Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease

Abstract

The present invention relates to Compound (A), pharmaceutically acceptable salts thereof, methods of making, and use thereof optionally in combination with one or more additional therapeutic agents for the treatment of disease.

Description

ALLOSTERIC CHROMENONE INHIBITORS OF PHOSPHOINOSITIDE 3-KINASE (PI3K) FOR THE TREATMENT OF DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims priority to U.S. Provisional Applications 63 / 421,716, filed November 02, 2022 (Attorney Docket 30461_US_PRI); 63 / 382,999, filed November 09, 2022 (Attorney Docket 30461A_US_PRI); 63 / 383,206, filed November 10, 2022 (Attorney Docket 30461B_US_PRI); and 63 / 488,875, filed March 07, 2023 (Attorney Docket 30461C_US_PRI); the content of each of which is herein incorporated by reference in its entirety. TECHNICAL FIELD [2] The present invention is directed to 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid (“Compound A”), pharmaceutically acceptable salts thereof, and use thereof optionally in combination with one or more additional therapeutic agents for the treatment of disease. BACKGROUND [3] The PIK3CA gene encoding the phosphoinositide 3-kinase (PI3K) catalytic isoform p110α is the most frequently mutated gene in solid tumors and is also the most frequent site of genetic alteration within the PI3K pathway. PIK3CA mutations are most frequently found in endometrial, breast, and head and neck cancers. Approximately 40% of patients with HR+ / HER2- breast cancer harbor activating mutations in PIK3CA, which activates p110α and the PI3K / AKT / mTOR signaling network. H1047R is the most common missense mutation in PIK3CA. [4] Activating mutations in PIK3CA are associated with resistance to endocrine therapy and disease progression. Emergence of new driver mutations in PIK3CA may also be a mechanism of resistance to CDK4 / 6 inhibitor therapy. Resistance to paclitaxel has also been associated with PI3K / mTOR pathway activation in preclinical models. [5] Several PI3K-targeting agents have been tested in breast cancer patients. In a randomized Phase 3 study (SOLAR-1; NCT02437318), the PI3Kα specific inhibitor alpelisib in combination with fulvestrant increased progression-free survival to 11.0 months compared to5.7 months with fulvestrant alone, leading to FDA approval of alpelisib in combination with fulvestrant for the treatment of HR+ / HER2- PIK3CA-mutant advanced or metastatic breast cancer patients. While this approval represented a significant therapeutic advancement for PIK3CA-mutant breast cancer, alpelisib along with other investigational PI3Kα inhibitors in the clinic, inhibit both wild-type (WT) and mutated PI3Kα with approximately equal potency. As a result, their efficacy is potentially limited by on-target WT PI3Kα mediated toxicity including dose-limiting hyperglycemia as well as cutaneous and GI toxicity, that has somewhat limited the broad clinical utility of PI3Kα inhibitors. For example, in the SOLAR- 1 trial, adverse events that occurred in at least 35% of participants in either of the alpelisib / fulvestrant or placebo / fulvestrant groups 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%), respectively (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). Furthermore, hyperglycemia and rash were the most frequent AEs leading to discontinuation of alpelisib. Percentages of participants who discontinued alpelisib and placebo due to AEs were 25.0% and 4.2%, respectively (Andre et al.2019). [6] There is a need for PI3Kα inhibitors with improved therapeutic indices, and for 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, to achieve effective disease treatment, maximize patient compliance, convenience, and tolerability, while limiting dose interruptions and discontinuations, and minimizing the risk of adverse events, such as hyperglycemia, diarrhea, nausea, decreased appetite, and rash. There is also a need for solid forms of PI3Kα inhibitors having advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. SUMMARY [7] In one aspect, provided are solid forms of Compound A. [8] In another aspect, provided are pharmaceutically acceptable salts of Compound A, and solid forms thereof.[9] In another aspect, provided are therapies including Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of disease, such as PIK3CA-mutated cancer.

[0010] In another aspect, provided are doses and dosing regimens including Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of disease, such as PIK3CA- mutated cancer. BRIEF DESCRIPTION OF THE FIGURES

[0011] FIG.1 is an XRPD pattern of crystalline Compound A Form A.

