a method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0060] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0061] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0062] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0063] In another aspect, a method for treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0064] In another aspect, a method for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of Fulvestrant.

[0065] On the other hand, a method for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer previously treated with endocrine therapy is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of Fulvestrant.

[0066] On the other hand, a method for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of imlunestrant.

[0067] In another aspect, a method is provided for treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer previously treated with endocrine therapy, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of imrustatin.

[0068] In another aspect, a method for treating a patient having a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, a method for treating a patient having a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0070] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0071] In another aspect, a method for treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0072] In another aspect, a method of treating a patient having a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, a method for treating a patient having a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0074] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0075] In another aspect, a method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0076] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0077] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0078] In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0079] In another aspect, a method for treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0080] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0081] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0082] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0083] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0084] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a platinum agent.

[0085] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a platinum agent.

[0086] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.

[0087] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.

[0088] In another aspect, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0089] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0090] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.

[0091] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.

[0092] In another aspect, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0093] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0094] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.

[0095] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.

[0096] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.

[0097] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.

[0098] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0099] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0100] In another aspect, a method of treating a patient having a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a SERD, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0101] In another aspect, a method for treating a patient having a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0102] In another aspect, a method for treating a patient having a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0103] In another aspect, a method for treating a patient having a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0104] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0105] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0106] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERM or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERM or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0109] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0110] In another aspect, a method of treating a patient having a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0111] In another aspect, a method for treating a patient having a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0112] In another aspect, a method of treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0113] In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0114] In another aspect, a method of treating a patient suffering from CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS) is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0115] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0116] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating PIK3CA mutant cancer.

[0117] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating PIK3CA mutant solid tumors.

[0118] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating PIK3CA mutant breast cancer.

[0119] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating PIK3CA-mutated, advanced or metastatic breast cancer.

[0120] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer.

[0121] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer previously treated with endocrine therapy.

[0122] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination, simultaneously, separately or sequentially, with the following drugs for the treatment of PIK3CA mutant cancer: CDK4 and 6 inhibitors or pharmaceutically acceptable salts thereof; SERDs or pharmaceutically acceptable salts thereof; aromatase inhibitors or pharmaceutically acceptable salts thereof; taxanes or pharmaceutically acceptable salts thereof; mTOR inhibitors or pharmaceutically acceptable salts thereof; tyrosine kinase inhibitors or pharmaceutically acceptable salts thereof; platinum agents; anthracyclines or pharmaceutically acceptable salts thereof; immune checkpoint inhibitors or pharmaceutically acceptable salts thereof; anti-androgens or pharmaceutically acceptable salts thereof; anti-HER2 monoclonal antibodies; anti-HER2 antibody-drug conjugates; KRAS inhibitors or pharmaceutically acceptable salts thereof; MEK inhibitors or pharmaceutically acceptable salts thereof; ERK inhibitors or pharmaceutically acceptable salts thereof; topoisomerase inhibitors or pharmaceutically acceptable salts thereof; SERMs or pharmaceutically acceptable salts thereof; or PARP inhibitors or pharmaceutically acceptable salts thereof; or a combination thereof;

[0123] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancers simultaneously, separately or sequentially.

[0124] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0125] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant breast cancer.

[0126] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0127] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0128] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0129] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant breast cancer.

[0130] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0131] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with fulvestrant for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CAH1047R mutated, advanced or metastatic breast cancer.

[0132] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with fulvestrant for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation, advanced or metastatic breast cancer previously treated with endocrine therapy.

[0133] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with imrusetran for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0134] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use simultaneously, separately or sequentially in combination with imrusetran for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer previously treated with endocrine therapy.

[0135] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0136] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0137] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant breast cancer.

[0138] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0139] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0140] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0141] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant breast cancer.

[0142] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0143] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for the treatment of PIK3CA mutant cancer.

[0144] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0145] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0146] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0147] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0148] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0149] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0150] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0151] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a platinum agent, simultaneously, separately or sequentially, in the treatment of PIK3CA mutant cancer.

[0152] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a platinum agent simultaneously, separately or sequentially in the treatment of PIK3CA mutant solid tumors.

[0153] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with an anthracycline or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0154] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an anthracycline or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0155] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0156] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0157] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate in the treatment of PIK3CA mutant cancer.

[0158] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate in the treatment of PIK3CA mutant solid tumors.

[0159] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially, in the treatment of PIK3CA mutant cancer.

[0160] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0161] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0162] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0163] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0164] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0165] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0166] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0167] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0168] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0169] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially, in the treatment of PIK3CA mutant cancer.

[0170] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0171] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0172] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a SERM or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0173] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the treatment of PIK3CA mutant cancer.

[0174] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0175] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a platinum agent and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0176] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with (i) a platinum agent and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0177] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant cancer.

[0178] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0179] In another aspect, provided is Compound A or a pharmaceutically acceptable salt thereof for use in treating CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

[0180] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0181] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer.

[0182] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors.

[0183] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer.

[0184] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer.

[0185] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0186] In another aspect, provided is the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer previously treated with endocrine therapy.

[0187] In another aspect, provided is the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is used in combination with the following simultaneously, separately or sequentially: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an anti-androgen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof.

[0188] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0189] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0190] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0191] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0192] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0193] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.

[0194] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.

[0195] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.

[0196] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with Fulvestrant.

[0197] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with fulvestrant simultaneously, separately or sequentially.

[0198] On the other hand, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with imrusetran.

[0199] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is to be administered simultaneously, separately or sequentially in combination with imrusetran.

[0200] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.

[0201] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.

[0202] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.

[0203] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.

[0204] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0205] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0206] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0207] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0208] In another aspect, provided is a use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0209] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0210] In another aspect, provided is a use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0211] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0212] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0213] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0214] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0215] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0216] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a platinum agent simultaneously, separately or sequentially.

[0217] In another aspect, provided is a use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a platinum agent.

[0218] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with anthracyclines or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0219] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with anthracyclines or a pharmaceutically acceptable salt thereof.

[0220] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0221] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0222] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0223] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0224] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0225] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0226] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0227] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0228] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0229] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0230] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0231] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0232] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0233] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0234] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0235] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0236] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0237] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a SERM or a pharmaceutically acceptable salt thereof.

[0238] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0239] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0240] In another aspect, provided is the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0241] In another aspect, provided is the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0242] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0243] In another aspect, provided is the use of Compound A or a pharmaceutical salt thereof in the preparation of a medicament for treating PIK3CA mutant solid tumors, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.

[0244] In another aspect, provided is the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

[0245] In one embodiment, the PIK3CA mutant cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary site, cardiac (heart) tumor, atypical teratoma Rhabdoid tumor, primary CNS lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma sarcoma), extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, 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 alterations, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, myelodysplastic syndrome, myelodysplastic neoplasms, myeloproliferative neoplasms neoplasm), chronic myeloproliferative neoplasms, nasal cavity and paranasal sinus cancercancer), 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 neoplasms, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma tumors, 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 carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0246] In one embodiment, the PIK3CA mutant cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, 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.

[0247] In one embodiment, the PIK3CA mutant 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.

[0248] In one embodiment, the PIK3CA mutant cancer is breast cancer, prostate cancer, or brain cancer. In one embodiment, the PIK3CA mutant cancer is breast cancer. In one embodiment, the PIK3CA mutant cancer is prostate cancer. In one embodiment, the PIK3CA mutant cancer is brain cancer.

[0249] In one embodiment, the PIK3CA mutant cancer is a breast tumor, a thyroid tumor, an ovarian tumor, a non-small cell lung cancer, an endometrial tumor, or a pancreatic tumor. In one embodiment, the PIK3CA mutant cancer is a breast tumor. In one embodiment, the PIK3CA mutant cancer is a thyroid tumor. In one embodiment, the PIK3CA mutant cancer is an ovarian tumor. In one embodiment, the PIK3CA mutant cancer is a non-small cell lung cancer. In one embodiment, the PIK3CA mutant cancer is an endometrial tumor. In one embodiment, the PIK3CA mutant cancer is a pancreatic tumor.

[0250] In one embodiment, the PIK3CA mutation, late stage or metastatic breast cancer is PIK3CA H1047R mutant late stage or metastatic breast cancer. In one embodiment, the PIK3CA mutation, late stage or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA mutation, late stage or metastatic breast cancer. In one embodiment, the PIK3CA mutation, late stage or metastatic breast cancer is estrogen receptor positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA mutation, late stage or metastatic breast cancer. In one embodiment, the PIK3CA mutation, late stage or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA mutation, late stage or metastatic breast cancer. In one embodiment, the PIK3CA mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0251] In one embodiment, the PIK3CA mutant solid tumor is a late solid tumor mutated by PIK3CA. In one embodiment, the late solid tumor mutated by PIK3CA is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer. In one embodiment, the late solid tumor mutated by PIK3CA is a gynecological cancer. In one embodiment, the late solid tumor mutated by PIK3CA is head and neck cancer. In one embodiment, the late solid tumor mutated by PIK3CA is triple-negative breast cancer.

[0252] In one embodiment, the patient is female.

[0253] In one embodiment, the patient is a postmenopausal female.

[0254] In one embodiment, the patient has type 1 diabetes. In one embodiment, the patient has type 2 diabetes.

[0255] In one embodiment, the patient has not received prior treatment with a PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0256] In one embodiment, the patient has received prior treatment with a PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0257] In one embodiment, the patient has not received prior treatment with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0258] In one embodiment, the patient has received prior treatment with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0259] In one embodiment, the patient has progressed or relapsed on or after endocrine therapy (alone or in combination with a CDK4 and 6 inhibitor).

[0260] dose

[0261] Compound A or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents and their respective pharmaceutically acceptable salts are generally effective over a wide dosage range. It will be understood that the amount of compound actually administered will be determined by the physician based on the relevant circumstances, including the condition to be treated, the selected route of administration, the one or more compounds actually administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.

[0262] It is understood that Compound A can be administered in the form of a non-salt free acid or a pharmaceutically acceptable salt thereof; however, unless otherwise indicated, the amount of Compound A or a pharmaceutically acceptable salt thereof administered is expressed herein based on the weight of the non-salt free acid form of Compound A.

[0263] In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 200 mg to 2400 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 400 mg to 2000 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 600 mg to 1200 mg.

[0264] In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 200 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 300 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 400 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 500 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 600 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 700 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 800 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 900 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1000 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1100 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1200 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1300 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1400 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1500 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1600 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1700 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1800 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1900 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2000 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2100 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2200 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2300 mg. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2400 mg.

[0265] In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 300 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 400 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 500 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 600 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 700 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 800 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 900 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1000 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1100 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1300 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1400 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1500 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1600 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1700 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1800 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 1900 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2000 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2100 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2300 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a total daily dose of 2400 mg over a 28-day cycle.

[0266] In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 100 mg to 1200 mg twice a day. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 200 mg to 1000 mg twice a day. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 300 mg to 600 mg twice a day.

[0267] In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 100 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 150 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 200 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 250 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 300 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 350 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 400 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 450 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 500 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 550 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 600 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 650 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 700 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 750 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 800 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 850 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 900 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 950 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 1000 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 1050 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 1100 mg twice a day. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 1150 mg twice a day. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice a day.

[0268] In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 100 mg to 1200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 200 mg to 1000 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 100 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 150 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 250 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered twice a day at a dose of 300 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 350 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 400 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 450 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 500 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 550 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 600 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 650 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 700 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically salt thereof is administered at a dose of 750 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 800 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 850 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 900 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 950 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice a day over a 28-day cycle.In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1050 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1100 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1150 mg twice a day over a 28-day cycle. In one embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice a day over a 28-day cycle.

[0269] In a preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 200 mg twice a day over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 400 mg twice a day over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 600 mg twice a day over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 800 mg twice a day over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice a day over a 28-day cycle.

[0270] In a preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a total daily dose of 200 mg to 800 mg, more preferably 300 mg to 600 mg. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 300 mg twice a day, 300 mg once a day, or 600 mg once a day. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 300 mg twice a day. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 300 mg once a day. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 300 mg once a day. In another preferred embodiment, Compound A or a pharmaceutical salt thereof is administered at a dose of 600 mg once a day.

[0271] Pharmaceutical composition

[0272] Compound A or its pharmaceutical salt can be formulated for oral administration in dosage forms such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Compound A or its pharmaceutical salt can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all of which are well known to those of ordinary skill in the pharmaceutical art.

[0273] Compound A or a pharmaceutical salt thereof or a pharmaceutical composition thereof may be administered to the subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the site of desired action).

[0274] Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a depot or reservoir (e.g., subcutaneous or intramuscular).

[0275] Synthesis method

[0276] Compound A can be synthesized using the methods described below, in combination with synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. Compound A can be synthesized by the following steps outlined in General Schemes 1 and 2. Starting materials are commercially available or made by known procedures reported in the literature or as described below.

[0277] Solution 1

[0278]

[0279] Scheme 1 describes an exemplary preparation of compound A. Acylation of substituted phenol (1) can provide ester (2). Ester (2) is esterified in the presence of a Lewis acid (e.g., AlCl3) or a Bronsted acid ( Acidic condensation of aromatic aldehydes with hydroxyaryl ketones (3) can produce hydroxyaryl ketones (3). Acidic condensation of aromatic aldehydes with hydroxyaryl ketones (3) can provide keto-olefins (4), which can be cyclized to produce 2-substituted chromen-4-ones (5). Alternatively, alkylation of hydroxyaryl ketones (3) with aryl halides in the presence of a base (such as pyridine or lithium bis(trimethylsilyl)amide) can then be carried out, followed by cyclization under acidic conditions (such as HCl) to produce 2-substituted chromen-4-ones (5).

[0280] Phenyl bromide (5) can be acylated to acylchromen-4-one (6) by palladium catalysis. Exemplary palladium catalytic conditions include: phenyl bromide (5), about 5-10 mol% PdCl2(Ph3)2, and about 1.2 mol% tributyl(1-ethoxyvinyl)stannane in about 30-35 equivalents of dioxane at 95°C for about 16 hours; or phenyl bromide (5), about 1 mol% Pd(OAc)2, about 2 mol% 1,3-bis(diphenylphosphino)propane, about 5 equivalents of butyl vinyl ether, about 3 equivalents of triethylamine, and about 10 volumes of ethylene glycol at about 100°C for about 16 hours. Condensation of ketone (6) with tert-butylsulfenamide using a Lewis acid dehydrating agent (e.g., titanium(IV) alkoxide) can provide ketimine (7). Sulfenyl imines (7) can be asymmetric reduced with borohydride reagents in the presence of transition metal catalysts (e.g., cerium trichloride) to produce chirally enriched sulfenamides (8). Removal of the sulfenyl group under acidic conditions can be used to convert sulfenamides (8) to benzylamines (9), which can be alkylated with aryl halides (10) under Finkelstein or Ullmann-type conditions to give compound A.

[0281] Option 2

[0282]

[0283] Scheme 2 describes another exemplary preparation method for compound A. Ketone (6) can be reduced to a hydroxy compound (11) using a chiral catalyst (e.g., Noyori's catalyst). The hydroxy group can be converted to a leaving group using methanesulfonic anhydride or methanesulfonyl chloride to provide a mesylate (12). The mesylate (12) can be used to alkylate an aromatic amine (13) to provide compound A. Alternatively, ketone (6) can be reduced to a hydroxy compound (14) using a chiral catalyst (e.g., Noyori's catalyst). The hydroxy group can be converted to a chloride (15) using a chlorinating agent (e.g., 2,4,6-trichloro-1,3,5-triazine). The chloride (15) can then be used to alkylate an aromatic amine (13) to provide compound A.

[0284] definition

[0285] "CDK4 and 6 inhibitors" or "CDK4 / 6 inhibitors" refer to molecules that inhibit the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinase (CDK4 and 6) protein complexes (e.g., cyclin D:CDK4 and 6 complexes), and are typically used to block the transition from the G1 phase to the S phase of the cell cycle by inhibiting kinase activity. In some embodiments, the CDK4 and 6 inhibitors are palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitors are palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitors are ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitors are abemaciclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitors are abemaciclib or a pharmaceutically acceptable salt thereof. In preferred embodiments, the CDK4 and 6 inhibitors are abemaciclib.

[0286] Palbociclib, [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3,-d]pyrimidin-7(8H)-one], is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or men, or (ii) in combination with fulvestrant in patients whose disease has progressed after endocrine therapy.

[0287] Palbociclib is taken orally and is available as capsules (125 mg, 100 mg and 75 mg), with a recommended starting dose of 125 mg once a day for 21 days, followed by a 7-day break. Palbociclib can be prepared as a free base or a pharmaceutically acceptable salt thereof, including mono- and diacid addition salts, such as monoisothionate, polymorphs of isethionate or hydrochloride (see, for example, WO 2003 / 062236, WO 2005 / 005426, WO 2008 / 032157, U.S. Patent Nos. 6,936,612; 7,208,489; 7,345,171; 7,456,168; 7,781,583 and 7,863,278). Palbociclib can be anhydrous when in its free base form, or can contain varying amounts of water or one or more solvents (see, for example, U.S. Patent No. 10,723,730).

[0288] Ribociclib, [7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide], is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as initial endocrine-based therapy in pre- / perimenopausal or postmenopausal women, or (ii) in postmenopausal women as initial endocrine-based therapy or after disease progression on endocrine therapy in combination with fulvestrant.

[0289] Ribociclib is taken orally and is taken as a tablet (200 mg, equivalent to 254.40 mg of ribociclib succinate). The recommended starting dose is 600 mg (3 x 200 mg tablets) taken once daily for 21 days, followed by a 7-day break from treatment. Ribociclib can be prepared as a free base or a pharmaceutically acceptable salt thereof, such as ribociclib succinate (see, for example, U.S. Patent Nos. 9,868,739; 9,193,732).

[0290] Abemaciclib, [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine, its salt forms (including hydrochloride and methanesulfonate), and methods of making and using the compounds (including for treating cancer, particularly breast cancer) are disclosed in WO2010 / 075074.

[0291] Abemaciclib has been approved for the treatment of several breast cancer indications, including: (i) in combination with endocrine therapy (tamoxifen or aromatase inhibitors) for the adjuvant treatment of adult patients with HR+, HER2-node-positive, high-risk early breast cancer; (ii) in combination with aromatase inhibitors as initial endocrine-based therapy for the treatment of postmenopausal women and men with HR+, HER2-advanced or metastatic breast cancer; (iii) in combination with fulvestrant for the treatment of adult patients with HR+, HER2-advanced or metastatic breast cancer whose disease has progressed after endocrine therapy; and (iv) as a monotherapy for the treatment of adult patients with HR+, HER2-advanced or metastatic breast cancer whose disease has progressed after endocrine therapy and prior chemotherapy in the metastatic setting. Preferably, abemaciclib is administered as described on the approved label. In some preferred embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 50 mg to 200 mg. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of 100 mg to 150 mg twice a day. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg twice a day. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg twice a day over a 28-day period. Preferably, abemaciclib is administered orally. Preferably, abemaciclib is administered via capsule. Also preferably, abemaciclib is administered via tablet.

[0292] Selective estrogen receptor degraders ("SERDs") refer to molecules that bind to estrogen receptors (ERs) and downregulate ER-mediated transcriptional activity. In some embodiments, the SERD is fulvestrant, imrudestrant, giredestrant, amcenestrant, rintodestrant, AZD9833, or LSZ102, or a pharmaceutically acceptable salt thereof. In some embodiments, the SERD is fulvestrant, or imrudestrant, or a pharmaceutically acceptable salt thereof. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is imrudestrant.

[0293] Fulvestrant is a SERD approved for the treatment of HR+ metastatic breast cancer, either as a monotherapy or in combination with an approved CDK4 / 6 inhibitor. Fulvestrant is also approved in combination with apellix, specifically for HR+HER2- advanced breast cancer with PIK3CA mutations. Fulvestrant is formulated for injection (intravenous (IV) or intramuscular (IM)). Fulvestrant is preferably administered as described on the approved label, e.g., the recommended dose is 500 mg administered intramuscularly slowly (1-2 minutes per injection) into the buttocks as two 5 mL injections, one in each buttock, on days 1, 15, and 29, and monthly thereafter.

[0294] Imurustrant, (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, is an investigational oral SERD. The compound can be prepared as a free base or a pharmaceutically acceptable salt thereof using the synthetic procedures described in WO20 / 014435 or US10,654,866. In a Phase 1 study, Imurustrant monotherapy had a favorable safety profile and demonstrated encouraging antitumor activity in patients with heavily pretreated ER+HER2- advanced breast cancer. Imurustrant is still being evaluated in a Phase 1b dose expansion of Imurustrant (as monotherapy and in combination with everolimus, abemaciclib, apelisib, or trastuzumab). In addition, a pivotal Phase 3 study of Imurustrant is ongoing. Preferably, imaruxtran is administered once daily at a dose of 200 mg to 400 mg; more preferably, imaruxtran is administered once daily at a dose of 400 mg. Preferably, imaruxtran is administered once daily over a 28-day period at a dose of 200 mg to 400 mg; more preferably, imaruxtran is administered once daily over a 28-day period at a dose of 400 mg. Preferably, imaruxtran is administered orally. Preferably, imaruxtran is administered via capsules. Also preferably, imaruxtran is administered via tablets.