[0012] FIG.2 is an XRPD pattern of crystalline Compound A Form B.

[0013] FIG.3 is an XRPD pattern of crystalline Compound A Form C.

[0014] FIG.4 is an XRPD pattern of crystalline Compound A Tromethamine Salt Form A.

[0015] FIG.5 is an XRPD pattern of crystalline Compound A Tromethamine Salt Form C.

[0016] FIG.6 is an XRPD pattern of crystalline Compound A Tromethamine Salt Form D.

[0017] FIG.7 is an XRPD pattern of a crystalline Compound A Erbumine Salt. DETAILED DESCRIPTION

[0018] The compound 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid (“Compound A”) is a potent and mutant-selective inhibitor of PI3Kα H1047R.

[0019] In one aspect, provided herein are solid forms of Compound A. Compound A Form A

[0020] 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 anembodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2-theta of 12.1° ± 0.2° in combination with the peaks 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 angle 2-theta 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°. Compound A Form B

[0021] 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 an embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 CuKa radiation having a peak at diffraction angle 2-theta 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 powderdiffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2- theta 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 CuKa radiation having peaks at diffraction angle 2-theta of 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2°, and 17.4° ± 0.2°. Compound A Form C

[0022] 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 an embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having a peak at diffraction angle 2-theta 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 CuKa radiation having peaks at diffraction angle 2-theta of 7.4° ± 0.2°, 8.5° ± 0.2°, 10.6° ± 0.2°, 13.4° ± 0.2°, and 15.7° ± 0.2°.

[0023] In another aspect, provided herein is a tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain tromethamine salts ofCompound A may have advantageous 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 a chiral enhancement of Compound A upon crystallization of the tromethamine salt. Compound A Tromethamine Salt Form A

[0024] 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, referred to as Compound A Tromethamine Salt Form A. In an 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 diffraction angle 2-theta selected from 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta of 6.4° ± 0.2° in combination with the peaks 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 having peaks at diffraction angle 2-theta 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°.

[0025] In another embodiment, Compound A Tromethamine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced toglycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively). In another embodiment, Compound A Tromethamine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively). In another embodiment, Compound A Tromethamine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises 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 (± 0.2 ppm, respectively). Compound A Tromethamine Salt Form C

[0026] 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, referred to as Compound A Tromethamine Salt Form C. In an embodiment, Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 an embodiment, Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2°, and 17.4° ± 0.2°.Compound A Tromethamine Salt Form D

[0027] 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, referred to as Compound A Tromethamine Salt Form D. In an embodiment, Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 having a peak at diffraction angle 2-theta 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 an embodiment, Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2°, and 18.9° ± 0.2°.

[0028] In another aspect, provided herein is an erbumine salt of 2-[[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain erbumine salts of Compound A may have advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain erbumine salts of Compound A may have processability or other manufacturing advantages. Compound A Erbumine Salt Form A

[0029] In another aspect, provided is a crystalline erbumine salt of 2-[[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid, referred to as Compound A Erbumine Salt Form A. In an embodiment, Compound A Erbumine Salt Form A is characterized by anX-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 Erbumine Salt Form A is characterized by an X- ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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 Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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 Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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 Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 11.1° ± 0.2° in combination with the peaks 10.5° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, and 19.3° ± 0.2°. In an embodiment, Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta 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°.

[0030] In another embodiment, Compound A Erbumine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively). In another embodiment, Compound A Erbumine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (± 0.2 ppm, respectively). In another embodiment, Compound A Erbumine Salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises 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 (± 0.2ppm, respectively). Therapeutic Uses

[0031] Also provided herein are therapies including Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of patients with a disease, including PIK3CA- mutated cancer, such as PIK3CA-mutated advanced or metastatic breast cancer, or other solid tumors with a PIK3CA mutation. Compound A, or a pharmaceutically acceptable salt thereof, may be used in monotherapy or in combination with one or more additional therapeutic agents. The therapies may provide new treatment options for patients, and may provide an enhanced and / or unexpected beneficial therapeutic effect in some patients over known therapies.