[0295] "Aromatase inhibitor" refers to a molecule that inhibits the enzyme aromatase, which is responsible for converting androgens (produced by women in the adrenal glands) into estrogens. In some embodiments, the aromatase inhibitor is anastrozole, letrozole, or exemestane, or a pharmaceutically acceptable salt thereof. In some embodiments, the aromatase inhibitor is anastrozole. Preferably, anastrozole is administered at a 1 mg oral dose once daily. In some embodiments, the aromatase inhibitor is letrozole. Preferably, letrozole is administered at a 2.5 mg oral dose once daily, or for patients with cirrhosis or severe hepatic insufficiency, at a 2.5 mg oral dose once every other day. In some embodiments, the aromatase inhibitor is exemestane. Preferably, exemestane is administered at a 25 mg oral dose once daily.

[0296] "Taxane" refers to a molecule in the diterpenoid class that exerts its anticancer effect by stabilizing tubulin microtubules involved in cell division. In some embodiments, the taxane is paclitaxel or docetaxel, or a pharmaceutically acceptable salt thereof. In some embodiments, the taxane is paclitaxel. Paclitaxel is a taxane that inhibits microtubule dynamics and is approved for the treatment of metastatic breast cancer. Paclitaxel is formulated to be injectable (intravenous (IV)). Preferably, paclitaxel is administered as described in the approved label, for example, on days 8, 15, and 22 of the first dosage cycle, and then at 80 mg / m2 on days 1, 8, 15, and 22 of all subsequent dosage cycles. 2 After the first dose cycle, the dose on Day 22 is optional.

[0297] "Immune checkpoint inhibitors" refer to molecules that inhibit the function of immune checkpoint proteins. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab. In some embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.

[0298] "mTOR inhibitor" refers to a molecule that inhibits the mammalian target of rapamycin protein. In some embodiments, the mTOR inhibitor is sirolimus, temsirolimus, everolimus, or RMC-5552. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is RMC-5552.

[0299] "Tyrosine kinase inhibitor" refers to a molecule that inhibits tyrosine kinase. In some embodiments, the tyrosine kinase inhibitor is neratinib or afatinib. In some embodiments, the tyrosine kinase inhibitor is neratinib. In some embodiments, the tyrosine kinase inhibitor is afatinib.

[0300] "Platinum agent" refers to cisplatin, carboplatin, or oxaliplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the platinum agent is carboplatin. In some embodiments, the platinum agent is oxaliplatin.

[0301] "Anti-androgen" refers to a molecule that inhibits androgens or androgen-regulating molecules. In some embodiments, the anti-androgen is abiraterone, enzalutamide, nilutamide, or flutamide. In some embodiments, the anti-androgen is abiraterone. In some embodiments, the anti-androgen is enzalutamide. In some embodiments, the anti-androgen is nilutamide. In some embodiments, the anti-androgen is flutamide.

[0302] "Anti-HER2 monoclonal antibody" refers to a recombinant humanized anti-HER2 monoclonal antibody used to treat HER2-positive cancer. In some embodiments, the anti-HER2 monoclonal antibody is trastuzumab, margetuximab, or pertuzumab. In some embodiments, the anti-HER2 monoclonal antibody is trastuzumab. In some embodiments, the anti-HER2 monoclonal antibody is margetuximab. In some embodiments, the anti-HER2 monoclonal antibody is pertuzumab.

[0303] "Anti-HER2 antibody-drug conjugate" refers to a recombinant humanized anti-HER2 monoclonal antibody linked to a biologically active payload or drug, wherein the anti-HER2 antibody-drug conjugate is used to treat HER2-positive cancers. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab emtansine.

[0304] "Anthracycline" generally refers to a class of antitumor antibiotics from certain types of Streptomyces bacteria. In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, or idarubicin. In some embodiments, the anthracycline antibiotic is doxorubicin. In some embodiments, the anthracycline antibiotic is daunorubicin. In some embodiments, the anthracycline antibiotic is epirubicin. In some embodiments, the anthracycline antibiotic is idarubicin.

[0305] "KRAS inhibitor" refers to a molecule that inhibits the Kirsten Rat Sarcoma protein. In some embodiments, the KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the KRAS inhibitor is sotorasib. In some embodiments, the KRAS inhibitor is adagrasib.

[0306] "MEK inhibitor" refers to a molecule that inhibits mitogen-activated protein kinase kinase. In some embodiments, the MEK inhibitor is trametinib.

[0307] "ERK inhibitor" refers to a molecule that inhibits extracellular signal-regulated kinase.

[0308] "Topoisomerase inhibitor" refers to a molecule that inhibits a topoisomerase (eg, type I topoisomerase or type II topoisomerase). In some embodiments, the topoisomerase inhibitor is etoposide.

[0309] "SERM" refers to a selective estrogen receptor modulator, which blocks estrogen from connecting to hormone receptors. In some embodiments, the SERM is tamoxifen or toremifene. In some embodiments, the SERM is tamoxifen. In some embodiments, the SERM is toremifene.

[0310] "PARP inhibitor" refers to a molecule that inhibits poly (ADP-ribose) polymerase. In some embodiments, the PARP inhibitor is olaparib or talazoparib. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is talazoparib.

[0311] As used herein, the terms "treating," "to treat," or "treatment" refer to inhibiting, slowing, halting, reducing, diminishing, maintaining stability of disease, or reversing the progression or severity of existing symptoms, disorders, conditions, or diseases.

[0312] As used herein, the term "patient" refers to a mammal, preferably a human.

[0313] As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is typically characterized by unregulated cell proliferation. This definition includes both benign and malignant cancers.

[0314] As used herein, the term "advanced" or "metastatic" means that the cancer has spread to one or more parts of the body other than the site of the original cancerous tissue.

[0315] As used herein, the term "effective amount" refers to the amount or dosage of a therapeutic agent or a pharmaceutically acceptable salt thereof (e.g., Compound A or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional drugs or pharmaceutically acceptable salts thereof) that provides an effective response to the patient being diagnosed or treated.

[0316] As used herein, the term "effective response" of a patient to a therapeutic agent or a pharmaceutically acceptable salt thereof, or "responsiveness" of a patient, refers to the clinical or therapeutic benefit conferred on the patient following administration of a therapeutic agent or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents or pharmaceutically acceptable salts thereof.

[0317] As used herein, the term "in combination with" refers to the administration of one therapeutic agent, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or pharmaceutically acceptable salts thereof, separately, simultaneously, or in any sequential order, for example, at repeated intervals during a single cycle or more than one cycle of standard treatment, such that one agent may be administered before, simultaneously with, or after the other agent, or any combination thereof.

[0318] As used herein, "prior treatment" refers to a treatment previously administered or used to treat cancer (eg, a treatment previously treated with drugs, surgery, or radiation to treat cancer). In some embodiments, the patient has previously received endocrine therapy to treat cancer.

[0319] As used herein, the term "tromethamine" may be referred to alternatively as tris(hydroxymethyl)aminomethane or tris.

[0320] As used herein, the term "tert-butylamine" may alternatively be referred to as tert-butylamine.

[0321] As used herein, "endocrine therapy" refers to hormone therapy used to treat cancer. Exemplary endocrine therapies include tamoxifen or a pharmaceutically acceptable salt thereof, and aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane).

[0322] Exemplary Aspects

[0323] Various aspects of the invention are set out in the following numbered clauses.

[0324] Item 1. A compound which is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid; or a pharmaceutically acceptable salt thereof.

[0325] Item 2. A compound which is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

[0326] Item 3. A compound which is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

[0327] Item 4. The compound of any one of Items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 7.8°±0.2°, 12.1°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 21.2°±0.2°, and 24.1°±0.2°.

[0328] Item 5. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 12.1°±0.2°, combined with at least one peak selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2° and 20.7°±0.2°.

[0329] Item 6. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 12.1°±0.2°, combined with at least two peaks selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2° and 20.7°±0.2°.

[0330] Item 7. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 12.1°±0.2°, combined with at least three peaks selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2° and 20.7°±0.2°.

[0331] Item 8. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2°, combined with peaks at 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°.

[0332] Item 9. The compound of any one of Items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.8°±0.2°, 12.1°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 21.2°±0.2° and 24.1°±0.2°.

[0333] Item 10. The compound of any one of Items 1-3, which has substantially Figure 1 The X-ray powder diffraction spectrum is shown.

[0334] Item 11. The compound of any one of Items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2°, and 17.4°±0.2°.

[0335] Item 12. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 9.7°±0.2°, combined with at least one peak selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2° and 7.0°±0.2°.

[0336] Item 13. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 9.7°±0.2°, combined with at least two peaks selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2° and 7.0°±0.2°.

[0337] Item 14. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 9.7°±0.2°, combined with at least three peaks selected from 14.9°±0.2°, 11.9°±0.2°, 17.4°±0.2° and 7.0°±0.2.

[0338] Item 15. The compound of any one of Items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2°, and 17.4°±0.2°.

[0339] Clause 16. The compound of any one of clauses 1 to 3, which has substantially Figure 2 The X-ray powder diffraction spectrum is shown.

[0340] Item 17. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2°.

[0341] Item 18. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4°±0.2°, combined with at least one peak selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2° and 7.4°±0.2°.

[0342] Item 19. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, wherein the X-ray powder diffraction pattern has a peak at a diffraction angle 2-θ of 13.4°±0.2°, combined with at least two peaks selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2° and 7.4°±0.2°.

[0343] Item 20. The compound of any one of Items 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4°±0.2°, combined with at least three peaks selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2° and 7.4°±0.2°.

[0344] Item 21. The compound of any one of Items 1 to 3, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2°.

[0345] Clause 22. The compound of any one of clauses 1 to 3, which has substantially Figure 3 The X-ray powder diffraction spectrum is shown.

[0346] Item 23. Tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

[0347] Item 24. The tromethamine salt of Item 23 which is crystalline.

[0348] Item 25. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

[0349] Item 26. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least one peak selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

[0350] Item 27. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, combined with at least two peaks selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

[0351] Item 28. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, combined with at least three peaks selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

[0352] Item 29. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with peaks at 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

[0353] Item 30. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

[0354] Item 31. The tromethamine salt of Item 23 or Item 24 having substantially Figure 4 The X-ray powder diffraction spectrum is shown.

[0355] Clause 32. The tromethamine salt of any one of clauses 23-31, which is 13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

[0356] Clause 33. The tromethamine salt of any one of clauses 23-31, which is 13 The samples were characterized by C solid-state NMR (100.6 MHz) spectroscopy including at least one peak selected from the group consisting of 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm each) with reference to glycine (external reference at 176.5 ppm).

[0357] Clause 34. The tromethamine salt of any one of clauses 23-31, which is 13 The sample was characterized by C solid-state NMR (100.6 MHz) spectroscopy, which included peaks at 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).