[0032] The efficacy of a cancer treatment can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, best overall response, disease control rate, clinical benefit rate, time to response, and quality of life. Therapeutic agents may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Novel approaches to determining efficacy of any particular mono- or combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and / or cell cycle activity, tissue-based biomarkers for angiogenesis and / or cell cycle activity, and measurement of response through radiological imaging.

[0033] In one aspect, provided is a method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, provided is a method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, provided is a method of treating a patient with PIK3CA-mutatedbreast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0038] In another aspect, provided is a method of treating a patient with hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0039] In another aspect, provided is a method of treating a patient with 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, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0040] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 one or more therapeutic agents. In some embodiments, combination of an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, with an effective amount of the one or more therapeutic agents may provide an additive or synergistic effect in the treatment of PIK3CA-mutated cancer. In some embodiments, an effective amount of one or more of the therapeutic agents (e.g., a taxane, such as paclitaxel) in the combination therapy may be less than an effective amount of the agent in treatment of PIK3CA-mutated cancer where Compound A, or a pharmaceutically acceptable salt thereof, is not administered in combination with the one or more agents.

[0041] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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; 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 apharmaceutically 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 antiandrogen, 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; an 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.

[0042] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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.

[0043] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0044] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of 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.

[0045] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of 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.

[0046] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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.

[0047] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of aSERD, or a pharmaceutically acceptable salt thereof.

[0048] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0050] In another aspect, provided is a method of treating a patient with hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-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 fulvestrant.

[0051] In another aspect, provided is a method of treating a patient with 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, 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.

[0052] In another aspect, provided is a method of treating a patient with hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-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 imlunestrant.

[0053] In another aspect, provided is a method of treating a patient with 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, 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 imlunestrant.

[0054] In another aspect, provided is a method of treating a patient with PIK3CA-mutatedcancer, 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.

[0055] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0056] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of 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.

[0057] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of 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.

[0058] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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.

[0059] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0060] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of 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.

[0061] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of 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.

[0062] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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.

[0063] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0064] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0065] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0067] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of anmTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0068] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0070] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 platinum agent.

[0071] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a platinum agent.

[0072] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an anthracycline, or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anthracycline, or a pharmaceutically acceptable salt thereof.

[0074] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0075] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of animmune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0076] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an antiandrogen, or a pharmaceutically acceptable salt thereof.

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

[0078] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an anti- HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0079] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0080] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0082] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an MEK inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0084] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0086] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 SERD, or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0087] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0088] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0089] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

[0090] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 atopoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0092] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 SERM, or a pharmaceutically acceptable salt thereof.

[0093] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of SERM, or a pharmaceutically acceptable salt thereof.

[0094] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 PARP inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0096] In another aspect, provided is a method of treating a patient with PIK3CA-mutated 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 platinum agent; and (ii) an effective amount of a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0097] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of 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.

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

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

[0100] In another aspect, provided is a method of treating a patient with CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS), comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0101] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with mutant phosphoinositide 3- kinase (PI3K).

[0102] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3CA-mutated cancer.

[0103] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PIK3CA-mutated solid tumor.

[0104] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3CA-mutated breast cancer.

[0105] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0106] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer.

[0107] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in 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.

[0108] In another aspect, provided is Compound A, or a pharmaceutically acceptable saltthereof, for use in simultaneous, separate, or sequential 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; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, 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; an 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; in the treatment of PIK3CA-mutated cancer.

[0109] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0110] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0111] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0112] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0113] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERD, or apharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0114] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0115] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0116] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0117] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with fulvestrant, in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer.

[0118] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with fulvestrant, in 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.

[0119] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with imlunestrant, in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer.

[0120] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with imlunestrant, in 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.

[0121] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with (i) a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a SERD, or apharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0122] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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 a PIK3CA-mutated solid tumor.

[0123] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated breast cancer.

[0124] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

[0125] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated cancer.

[0126] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated solid tumor.

[0127] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated breast cancer.

[0128] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

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

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

[0131] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0132] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0133] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0134] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0135] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0136] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0137] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent in the treatment of PIK3CA-mutated cancer.

[0138] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent inthe treatment of a PIK3CA-mutated solid tumor.

[0139] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0140] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0141] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0142] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0143] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate in the treatment of PIK3CA- mutated cancer.

[0144] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate in the treatment of a PIK3CA-mutated solid tumor.

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

[0146] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a KRAS inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0147] In another aspect, provided is Compound A, or a pharmaceutically acceptable saltthereof, for use in simultaneous, separate, or sequential combination with an MEK inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

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

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

[0150] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0151] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated cancer.

[0152] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated solid tumor.

[0153] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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-mutated cancer.

[0154] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential 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 a PIK3CA- mutated solid tumor.

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

[0156] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0157] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0158] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0159] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a PARP inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

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

[0161] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0162] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0163] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

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

[0165] In another aspect, provided is Compound A, or a pharmaceutically acceptable salt thereof, for use in the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0166] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0167] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of PIK3CA- mutated cancer.

[0168] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA- mutated solid tumor.

[0169] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of PIK3CA- mutated breast cancer.

[0170] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of PIK3CA- mutated, advanced or metastatic breast cancer.

[0171] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutated, advanced or metastatic breast cancer.

[0172] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament 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.

[0173] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, 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; an 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.

[0174] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0175] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0176] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0177] In another aspect, provided is the use of Compound A, or a pharmaceutically saltthereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0178] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof.

[0179] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof.

[0180] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof.

[0181] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof.

[0182] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R- mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with fulvestrant.

[0183] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament 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, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with fulvestrant.

[0184] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R- mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with imlunestrant.

[0185] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament 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, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with imlunestrant.

[0186] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a SERD, or a pharmaceutically acceptable salt thereof.

[0187] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a SERD, or a pharmaceutically acceptable salt thereof.

[0188] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a CDK4 and 6inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a SERD, or a pharmaceutically acceptable salt thereof.

[0189] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) a SERD, or a pharmaceutically acceptable salt thereof.

[0190] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0191] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0192] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0193] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0194] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof.

[0195] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof.

[0196] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof.

[0197] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof.

[0198] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0199] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0200] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer,wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0201] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0202] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a platinum agent.

[0203] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a platinum agent.

[0204] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof.

[0205] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof.

[0206] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0207] In another aspect, provided is the use of Compound A, or a pharmaceutically saltthereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0208] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0209] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0210] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0211] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0212] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an MEK inhibitor, or a pharmaceutically acceptable salt thereof.

[0213] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to beadministered in simultaneous, separate, or sequential combination with an MEK inhibitor, or a pharmaceutically acceptable salt thereof.

[0214] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

[0215] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

[0216] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a SERD, or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0217] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a SERD, or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0218] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0219] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solidtumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential 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.

[0220] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0221] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0222] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof.

[0223] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof.

[0224] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

[0225] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to beadministered in simultaneous, separate, or sequential combination with a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

[0226] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0227] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0228] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0229] In another aspect, provided is the use of Compound A, or a pharmaceutically salt thereof, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor, wherein Compound A, or pharmaceutically acceptable salt thereof, is to be administered in simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0230] In another aspect, provided is the use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0231] In an embodiment, the PIK3CA-mutated cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid / rhabdoid tumor, primary CNSlymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0232] In an embodiment, the PIK3CA-mutated cancer is endometrial cancer, breast cancer, oesophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma,ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germ- cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0233] In an embodiment, the PIK3CA-mutated cancer is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0234] In an embodiment, the PIK3CA-mutated cancer is breast cancer, prostate cancer, or brain cancer. In an embodiment, the PIK3CA-mutated cancer is breast cancer. In an embodiment, the PIK3CA-mutated cancer is prostate cancer. In an embodiment, the PIK3CA-mutated cancer is brain cancer.