[0358] Clause 35. The tromethamine salt of any one of clauses 23-31, which is 13The chromatograms were characterized by C solid-state NMR (100.6 MHz) spectroscopy including peaks referenced to glycine (external reference at 176.5 ppm) at 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

[0359] Item 36. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°.

[0360] Item 37. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2°, in combination with at least one peak selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°.

[0361] Item 38. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2°, combined with at least two peaks selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°.

[0362] Item 39. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2°, combined with at least three peaks selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°.

[0363] Item 40. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°.

[0364] Clause 41. The tromethamine salt of Clause 23 or Clause 24 having substantially Figure 5 The X-ray powder diffraction spectrum is shown.

[0365] Item 42. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°.

[0366] Item 43. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least one peak selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°.

[0367] Item 44. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, combined with at least two peaks selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°.

[0368] Item 45. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least three peaks selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°.

[0369] Item 46. The tromethamine salt of Item 23 or Item 24, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°.

[0370] Clause 47. The tromethamine salt of Clause 23 or Clause 24 having substantially Figure 6 The X-ray powder diffraction spectrum is shown.

[0371] Item 48. The tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

[0372] Item 49. The tert-butylamine salt of Item 48, which is crystalline.

[0373] Item 50. The tert-butylamine salt of Item 48 or Item 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.5°±0.2°, 10.5°±0.2°, 11.1°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 21.5°±0.2°, 22.2°±0.2°, 22.7°±0.2°, and 26.3°±0.2°.

[0374] Item 51. The tert-butylamine salt of Item 48 or Item 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, combined with at least one peak selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

[0375] Item 52. The tert-butylamine salt of Item 48 or Item 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, combined with at least two peaks selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

[0376] Item 53. The tert-butylamine salt of Item 48 or Item 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, combined with at least three peaks selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

[0377] Item 54. The tert-butylamine salt of Item 48 or Item 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with peaks at 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

[0378] Item 55. The tert-butylamine salt of Item 48 or 49, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 66.5°±0.2°, 10.5°±0.2°, 11.1°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 21.5°±0.2°, 22.2°±0.2°, 22.7°±0.2°, and 26.3°±0.2°.

[0379] Item 56. The tert-butylamine salt of Item 48 or Item 49, which has substantially Figure 7 The X-ray powder diffraction spectrum is shown.

[0380] Item 57. The tert-butylamine salt of any one of Items 48-56, which is 13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm).

[0381] Item 58. The tert-butylamine salt of any one of Items 48-56, which is 13 The samples were characterized by a C solid-state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (each ± 0.2 ppm) with reference to glycine (external reference at 176.5 ppm).

[0382] Item 59. The tert-butylamine salt of any one of Items 48-56, which is 13 The product was characterized by C solid-state NMR (100.6 MHz) spectroscopy containing peaks referenced to glycine (external reference at 176.5 ppm) at 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (±0.2 ppm each).

[0383] Clause 60. The tert-butylamine salt of any one of clauses 48-56, which is 13The chromatograms were characterized by C solid-state NMR (100.6 MHz) spectroscopy containing peaks referenced to glycine (external reference at 176.5 ppm) at 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm).

[0384] Clause 61. A pharmaceutical composition comprising a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, or an erbumine salt of any one of Clauses 48-60, and a pharmaceutically acceptable carrier.

[0385] Item 62. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumine salt of any one of Items 48-60, or a pharmaceutical composition of Item 61.

[0386] Clause 63. A method of treating a patient suffering from a disease associated with a mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumine salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61.

[0387] Clause 64. The method of Clause 62 or Clause 63, wherein the PI3K is PI3Kα.

[0388] Clause 65. The method of any one of clauses 62-64, wherein the PI3K has an H1047R mutation.

[0389] Clause 66. The method of any one of clauses 63-65, wherein the disease is cancer.

[0390] Clause 67. The method of Clause 66, 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.

[0391] Clause 68. The method of Clause 66, wherein the cancer is breast cancer.

[0392] Clause 69. The method of Clause 66, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0393] Clause 70. The method of any one of clauses 63-65, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

[0394] Clause 71. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.

[0395] Clause 72. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumine salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61.

[0396] Clause 73. A method of treating a patient having PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.

[0397] Clause 74. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumine salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61.

[0398] Clause 75. A method of treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. Kinase inhibitors or pharmaceutically acceptable salts thereof; platinum agents; anthracyclines or pharmaceutically acceptable salts thereof; immune checkpoint inhibitors or pharmaceutically acceptable salts thereof; anti-androgens or pharmaceutically acceptable salts thereof; anti-HER2 monoclonal antibodies; anti-HER2 antibody-drug conjugates; KRAS inhibitors or pharmaceutically acceptable salts thereof; MEK inhibitors or pharmaceutically acceptable salts thereof; ERK inhibitors or pharmaceutically acceptable salts thereof; topoisomerase inhibitors or pharmaceutically acceptable salts thereof; SERMs or pharmaceutically acceptable salts thereof; or PARP inhibitors or pharmaceutically acceptable salts thereof; or any combination thereof.

[0399] Clause 76. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0400] Clause 77. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0401] Clause 78. A method of treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0402] Clause 79. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0403] Clause 80. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0404] Clause 81. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0405] Clause 82. A method of treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0406] Clause 83. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0407] Clause 84. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0408] Clause 85. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0409] Clause 86. A method of treating a patient having PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0410] Clause 87. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

[0411] Clause 88. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0412] Clause 89. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0413] Clause 90. A method of treating a patient having PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0414] Clause 91. A method of treating a patient having PIK3CA mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0415] Clause 92. A method of treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0416] Clause 93. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0417] Clause 94. A method of treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0418] Clause 95. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

[0419] Clause 96. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0420] Clause 97. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0421] Clause 98. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0422] Clause 99. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0423] Clause 100. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a platinum agent.

[0424] Clause 101. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a platinum agent.

[0425] Clause 102. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0426] Item 103. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, in combination with an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0427] Clause 104. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.

[0428] Clause 105. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.

[0429] Clause 106. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0430] Clause 107. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0431] Clause 108. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.

[0432] Clause 109. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.

[0433] Clause 110. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.

[0434] Clause 111. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.

[0435] Clause 112. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.

[0436] Clause 113. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.

[0437] Clause 114. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0438] Clause 115. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.

[0439] Clause 116. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0440] Clause 117. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0441] Clause 118. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0442] Item 119. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.

[0443] Clause 120. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0444] Clause 121. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0445] Clause 122. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a SERM or a pharmaceutically acceptable salt thereof.

[0446] Clause 123. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a SERM or a pharmaceutically acceptable salt thereof.

[0447] Clause 124. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0448] Clause 125. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0449] Clause 126. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0450] Clause 127. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0451] Clause 128. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0452] Clause 129. A method of treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0453] Clause 130. A method of treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0454] Clause 131. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, in combination with an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0455] Clause 132. The method of clause 71, clause 75, clause 76, clause 80, clause 84, clause 88, clause 92, clause 96, clause 98, clause 100, clause 102, clause 104, clause 106, clause 108, clause 110, clause 112, clause 114, clause 116, clause 118, clause 120, clause 122, clause 124, clause 126 or clause 128, wherein the PIK3CA mutant cancer is a cancer with a PIK3CA H1047R mutation.

[0456] Clause 133. The method of Clause 71, Clause 75, Clause 76, Clause 80, Clause 84, Clause 88, Clause 92, Clause 96, Clause 98, Clause 100, Clause 102, Clause 104, Clause 106, Clause 108, Clause 110, Clause 112, Clause 114, Clause 116, Clause 118, Clause 120, Clause 122, Clause 124, Clause 126, Clause 128 or Clause 132, wherein the PIK3CA mutant 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.

[0457] Clause 134. The method of Clause 133, wherein the PIK3CA mutant cancer is endometrial cancer.

[0458] Clause 135. The method of Clause 133, wherein the PIK3CA mutant cancer is gastric cancer.

[0459] Clause 136. The method of Clause 133, wherein the PIK3CA mutant cancer is a leukemia.

[0460] Clause 137. The method of Clause 133, wherein the PIK3CA mutant cancer is a lymphoma.

[0461] Clause 138. The method of Clause 133, wherein the PIK3CA mutant cancer is a sarcoma.

[0462] Clause 139. The method of Clause 133, wherein the PIK3CA mutant cancer is colorectal cancer.

[0463] Clause 140. The method of Clause 133, wherein the PIK3CA mutant cancer is lung cancer.

[0464] Clause 141. The method of Clause 133, wherein the PIK3CA mutant cancer is ovarian cancer.

[0465] Clause 142. The method of Clause 133, wherein the PIK3CA mutant cancer is skin cancer.

[0466] Clause 143. The method of Clause 133, wherein the PIK3CA mutant cancer is head and neck cancer.

[0467] Clause 144. The method of Clause 133, wherein the PIK3CA mutant cancer is breast cancer.

[0468] Clause 145. The method of Clause 133, wherein the PIK3CA mutant cancer is a brain cancer.

[0469] Clause 146. The method of Clause 133, wherein the PIK3CA mutant cancer is prostate cancer.

[0470] Clause 147. The method of Clause 72, Clause 77, Clause 81, Clause 85, Clause 89, Clause 93, Clause 97, Clause 99, Clause 101, Clause 103, Clause 105, Clause 107, Clause 109, Clause 111, Clause 113, Clause 115, Clause 117, Clause 119, Clause 121, Clause 123, Clause 125, Clause 127 or Clause 129, wherein the PIK3CA mutant solid tumor is a solid tumor with a PIK3CA H1047R mutation.

[0471] Clause 148. The method of Clause 72, Clause 77, Clause 81, Clause 85, Clause 89, Clause 93, Clause 97, Clause 99, Clause 101, Clause 103, Clause 105, Clause 107, Clause 109, Clause 111, Clause 113, Clause 115, Clause 117, Clause 119, Clause 121, Clause 123, Clause 125, Clause 127, Clause 129 or Clause 147, wherein the PIK3CA mutant solid tumor is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer.

[0472] Clause 149. The method of Clause 148, wherein the PIK3CA mutant solid tumor is a gynecological cancer.

[0473] Clause 150. The method of Clause 148, wherein the PIK3CA mutant solid tumor is head and neck cancer.

[0474] Clause 151. The method of Clause 148, wherein the PIK3CA mutant solid tumor is triple-negative breast cancer.

[0475] Clause 152. The method of clause 73, clause 78, clause 82, clause 86, clause 90, clause 94 or clause 130, wherein the PIK3CA mutant breast cancer is a PIK3CA H1047R mutant breast cancer.

[0476] Clause 153. The method of Clause 74, Clause 79, Clause 83, Clause 87, Clause 91, Clause 95 or Clause 131, wherein the PIK3CA mutated, advanced or metastatic breast cancer is PIK3CA H1047R mutated advanced or metastatic breast cancer.

[0477] Clause 154. A method according to Clause 74, Clause 79, Clause 83, Clause 87, Clause 91, Clause 95 or Clause 131, wherein 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, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0478] Clause 155. A method according to Clause 74, Clause 79, Clause 83, Clause 87, Clause 91, Clause 95 or Clause 131, wherein the PIK3CA mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0479] Clause 156. The method according to any one of clauses 62-155, wherein the patient is a postmenopausal female.

[0480] Clause 157. The method according to any one of clauses 62-156, wherein the patient suffers from type 1 diabetes.

[0481] Clause 158. The method according to any one of clauses 62-156, wherein the patient suffers from type 2 diabetes.

[0482] Clause 159. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 200 mg to 2400 mg.

[0483] Clause 160. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 400 mg to 2000 mg.

[0484] Clause 161. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 600 mg to 1200 mg.

[0485] Clause 162. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 400 mg.

[0486] Clause 163. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 450 mg.

[0487] Clause 164. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 500 mg.

[0488] Clause 165. The method of any one of clauses 62-158, wherein the compound, the tromethamine salt, or the terbumine salt is administered at a total daily dose of 550 mg.

[0489] Clause 166. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 600 mg.

[0490] Clause 167. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 650 mg.

[0491] Clause 168. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 700 mg.

[0492] Clause 169. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 750 mg.

[0493] Clause 170. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 800 mg.

[0494] Clause 171. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered in a total daily dose of 850 mg.

[0495] Clause 172. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 900 mg.

[0496] Clause 173. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 950 mg.

[0497] Clause 174. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1000 mg.

[0498] Clause 175. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1050 mg.

[0499] Clause 176. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1100 mg.

[0500] Clause 177. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1150 mg.

[0501] Clause 178. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1200 mg.

[0502] Clause 179. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1250 mg.

[0503] Clause 180. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1300 mg.

[0504] Clause 181. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 1350 mg.

[0505] Clause 182. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1400 mg.

[0506] Clause 183. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1450 mg.

[0507] Clause 184. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1500 mg.

[0508] Clause 185. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1550 mg.

[0509] Clause 186. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1600 mg.

[0510] Clause 187. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1650 mg.

[0511] Clause 188. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1700 mg.

[0512] Clause 189. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1750 mg.

[0513] Clause 190. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1800 mg.

[0514] Clause 191. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1850 mg.

[0515] Clause 192. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 1900 mg.

[0516] Clause 193. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 1950 mg.

[0517] Clause 194. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2000 mg.

[0518] Clause 195. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2050 mg.

[0519] Clause 196. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2100 mg.

[0520] Clause 197. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2150 mg.

[0521] Clause 198. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2200 mg.

[0522] Clause 199. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2250 mg.

[0523] Clause 200. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 2300 mg.

[0524] Clause 201. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 2350 mg.

[0525] Clause 202. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered in a total daily dose of 2400 mg.

[0526] Clause 203. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day in a dose of 200 mg to 2400 mg.

[0527] Clause 204. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day in a dose of 400 mg to 2000 mg.

[0528] Clause 205. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered once a day in a dose of 600 mg to 1200 mg.

[0529] Clause 206. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 200 mg.

[0530] Clause 207. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 250 mg.

[0531] Clause 208. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 300 mg once a day.

[0532] Clause 209. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 350 mg.

[0533] Clause 210. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 400 mg.

[0534] Clause 211. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 450 mg.

[0535] Clause 212. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 500 mg.

[0536] Clause 213. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 550 mg once a day.

[0537] Clause 214. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 600 mg once a day.

[0538] Clause 215. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 650 mg once a day.

[0539] Clause 216. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 700 mg once a day.

[0540] Clause 217. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 750 mg.

[0541] Clause 218. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 800 mg.

[0542] Clause 219. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 850 mg once a day.

[0543] Clause 220. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 900 mg once a day.

[0544] Clause 221. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 950 mg once a day.

[0545] Clause 222. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1000 mg.

[0546] Clause 223. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1050 mg.

[0547] Clause 224. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1100 mg.

[0548] Clause 225. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1150 mg.

[0549] Clause 226. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1200 mg.

[0550] Clause 227. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1250 mg.

[0551] Clause 228. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1300 mg.

[0552] Clause 229. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1350 mg.

[0553] Clause 230. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1400 mg.

[0554] Clause 231. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1450 mg.

[0555] Clause 232. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1500 mg.

[0556] Clause 233. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1550 mg.

[0557] Clause 234. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1600 mg.

[0558] Clause 235. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1650 mg.

[0559] Clause 236. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1700 mg.

[0560] Clause 237. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1750 mg.

[0561] Clause 238. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1800 mg.

[0562] Clause 239. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1850 mg.

[0563] Clause 240. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1900 mg.

[0564] Clause 241. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 1950 mg.

[0565] Clause 242. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2000 mg.

[0566] Clause 243. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2050 mg.

[0567] Clause 244. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2100 mg.

[0568] Clause 245. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2150 mg.

[0569] Clause 246. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2200 mg.

[0570] Clause 247. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2250 mg.

[0571] Clause 248. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2300 mg.

[0572] Clause 249. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered once a day at a dose of 2350 mg.

[0573] Clause 250. The method according to any one of clauses 62-158, wherein said compound, said tromethamine salt or said terbumine salt is administered once a day at a dose of 2400 mg.

[0574] Clause 251. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 100 mg to 1200 mg twice a day.

[0575] Clause 252. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 200 mg to 1000 mg twice a day.

[0576] Clause 253. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 300 mg to 600 mg twice a day.

[0577] Clause 254. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 100 mg twice a day.

[0578] Clause 255. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 150 mg twice a day.

[0579] Clause 256. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 200 mg twice a day.

[0580] Clause 257. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 250 mg twice a day.

[0581] Clause 258. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 300 mg twice a day.

[0582] Clause 259. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 350 mg twice a day.

[0583] Clause 260. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 400 mg twice a day.

[0584] Clause 261. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 450 mg twice a day.

[0585] Clause 262. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 500 mg twice a day.

[0586] Clause 263. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 550 mg twice a day.

[0587] Clause 264. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 600 mg twice a day.

[0588] Clause 265. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 650 mg twice a day.

[0589] Clause 266. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 700 mg twice a day.

[0590] Clause 267. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 750 mg twice a day.

[0591] Clause 268. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 800 mg twice a day.

[0592] Clause 269. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 850 mg twice a day.

[0593] Clause 270. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 900 mg twice a day.

[0594] Clause 271. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 950 mg twice a day.

[0595] Clause 272. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1000 mg twice a day.

[0596] Clause 273. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1050 mg twice a day.

[0597] Clause 274. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1100 mg twice a day.

[0598] Clause 275. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1150 mg twice a day.

[0599] Clause 276. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1200 mg twice a day.

[0600] Clause 277. The method according to any one of clauses 62-276, wherein the compound, the tromethamine salt or the terbumine salt is administered via an oral dosage form.

[0601] Clause 278. The method according to Clause 277, wherein the oral dosage form is a tablet.

[0602] Clause 279. The method according to any one of clauses 75-79, 84-91, 118, 119 or 132-278, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is palbociclib, ribociclib or abemaciclib or a pharmaceutically acceptable salt thereof.

[0603] Clause 280. The method according to any one of clauses 75-79, 84-91, 118, 119 or 132-278, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.

[0604] Clause 281. The method according to Clause 280, wherein abemaciclib is administered at an oral dose of 50-200 mg twice a day.

[0605] Clause 282. The method according to Clause 280, wherein abemaciclib is administered at a 50 mg oral dose twice a day.

[0606] Clause 283. The method according to Clause 280, wherein abemaciclib is administered at an oral dose of 100 mg twice a day.

[0607] Clause 284. The method according to Clause 280, wherein abemaciclib is administered at an oral dose of 150 mg twice a day.

[0608] Clause 285. The method according to Clause 280, wherein abemaciclib is administered at an oral dose of 200 mg twice a day.

[0609] Clause 286. The method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant, imrustrant, girestrant, amrustrant, lintostrant, AZD9833 or LSZ102.

[0610] Clause 287. The method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant.

[0611] Clause 288. The method according to Clause 287, wherein fulvestrant is administered at a dose of 500 mg intramuscularly on days 1 and 15 of the first 28-day cycle (Cycle 1) and on day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).

[0612] Clause 289. The method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is imrustatin.

[0613] Clause 290. The method according to Clause 289, wherein imrustatan is administered in a 400 mg oral dose once daily.

[0614] Clause 291. The method according to any one of clauses 75, 88-91 or 128-285, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole, letrozole or exemestane.

[0615] Clause 292. The method according to Clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole.

[0616] Clause 293. The method according to Clause 292, wherein anastrozole is administered in an oral dose of 1 mg once daily.

[0617] Clause 294. The method according to Clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is letrozole.

[0618] Clause 295. The method according to Clause 294, wherein letrozole is administered at a dose of 2.5 mg orally once daily, or at a dose of 2.5 mg orally every other day for patients with cirrhosis or severe hepatic insufficiency.

[0619] Clause 296. The method according to Clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is exemestane.

[0620] Clause 297. The method according to Clause 296, wherein exemestane is administered in a 25 mg oral dose once daily.

[0621] Clause 298. The method according to any one of clauses 75, 92-95 or 132-278, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel or docetaxel.

[0622] Clause 299. The method according to any one of clauses 75, 92-95 or 132-278, wherein the taxane or pharmaceutically acceptable salt thereof is paclitaxel.

[0623] Clause 300. The method according to Clause 299, wherein paclitaxel is administered at 80 mg / m2 on days 8, 15, and 22 of the first dosage cycle and then on days 1, 8, 15, and 22 of all subsequent dosage cycles. 2 Administer by injection.

[0624] Clause 301. The method according to any one of clauses 75, 96, 97, 116, 117, 132-278, or 286-290, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is sirolimus, temsirolimus, everolimus, or RMC-5552.

[0625] Clause 302. The method according to Clause 301, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is everolimus.

[0626] Clause 303. The method according to Clause 302, wherein the everolimus is administered at a 10 mg oral dose once daily.

[0627] Clause 304. The method according to Clause 301, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is RMC-5552.

[0628] Clause 305. The method according to any one of clauses 75, 98, 99 or 132-278, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib or afatinib.

[0629] Clause 306. The method according to Clause 305, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib.

[0630] Clause 307. The method according to Clause 306, wherein the neratinib is administered at a 240 mg oral dose once daily.

[0631] Clause 308. The method according to Clause 305, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is afatinib.

[0632] Clause 309. The method according to Clause 308, wherein the afatinib is administered at a dose of 40 mg orally once daily or at a dose of 30 mg orally once daily in patients with severe renal impairment.