[0235] In an embodiment, the PIK3CA-mutated cancer is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm. In an embodiment, the PIK3CA-mutated cancer is a breast neoplasm. In an embodiment, the PIK3CA-mutated cancer is a thyroid neoplasm. In an embodiment, the PIK3CA-mutated cancer is an ovarian neoplasm. In an embodiment, the PIK3CA- mutated cancer is non-small-cell lung carcinoma. In an embodiment, the PIK3CA-mutated cancer is an endometrial neoplasm. In an embodiment, the PIK3CA-mutated cancer is a pancreatic neoplasm.

[0236] In an embodiment, the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer. In an embodiment, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In an embodiment, the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In an embodiment, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer. In an embodiment, thePIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0237] In an embodiment, the PIK3CA-mutated solid tumor is a PIK3CA-mutated advanced solid tumor. In an embodiment, the PIK3CA-mutated advanced solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer. In an embodiment, the PIK3CA-mutated advanced solid tumor is gynecological cancer. In an embodiment, the PIK3CA-mutated advanced solid tumor is head and neck cancer. In an embodiment, the PIK3CA-mutated advanced solid tumor is triple negative breast cancer.

[0238] In an embodiment, the patient is a female.

[0239] In an embodiment, the patient is a postmenopausal female.

[0240] In an embodiment, the patient has type I diabetes mellitus. In an embodiment, the patient has type II diabetes mellitus.

[0241] In an embodiment, the patient has not received prior therapy with a PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0242] In an embodiment, the patient has received prior therapy with a PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0243] In an embodiment, the patient has not received prior therapy with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0244] In an embodiment, the patient has received prior therapy with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0245] In an embodiment, the patient has progressed or relapsed on or after endocrine therapy, alone or in combination with a CDK4 / 6 inhibitor. Dosages

[0246] Compound A, or a pharmaceutically acceptable salt thereof, and the 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 the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0247] It is to be understood Compound A may be administered as the non-salt free acid form, or a pharmaceutically acceptable salt thereof; however unless indicated otherwise, administered amounts of Compound A, or a pharmaceutically acceptable salt thereof, are expressed herein based on weight of the non-salt free acid form of Compound A.

[0248] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg to 2400 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg to 2000 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg to 1200 mg.

[0249] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 500 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 800 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1000 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1200 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1400 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1600 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg. In an embodiment, Compound A, or apharmaceutically salt thereof, is administered at a total daily dose of 1900 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2000 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2300 mg. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2400 mg.

[0250] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 500 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 800 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1000 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1200 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1400 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1600 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg in a 28-daycycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 1900 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2000 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2300 mg in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a total daily dose of 2400 mg in a 28-day cycle.

[0251] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 100 mg to 1200 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg to 1000 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 300 mg to 600 mg twice a day.

[0252] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 100 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 500 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 550 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day. In anembodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 700 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 900 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1100 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1200 mg twice a day.

[0253] In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 100 mg to 1200 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg to 1000 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 100 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day in a 28-day cycle. In an embodiment,Compound A, or a pharmaceutically salt thereof, is administered at a dose of 500 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 550 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 700 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 900 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1100 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day in a 28-day cycle. In an embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1200 mg twice a day in a 28-day cycle.

[0254] In a preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day in a 28-day cycle. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day in a 28-day cycle. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day in a 28-day cycle. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day in a 28-day cycle.

[0255] In a preferred embodiment, Compound A, or a pharmaceutically 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 pharmaceutically 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 pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 300 mg once a day. In another preferred embodiment, Compound A, or a pharmaceutically salt thereof, is administered at a dose of 600 mg once a day. Pharmaceutical Compositions

[0256] Compound A, or a pharmaceutically salt thereof, can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Compound A, or a pharmaceutically salt thereof can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0257] Compound A, or a pharmaceutically salt thereof, or a pharmaceutical composition thereof, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0258] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.Synthetic Methods

[0259] Compound A can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compound A can be synthesized by following the steps outlined in General Schemes 1 and 2. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below. Scheme 1

[0260] Scheme 1 depicts an exemplary preparation of Compound A. Acylation of substituted phenol (1) can provide ester (2). Ester (2) can undergo rearrangement under Lewis acid (e.g., AlCl3) or Brønsted acid (e.g., triflic acid) conditions to the hydroxy aryl ketone (3). Acidic condensation of an aryl aldehyde with hydroxy aryl ketone (3) can provide keto-alkene (4) which can cyclize to the 2-substituted chromen-4-one (5). Alternatively, alkylation ofhydroxy aryl ketone (3) with an aryl halide in the presence of a base (e.g., pyridine or lithium bis(trimethylsilyl)amide), followed by acidic conditions (e.g., HCl) can affect cyclization to 2-substituted chromen-4-one (5).