[0633] Clause 310. The method according to any one of clauses 75, 100, 101, 126, 127 or 132-278, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

[0634] Clause 311. The method according to Clause 310, wherein the platinum agent is cisplatin.

[0635] Clause 312. The method according to any one of clauses 75, 108, 109 or 132-278, wherein the anthracycline or a pharmaceutically acceptable salt thereof is doxorubicin, daunorubicin, epirubicin or idarubicin.

[0636] Clause 313. The method according to any one of clauses 75, 102, 103, 118, 119 or 132-285, wherein the immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

[0637] Clause 314. The method according to clause 313, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0638] Clause 315. The method according to Clause 314, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

[0639] Clause 316. The method according to clause 313, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

[0640] Clause 317. The method according to Clause 316, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplizumab or tislelizumab.

[0641] Clause 318. The method according to clause 313, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

[0642] Clause 319. The method according to Clause 318, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.

[0643] Clause 320. The method according to any one of clauses 75, 104, 105 or 132-278, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is abiraterone, enzalutamide, nilutamide, flutamide or darolutamide, preferably abiraterone, enzalutamide, nilutamide or flutamide.

[0644] Clause 321. The method according to Clause 320, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is enzalutamide.

[0645] Clause 322. The method according to Clause 321, wherein the enzalutamide is administered at a 160 mg oral dose once daily.

[0646] Clause 323. The method according to any one of clauses 75, 106, 107 or 132-278, wherein the anti-HER2 monoclonal antibody is trastuzumab, magetuximab or pertuzumab.

[0647] Clause 324. The method according to clause 323, wherein the anti-HER2 monoclonal antibody is trastuzumab.

[0648] Clause 325. The method according to any one of clauses 75, 106, 107, or 132-278, wherein the anti-HER2 antibody-drug conjugate is trastuzumab dextromethorphan or trastuzumab emtansine.

[0649] Clause 326. The method of clause 325, wherein the anti-HER2 antibody-drug conjugate is trastuzumab.

[0650] Clause 327. The method according to any one of clauses 75, 110, 111 or 132-278, wherein the KRAS inhibitor or a pharmaceutically acceptable salt thereof is sotolacib or adagraciib.

[0651] Clause 328. The method according to any one of clauses 75, 112, 113 or 132-278, wherein the MEK inhibitor or a pharmaceutically acceptable salt thereof is trametinib.

[0652] Clause 329. The method according to any one of clauses 75, 120, 121, 126, 127, 132-278, 310 or 311, wherein the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is etoposide.

[0653] Clause 330. The method according to any one of clauses 75, 122, 123, or 132-278, wherein the SERM or a pharmaceutically acceptable salt thereof is tamoxifen or toremifene.

[0654] Clause 331. The method according to any one of clauses 75, 124, 125, or 132-278, wherein the PARP inhibitor or a pharmaceutically acceptable salt thereof is olaparib or talazoparib.

[0655] Clause 332. The method according to any one of clauses 62-331, wherein the patient has not received prior treatment with a PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0656] Clause 333. The method according to any one of clauses 62-331, wherein the patient has received prior treatment with a PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof.

[0657] Clause 334. The method according to Clause 333, wherein the PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellisib or inavolisib.

[0658] Clause 335. The method according to Clause 334, wherein the PI3K / AKT / mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellix.

[0659] Clause 336. The method according to any one of clauses 62-335, wherein the patient has not received prior treatment with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0660] Clause 337. The method according to any one of clauses 62-335, wherein the patient has received prior treatment with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0661] Clause 338. The method according to any one of clauses 62-335, wherein the patient has received prior treatment with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with endocrine therapy.

[0662] Clause 339. The method according to any one of clauses 62-338, wherein the patient has not received prior treatment with a SERD or a pharmaceutically acceptable salt thereof.

[0663] Clause 340. The method according to any one of clauses 62-338, wherein the patient has received prior treatment with a SERD or a pharmaceutically acceptable salt thereof.

[0664] Clause 341. The method according to any one of clauses 62-340, wherein the patient has not received prior treatment with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0665] Clause 342. The method according to any one of clauses 62-340, wherein the patient has received prior treatment with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

[0666] Clause 343. The method according to any one of clauses 62-342, wherein the patient has not received prior treatment with a taxane or a pharmaceutically acceptable salt thereof.

[0667] Clause 344. The method according to any one of clauses 62-342, wherein the patient has received prior treatment with a taxane or a pharmaceutically acceptable salt thereof.

[0668] Clause 345. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in therapy.

[0669] Clause 346. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for use in treating a disease associated with a mutant phosphoinositide 3-kinase (PI3K).

[0670] Clause 347. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 346, wherein the PI3K is PI3Kα.

[0671] Clause 348. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to clause 346 or 347, wherein the PI3K has an H1047R mutation.

[0672] Clause 349. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 346-348, wherein the disease is cancer.

[0673] Clause 350. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 349, 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.

[0674] Clause 351. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 349, wherein the cancer is breast cancer.

[0675] Clause 352. The compound, tromethamine salt, terbuprenorphine salt or pharmaceutical composition for use according to Clause 349, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0676] Clause 353. A compound, a tromethamine salt, an terbuprenorphine salt or a pharmaceutical composition for use according to any one of clauses 346 to 348, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

[0677] Clause 354. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for use in treating a PIK3CA mutant cancer.

[0678] Clause 355. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for use in treating a PIK3CA mutant solid tumor.

[0679] Clause 356. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for use in treating PIK3CA mutant breast cancer.

[0680] Clause 357. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for use in treating PIK3CA-mutated, advanced or metastatic breast cancer.

[0681] Item 358. The compound of any one of Items 1-22, the tromethamine salt of any one of Items 23-47, the erbumin salt of any one of Items 48-60, or the pharmaceutical composition of Item 61, for use in the treatment of PIK3CA mutant cancer in combination with: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. anthracycline or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an anti-androgen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof.

[0682] Clause 359. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0683] Clause 360. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0684] Clause 361. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0685] Clause 362. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0686] Clause 363. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0687] Clause 364. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0688] Clause 365. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0689] Clause 366. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERD or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0690] Clause 367. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) a SERD or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0691] Clause 368. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) a SERD or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.

[0692] Item 369. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) a SERD or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0693] Clause 370. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) a SERD or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0694] Clause 371. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0695] Clause 372. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0696] Clause 373. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0697] Clause 374. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0698] Clause 375. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0699] Clause 376. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.

[0700] Clause 377. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0701] Clause 378. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a taxane or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0702] Clause 379. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0703] Clause 380. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0704] Clause 381. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0705] Item 382. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate or sequential use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0706] Clause 383. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for use in combination with a platinum agent, simultaneously, separately, or sequentially, for the treatment of a PIK3CA mutant cancer.

[0707] Clause 384. The compound of any one of Clauses 1-22, the tromethamine salt of any one of Clauses 23-47, the erbumin salt of any one of Clauses 48-60, or the pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a platinum agent in the treatment of a PIK3CA mutant solid tumor.

[0708] Item 385. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.

[0709] Item 386. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0710] Clause 387. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an antiandrogen or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0711] Clause 388. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an antiandrogen or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0712] Item 389. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate for the treatment of PIK3CA mutant cancer.

[0713] Item 390. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate in the treatment of PIK3CA mutant solid tumors.

[0714] Clause 391. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an anthracycline or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0715] Item 392. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate or sequential use in combination with an anthracycline or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.

[0716] Clause 393. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0717] Clause 394. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0718] Clause 395. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0719] Item 396. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate or sequential use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0720] Clause 397. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0721] Item 398. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate or sequential use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0722] Clause 399. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0723] Clause 400. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate, or sequential use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0724] Item 401. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0725] Item 402. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof in the treatment of PIK3CA mutant solid tumors.

[0726] Clause 403. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0727] Clause 404. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0728] Clause 405. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERM or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0729] Clause 406. A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for simultaneous, separate or sequential use in combination with a SERM or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0730] Clause 407. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0731] Clause 408. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0732] Clause 409. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with (i) a platinum agent and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant cancer.

[0733] Item 410. A compound of any one of Items 1-22, a tromethamine salt of any one of Items 23-47, an erbumin salt of any one of Items 48-60, or a pharmaceutical composition of Item 61, for simultaneous, separate, or sequential use in combination with (i) a platinum agent and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.

[0734] Clause 411. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant cancer.

[0735] Clause 412. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof in the treatment of a PIK3CA mutant solid tumor.

[0736] Clause 413. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.

[0737] Clause 414. A compound of any one of Clauses 1-22, a tromethamine salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, for simultaneous, separate or sequential use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0738] Clause 415. A compound, a tromethamine salt, a terbumine salt, or a pharmaceutical composition for use according to clause 354, clause 358, clause 359, clause 363, clause 367, clause 371, clause 375, clause 379, clause 381, clause 383, clause 385, clause 387, clause 389, clause 391, clause 393, clause 395, clause 397, clause 399, clause 401, clause 403, clause 405, clause 407, clause 409, or clause 411, wherein the PIK3CA mutant cancer is a PIK3CA H1047R mutant cancer.

[0739] Clause 416. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to clause 354, clause 358, clause 359, clause 363, clause 367, clause 371, clause 375, clause 379, clause 381, clause 383, clause 385, clause 387, clause 389, clause 391, clause 393, clause 395, clause 397, clause 399, clause 401, clause 403, clause 405, clause 407, clause 409, clause 411 or clause 415, wherein the PIK3CA mutant 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.

[0740] Clause 417. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is endometrial cancer.

[0741] Clause 418. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is gastric cancer.

[0742] Clause 419. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is a leukemia.

[0743] Clause 420. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is a lymphoma.

[0744] Clause 421. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is a sarcoma.

[0745] Clause 422. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is colorectal cancer.

[0746] Clause 423. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is lung cancer.

[0747] Clause 424. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is ovarian cancer.

[0748] Clause 425. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is skin cancer.

[0749] Clause 426. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is head and neck cancer.

[0750] Clause 427. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is breast cancer.

[0751] Clause 428. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is brain cancer.

[0752] Clause 429. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 416, wherein the PIK3CA mutant cancer is prostate cancer.

[0753] Clause 430. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to clause 355, clause 360, clause 364, clause 368, clause 372, clause 376, clause 380, clause 382, clause 384, clause 386, clause 388, clause 390, clause 392, clause 394, clause 396, clause 398, clause 400, clause 402, clause 404, clause 406, clause 408, clause 410 or clause 412, wherein the PIK3CA mutant solid tumor is a PIK3CA H1047R mutant solid tumor.

[0754] Clause 431. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to clause 355, clause 360, clause 364, clause 368, clause 372, clause 376, clause 380, clause 382, clause 384, clause 386, clause 388, clause 390, clause 392, clause 394, clause 396, clause 398, clause 400, clause 402, clause 404, clause 406, clause 408, clause 410, clause 412 or clause 430, wherein the PIK3CA mutant solid tumor is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer.