[0261] Phenyl bromide (5) can be acylated via palladium catalysis to produce acyl chromen-4- one (6). Exemplary palladium catalysis 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 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 butyl vinyl ether, about 3 equivalents triethylamine, and about 10 volumes of ethylene glycol at about 100°C for about 16 hours. Condensation of ketone (6) with tert-butanesulfinamide using a Lewis acidic dehydrating agent such as a titanium(IV) alkoxide can afford ketimine (7). Asymmetric reduction of sulfinimine (7) can be affected with a borohydride reagent in the presence of a transition metal catalyst such as cerium (III) chloride to yield chirally enriched sulfinamide (8). Removal of the sulfinyl group under acidic conditions may be used to transform sulfinamide (8) to benzylamine (9) which can be alkylated with aryl halide (10) under Finkelstein or Ullmann-type conditions to give Compound A. Scheme 2

[0262] Scheme 2 depicts another exemplary preparation of Compound A. Ketone (6) can bereduced to hydroxy compound (11) with a chiral catalyst such as the Noyori catalyst. The hydroxyl group can be converted into a leaving group with methanesulfonic anhydride or methanesulfonyl chloride to give mesylate (12). Mesylate (12) can be used to alkylate arylamine (13) to give Compound A. Alternatively, ketone (6) can be reduced to hydroxy compound (14) with a chiral catalyst such as the Noyori catalyst. The hydroxyl group can be converted to chloride (15) with a chlorinating agent such as 2,4,6-trichloro-1,3,5-triazine. Chloride (15) can then be used to alkylate arylamine (13) to give Compound A. Definitions

[0263] A “CDK4 and 6 inhibitor” or alternatively a "CDK4 / 6 inhibitor" refers to a molecule that inhibits the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinases (CDK4 and 6) protein complexes (e.g., cyclinD:CDK4 and 6 complexes), and generally functions to block transition from the G1 to S phase of cell cycle through inhibition of kinase activity. In some embodiments, the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is abemaciclib, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the CDK4 and 6 inhibitor is abemaciclib.

[0264] Palbociclib, [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridine-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 an initial endocrine based therapy in postmenopausal women or in men, or (ii) in combination with fulvestrant in patients with disease progression following endocrine therapy.

[0265] Palbociclib is taken orally and is available as capsules (125 mg, 100 mg, and 75 mg) with a recommended starting dosage of 125 mg, once daily for 21 days followed by 7 days of off treatment. Palbociclib may be prepared as the free base or as a pharmaceutically acceptable salt, including mono- and di-acid addition salts such as, for example, the mono- isethionate salt, polymorphic forms of the isethionate salt, or the hydrochloride salt (see, e.g., WO 2003 / 062236, WO 2005 / 005426, WO 2008 / 032157, U.S. Pat. Nos.6,936,612; 7,208,489; 7,345,171; 7,456,168; 7,781,583; and 7,863,278). Palbociclib in its free base formmay be anhydrous or may contain varying amounts of water or one or more solvents (see, e.g., U.S. Pat. No.10,723,730).

[0266] Ribociclib, [7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridine-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 an initial endocrine-based therapy in pre / perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant in postmenopausal women as an initial endocrine-based therapy or following disease progression on endocrine therapy.

[0267] Ribociclib is taken orally and is available as tablets (200 mg, equivalent to 254.40 mg ribociclib succinate) with a recommended starting dosage of 600 mg, (3x 200 mg tablets) taken once daily for 21 days followed by 7 days of off treatment. Ribociclib may be prepared as the free base or as a pharmaceutically acceptable salt, such as ribociclib succinate (see, e.g., U.S. Pat. Nos.9,868,739; 9,193,732).