[0755] Clause 432. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 431, wherein the PIK3CA mutant solid tumor is a gynecological cancer.

[0756] Clause 433. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 431, wherein the PIK3CA mutant solid tumor is head and neck cancer.

[0757] Clause 434. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 431, wherein the PIK3CA mutant solid tumor is triple-negative breast cancer.

[0758] Clause 435. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 356, Clause 361, Clause 365, Clause 369, Clause 373, Clause 377 or Clause 413, wherein the PIK3CA mutant breast cancer is a PIK3CA H1047R mutant breast cancer.

[0759] Clause 436. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 357, Clause 362, Clause 366, Clause 370, Clause 374, Clause 378 or Clause 414, wherein the PIK3CA mutated, advanced or metastatic breast cancer is PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0760] Clause 437. A compound, tromethamine salt, terbuprenorphine salt or pharmaceutical composition for use according to Clause 357, Clause 362, Clause 366, Clause 370, Clause 374, Clause 378 or Clause 414, wherein 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, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0761] Clause 438. A compound, tromethamine salt, terbuprenorphine salt or pharmaceutical composition for use according to Clause 357, Clause 362, Clause 366, Clause 370, Clause 374, Clause 378 or Clause 414, wherein the PIK3CA mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

[0762] Clause 439. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-438, wherein the patient is a postmenopausal female.

[0763] Clause 440. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient has type 1 diabetes.

[0764] Clause 441. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient suffers from type II diabetes.

[0765] Clause 442. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 200 mg to 2400 mg.

[0766] Clause 443. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 400 mg to 2000 mg.

[0767] Clause 444. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 600 mg to 1200 mg.

[0768] Clause 445. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 400 mg.

[0769] Clause 446. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 450 mg.

[0770] Clause 447. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 500 mg.

[0771] Clause 448. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 550 mg.

[0772] Clause 449. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 600 mg.

[0773] Clause 450. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 650 mg.

[0774] Clause 451. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 700 mg.

[0775] Clause 452. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 750 mg.

[0776] Clause 453. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 800 mg.

[0777] Clause 454. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 850 mg.

[0778] Clause 455. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 900 mg.

[0779] Clause 456. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 950 mg.

[0780] Clause 457. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered in a total daily dose of 1000 mg.

[0781] Clause 458. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1050 mg.

[0782] Clause 459. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1100 mg.

[0783] Clause 460. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1150 mg.

[0784] Clause 461. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1200 mg.

[0785] Clause 462. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1250 mg.

[0786] Clause 463. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1300 mg.

[0787] Clause 464. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1350 mg.

[0788] Clause 465. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1400 mg.

[0789] Clause 466. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1450 mg.

[0790] Clause 467. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered in a total daily dose of 1500 mg.

[0791] Clause 468. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1550 mg.

[0792] Clause 469. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1600 mg.

[0793] Clause 470. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1650 mg.

[0794] Clause 471. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1700 mg.

[0795] Clause 472. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1750 mg.

[0796] Clause 473. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 1800 mg.

[0797] Clause 474. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a total daily dose of 1850 mg.

[0798] Clause 475. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 1900 mg.

[0799] Clause 476. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered at a total daily dose of 1950 mg.

[0800] Clause 477. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2000 mg.

[0801] Clause 478. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2050 mg.

[0802] Clause 479. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2100 mg.

[0803] Clause 480. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2150 mg.

[0804] Clause 481. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2200 mg.

[0805] Clause 482. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered in a total daily dose of 2250 mg.

[0806] Clause 483. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2300 mg.

[0807] Clause 484. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2350 mg.

[0808] Clause 485. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a total daily dose of 2400 mg.

[0809] Clause 486. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered once a day at a dose of 200 mg to 2400 mg.

[0810] Clause 487. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered once a day in a dose of 400 mg to 2000 mg.

[0811] Clause 488. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered once a day at a dose of 600 mg to 1200 mg.

[0812] Clause 489. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 200 mg once a day.

[0813] Clause 490. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 250 mg once a day.

[0814] Clause 491. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 300 mg once a day.

[0815] Clause 492. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 350 mg once a day.

[0816] Clause 493. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 400 mg once a day.

[0817] Clause 494. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 450 mg once a day.

[0818] Clause 495. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 500 mg once a day.

[0819] Clause 496. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 550 mg once a day.

[0820] Clause 497. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 600 mg once a day.

[0821] Clause 498. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 650 mg once a day.

[0822] Clause 499. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 700 mg once a day.

[0823] Clause 500. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 750 mg once a day.

[0824] Clause 501. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 800 mg once a day.

[0825] Clause 502. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 850 mg once a day.

[0826] Clause 503. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 900 mg once a day.

[0827] Clause 504. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 950 mg once a day.

[0828] Clause 505. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1000 mg once a day.

[0829] Clause 506. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1050 mg once a day.

[0830] Clause 507. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1100 mg once a day.

[0831] Clause 508. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the terbumine salt is administered at a dose of 1150 mg once a day.

[0832] Clause 509. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1200 mg once a day.

[0833] Clause 510. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1250 mg once a day.

[0834] Clause 511. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1300 mg once a day.

[0835] Clause 512. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1350 mg once a day.

[0836] Clause 513. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1400 mg once a day.

[0837] Clause 514. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1450 mg once a day.

[0838] Clause 515. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1500 mg once a day.

[0839] Clause 516. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1550 mg once a day.

[0840] Clause 517. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1600 mg once a day.

[0841] Clause 518. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1650 mg once a day.

[0842] Clause 519. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1700 mg once a day.

[0843] Clause 520. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1750 mg once a day.

[0844] Clause 521. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1800 mg once a day.

[0845] Clause 522. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1850 mg once a day.

[0846] Clause 523. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1900 mg once a day.

[0847] Clause 524. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1950 mg once a day.

[0848] Clause 525. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2000 mg once a day.

[0849] Clause 526. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2050 mg once a day.

[0850] Clause 527. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2100 mg once a day.

[0851] Clause 528. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2150 mg once a day.

[0852] Clause 529. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2200 mg once a day.

[0853] Clause 530. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2250 mg once a day.

[0854] Clause 531. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2300 mg once a day.

[0855] Clause 532. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2350 mg once a day.

[0856] Clause 533. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 2400 mg once a day.

[0857] Clause 534. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 100 mg to 1200 mg twice a day.

[0858] Clause 535. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered in a dose of 200 mg to 1000 mg twice a day.

[0859] Clause 536. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 300 mg to 600 mg twice a day.

[0860] Clause 537. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 100 mg twice a day.

[0861] Clause 538. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 150 mg twice a day.

[0862] Clause 539. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 200 mg twice a day.

[0863] Clause 540. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 250 mg twice a day.

[0864] Clause 541. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 300 mg twice a day.

[0865] Clause 542. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 350 mg twice a day.

[0866] Clause 543. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 400 mg twice a day.

[0867] Clause 544. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 450 mg twice a day.

[0868] Clause 545. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 500 mg twice a day.

[0869] Clause 546. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 550 mg twice a day.

[0870] Clause 547. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 600 mg twice a day.

[0871] Clause 548. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 650 mg twice a day.

[0872] Clause 549. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 700 mg twice a day.

[0873] Clause 550. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 750 mg twice a day.

[0874] Clause 551. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 800 mg twice a day.

[0875] Clause 552. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 850 mg twice a day.

[0876] Clause 553. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 900 mg twice a day.

[0877] Clause 554. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 950 mg twice a day.

[0878] Clause 555. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1000 mg twice a day.

[0879] Clause 556. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumin salt is administered at a dose of 1050 mg twice a day.

[0880] Clause 557. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1100 mg twice a day.

[0881] Clause 558. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1150 mg twice a day.

[0882] Clause 559. The compound, tromethamine salt, erbumine salt or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt or the erbumine salt is administered at a dose of 1200 mg twice a day.

[0883] Clause 560. The compound, tromethamine salt, erbumin salt or pharmaceutical composition for use according to any one of clauses 345-559, wherein the compound, the tromethamine salt or the erbumin salt is administered via an oral dosage form.

[0884] Clause 561. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 560, wherein the oral dosage form is a tablet.

[0885] Clause 562. A compound, tromethamine salt, terbucrine salt or pharmaceutical composition for use according to any one of clauses 358-362, 367-374, 401, 402 or 415-561, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is palbociclib, ribociclib or abemaciclib, or a pharmaceutically acceptable salt thereof.

[0886] Clause 563. The compound, tromethamine salt, terbucrine salt or pharmaceutical composition for use according to any one of clauses 358-362, 367-374, 401, 402 or 415-561, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.

[0887] Clause 564. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 563, wherein abemaciclib is administered at an oral dose of 50-200 mg twice daily.

[0888] Clause 565. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 563, wherein abemaciclib is administered at a 50 mg oral dose twice daily.

[0889] Clause 566. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 563, wherein abemaciclib is administered at a 100 mg oral dose twice daily.

[0890] Clause 567. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 563, wherein abemaciclib is administered at a 150 mg oral dose twice daily.

[0891] Clause 568. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to Clause 563, wherein abemaciclib is administered at a 200 mg oral dose twice daily.

[0892] Clause 569. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or pharmaceutically acceptable salt thereof is fulvestrant, imrustrant, girestrant, amrustrant, lintostrant, AZD9833 or LSZ102.

[0893] Clause 570. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or pharmaceutically acceptable salt thereof is fulvestrant.

[0894] Clause 571. A compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 570, wherein fulvestrant is administered at a 500 mg intramuscular dose on Days 1 and 15 of the first 28-day cycle (Cycle 1) and on Day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).

[0895] Clause 572. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or pharmaceutically acceptable salt thereof is imrustatin.

[0896] Clause 573. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 572, wherein imrustatan is administered at a 400 mg oral dose once daily.

[0897] Clause 574. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 358, 371-374 or 411-568, wherein the aromatase inhibitor or pharmaceutically acceptable salt thereof is anastrozole, letrozole or exemestane.

[0898] Clause 575. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 574, wherein the aromatase inhibitor or pharmaceutically acceptable salt thereof is anastrozole.

[0899] Clause 576. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 575, wherein anastrozole is administered at a 1 mg oral dose once daily.

[0900] Clause 577. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 574, wherein the aromatase inhibitor or pharmaceutically acceptable salt thereof is letrozole.

[0901] Clause 578. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to clause 577, wherein letrozole is administered at a dose of 2.5 mg orally once daily, or at a dose of 2.5 mg orally every other day for patients with cirrhosis or severe hepatic insufficiency.

[0902] Clause 579. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 574, wherein the aromatase inhibitor or pharmaceutically acceptable salt thereof is exemestane.

[0903] Clause 580. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 579, wherein exemestane is administered at a 25 mg oral dose once daily.

[0904] Clause 581. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 358, 375-378 or 415-561, wherein the taxane or pharmaceutically acceptable salt thereof is paclitaxel or docetaxel.

[0905] Clause 582. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to any one of clauses 358, 375-378 or 415-561, wherein the taxane or pharmaceutically acceptable salt thereof is paclitaxel.

[0906] Clause 583. A compound, tromethamine salt, terbumin salt, or pharmaceutical composition for use according to Clause 582, wherein paclitaxel is administered at 80 mg / m2 on Days 8, 15, and 22 of the first dosage cycle and then on Days 1, 8, 15, and 22 of all subsequent dosage cycles. 2 Administer by injection.

[0907] Clause 584. A compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 379, 380, 399, 400, 415-561 or 569-573, wherein the mTOR inhibitor or pharmaceutically acceptable salt thereof is sirolimus, temsirolimus, everolimus or RMC-5552.

[0908] Clause 585. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 584, wherein the mTOR inhibitor or pharmaceutically acceptable salt thereof is everolimus.

[0909] Clause 586. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 585, wherein the everolimus is administered at a 10 mg oral dose once daily.

[0910] Clause 587. The compound, tromethamine salt, terbumine salt or pharmaceutical composition for use according to Clause 584, wherein the mTOR inhibitor or pharmaceutically acceptable salt thereof is RMC-5552.

[0911] Clause 588. The compound, tromethamine salt, terbumin salt or pharmaceutical composition for use according to a...

Claims

1. A method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.

2. A method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

3. A method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.

4. A method for treating a patient with PIK3CA mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.

5. A method for treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane or a pharmaceutically acceptable salt thereof.

6. The method according to any one of claims 1 to 5, wherein the PIK3CA mutated, advanced or metastatic breast cancer is PIK3CA H1047R mutated advanced or metastatic breast cancer.

7. The method of any one of claims 1-5, 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.

8. The method of any one of claims 1-5, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer.

9. The method of any one of claims 1-8, wherein the patient is a postmenopausal woman.

10. The method of any one of claims 1-9, wherein the patient has type 2 diabetes.

11. The method according to any one of claims 1 to 10, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 300 mg to 600 mg.

12. The method of any one of claims 1, 3, 4, or 6-11, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.

13. The method of claim 12, wherein abemaciclib is administered at an oral dose of 50-200 mg twice daily.

14. The method of claim 13, wherein abemaciclib is administered at a 150 mg oral dose twice daily.

15. The method of any one of claims 2, 3, or 6-14, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant.

16. The method of claim 15, wherein fulvestrant is administered at a 500 mg intramuscular dose on Days 1 and 15 of the first 28-day cycle (Cycle 1) and on Day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).

17. The method of any one of claims 2, 3, or 6-14, wherein the SERD or a pharmaceutically acceptable salt thereof is imrustatin.

18. The method of claim 17, wherein imrustatan is administered at a 400 mg oral dose once daily.

19. The method of any one of claims 4 or 6-14, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole, letrozole, or exemestane.

20. The method of claim 19, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole.

21. The method of claim 20, wherein anastrozole is administered at a 1 mg oral dose once daily.

22. The method of claim 19, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is letrozole.

23. The method of claim 22, wherein letrozole is administered at a dose of 2.5 mg orally once daily, or at a dose of 2.5 mg orally every other day for patients with cirrhosis or severe hepatic insufficiency.

24. The method of claim 19, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is exemestane.

25. The method of claim 24, wherein exemestane is administered at a 25 mg oral dose once daily.

26. The method of any one of claims 5-11, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel.

27. The method of claim 26, wherein paclitaxel is administered at 80 mg / m2 on days 8, 15, and 22 of the first dosage cycle and then on days 1, 8, 15, and 22 of all subsequent dosage cycles. 2 Administer by injection.

28. The method of any one of claims 1-27, wherein the Compound A or a pharmaceutically acceptable salt thereof is the tromethamine salt of Compound A.

29. The method of claim 28, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

30. The method of claim 28, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least one peak selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

31. The method of any one of claims 28-30, wherein the tromethamine salt of Compound A is prepared by 13 The chromatograms were characterized by a C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

32. The method of any one of claims 28-30, wherein the tromethamine salt of Compound A is prepared by 13 The product was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks at 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).

33. Compound A or a pharmaceutically acceptable salt thereof for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

34. Compound A or a pharmaceutically acceptable salt thereof, for use in combination with a SERD or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

35. Compound A or a pharmaceutically acceptable salt thereof for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

36. Compound A or a pharmaceutically acceptable salt thereof for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, simultaneously, separately or sequentially.

37. Compound A or a pharmaceutically acceptable salt thereof, for use in combination with a taxane or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially, for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

38. The compound for use according to any one of claims 33 to 37, or a pharmaceutically acceptable salt thereof, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutated advanced or metastatic breast cancer.

39. The compound for use according to any one of claims 33 to 37, or a pharmaceutically acceptable salt thereof, 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.

40. The compound for use according to any one of claims 33 to 37, or a pharmaceutically acceptable salt thereof, wherein the PIK3CA mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutated, advanced or metastatic breast cancer.

41. The compound for use according to any one of claims 33-40, or a pharmaceutically acceptable salt thereof, wherein the patient is a postmenopausal female.

42. The compound for use according to any one of claims 33-41, or a pharmaceutically acceptable salt thereof, wherein the patient has type 2 diabetes.

43. The compound for use according to any one of claims 33 to 42, or a pharmaceutically acceptable salt thereof, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 300 mg to 600 mg.

44. The compound for use according to any one of claims 33, 35, 36, or 38-43, or a pharmaceutically acceptable salt thereof, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.

45. The compound for use according to claim 44, or a pharmaceutically acceptable salt thereof, wherein abemaciclib is administered at an oral dose of 50-200 mg twice daily.

46. The compound for use according to claim 45, or a pharmaceutically acceptable salt thereof, wherein abemaciclib is administered at an oral dose of 150 mg twice daily.

47. The compound for use according to any one of claims 34, 35, or 38-46, or a pharmaceutically acceptable salt thereof, wherein the SERD or pharmaceutically acceptable salt thereof is fulvestrant.

48. The compound for use according to claim 47, or a pharmaceutically acceptable salt thereof, wherein fulvestrant is administered at a 500 mg intramuscular dose on Days 1 and 15 of the first 28-day cycle (Cycle 1) and on Day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).

49. The compound for use according to any one of claims 34, 35, or 38-46, or a pharmaceutically acceptable salt thereof, wherein the SERD or a pharmaceutically acceptable salt thereof is imrustatin.

50. The compound for use according to claim 49, or a pharmaceutically acceptable salt thereof, wherein imrustatan is administered at an oral dose of 400 mg once daily.

51. The compound for use according to any one of claims 36 or 38-46, or a pharmaceutically acceptable salt thereof, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole, letrozole, or exemestane.

52. The compound for use according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole.

53. The compound for use according to claim 52, or a pharmaceutically acceptable salt thereof, wherein anastrozole is administered at an oral dose of 1 mg once daily.

54. The compound for use according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is letrozole.

55. The compound for use according to claim 54, or a pharmaceutically acceptable salt thereof, wherein letrozole is administered at a dose of 2.5 mg orally once daily, or at a dose of 2.5 mg orally once every other day for patients with cirrhosis or severe hepatic insufficiency.

56. The compound for use according to claim 51, or a pharmaceutically acceptable salt thereof, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is exemestane.

57. The compound for use according to claim 56, or a pharmaceutically acceptable salt thereof, wherein exemestane is administered at an oral dose of 25 mg once daily.

58. The compound for use according to claim 37, or a pharmaceutically acceptable salt thereof, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel.

59. The compound for use according to claim 58, or a pharmaceutically acceptable salt thereof, wherein paclitaxel is administered at 80 mg / m2 on days 8, 15, and 22 of the first dosage cycle and then on days 1, 8, 15, and 22 of all subsequent dosage cycles. 2 Administer by injection.

60. The compound for use according to any one of claims 33 to 59, or a pharmaceutically acceptable salt thereof, wherein the Compound A or a pharmaceutically acceptable salt thereof is a tromethamine salt of Compound A.

61. The compound for use according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of: 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

62. The compound for use according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least one peak selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

63. The compound for use according to any one of claims 60-62, or a pharmaceutically acceptable salt thereof, wherein the tromethamine salt of Compound A is prepared by 13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

64. The compound for use according to any one of claims 60-62, or a pharmaceutically acceptable salt thereof, wherein the tromethamine salt of Compound A is prepared by 13 The product was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks at 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).

65. Tromethamine salt of 2-[[(1R)-1-(3,6-Dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

66. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.4°±0.2°, 8.4°±0.2°, 10.9°±0.2°, 11.8°±0.2°, 13.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, and 24.9°±0.2°.

67. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with at least one peak selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

68. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 6.4°±0.2°, in combination with peaks at 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2°, and 22.1°±0.2°.

69. The tromethamine salt according to any one of claims 65 to 68, which is 13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm).

70. The tromethamine salt according to any one of claims 65 to 68, which is 13 The product was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks at 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (±0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).

71. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°.

72. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2°, in combination with at least one peak selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2°, and 14.5°±0.2°.

73. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angles 2-θ of 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°.

74. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°.

75. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least one peak selected from the group consisting of 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2°, and 18.9°±0.2°.

76. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angles 2-θ of 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°.

77. The tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

78. The terbuthylamine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.5°±0.2°, 10.5°±0.2°, 11.1°±0.2°, 15.2°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 18.0°±0.2°, 19.3°±0.2°, 21.5°±0.2°, 22.2°±0.2°, 22.7°±0.2°, and 26.3°±0.2°.

79. The terbuthylamine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with at least one peak selected from the group consisting of 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

80. The tert-butylamine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKα radiation, the X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2°, in combination with peaks at 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2°, and 19.3°±0.2°.

81. The terbuthylamine salt according to any one of claims 77 to 80, which is 13 C solid-state NMR (100.6 MHz) spectrum comprising at least one peak referenced to glycine (external reference at 176.5 ppm) selected from the group consisting of 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm).

82. The terbuthylamine salt according to any one of claims 77 to 80, which is 13 The product was characterized by a C solid-state NMR (100.6 MHz) spectrum containing peaks at 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (each ± 0.2 ppm) referenced to glycine (external reference at 176.5 ppm).

83. A pharmaceutical composition comprising the tromethamine salt of any one of claims 65-76, or the erbumine salt of any one of claims 77-82, and a pharmaceutically acceptable carrier.

84. Crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2° and 17.4°±0.2°.

85. Crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid characterized by an X-ray powder diffraction pattern using CuKa radiation, the X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2° and 15.7°±0.2.

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