[0268] Abemaciclib, [5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3- isopropyl-2-methyl-3H-benzoimidazol-5-yl )-pyrimidin-2-yl ]-amine, its salt forms including the hydrochloride and mesylate salts, and methods of making and using the compound including for the treatment of cancer, in particular, breast cancer are disclosed in WO2010 / 075074.

[0269] Abemaciclib is approved for the treatment of several breast cancer indications, including (i) in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR+, HER2- node-positive, early breast cancer at high risk of recurrence; (ii) in combination with an aromatase inhibitor 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 with disease progression following endocrine therapy; and (iv) as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following 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 at a dose of 50 mg to 200 mg twice a day. Also preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg to 150 mg twice a day. Alsopreferably, 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 in a 28-day cycle. Preferably, abemaciclib is administered orally. Preferably, abemaciclib is administered by capsule. Also preferably, abemaciclib is administered by tablet.

[0270] A selective estrogen receptor degrader (“SERD”) refers to a molecule that binds to the estrogen receptor (ER) and downregulates ER-mediated transcriptional activity. In some embodiments, the SERD is fulvestrant, imlunestrant, giredestrant, amcenestrant, rintodestrant, AZD9833, or LSZ102, or a pharmaceutically acceptable salt thereof. In some embodiments, the SERD is fulvestrant, or imlunestrant, or a pharmaceuticaly acceptable salt thereof. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is imlunestrant.

[0271] Fulvestrant is a SERD approved for the treatment of HR+ metastatic breast cancer as either a monotherapy or as a combination therapy with approved CDK4 / 6 inhibitors. Fulvestrant is also approved in combination with alpelisib, specifically for PIK3CA mutated HR+ HER2- advanced breast cancer. Fulvestrant is formulated as an injectable (intravenous (IV) or intramuscular (IM)). Preferably fulvestrant is administered as described on the approved label, for example, the recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter.

[0272] Imlunestrant, (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. This compound may be prepared as a free base or a pharmaceutically acceptable salt thereof, using the synthetic steps described in WO20 / 014435 or US10,654,866. In a Phase 1 study, imlunestrant monotherapy had a favorable safety profile and demonstrated encouraging anti- tumor activity in patients with heavily pretreated, ER+ HER2- advanced breast cancer. Imlunestrant remains under evaluation in a Phase 1b dose expansion of imlunestrant (as monotherapy and in combination with everolimus, abemaciclib, alpelisib, or trastuzumab). Additionally, the pivotal Phase 3 study of imlunestrant is underway. Preferably, imlunestrant is administered at a dose of 200 mg to 400 mg once a day, more preferably imlunestrant is administered at a dose of 400 mg once a day. Preferably, imlunestrant is administered at a dose of 200 mg to 400 mg once a day in a 28-day cycle, more preferably imlunestrant isadministered at a dose of 400 mg once a day in a 28-day cycle. Preferably, imlunestrant is administered orally. Preferably, imlunestrant is administered by capsule. Also preferably, imlunestrant is administered by tablet.

[0273] An “aromatase inhibitor” refers to a molecule that inhibits the enzyme aromatase, which is responsible for converting androgens (produced by women in the adrenal glands) to estrogen. 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 as a 1 mg oral dose once daily. In some embodiments, the aromatase inhibitor is letrozole. Preferably, letrozole is administered as a 2.5 mg oral dose once daily, or as a 2.5 mg oral dose once every other day for patients with cirrhosis or severe hepatic impairment. In some embodiments, the aromatase inhibitor is exemestane. Preferably, exemestane is administered as a 25 mg oral dose once daily.

[0274] A “taxane” refers to a molecule in the class of diterpenes that exert an anticancer effect by stabilization of 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, which suppresses microtubule dynamics, and is approved for the treatment of metastatic breast cancer. Paclitaxel is formulated as an injectable (intravenous (IV)). Preferably paclitaxel is administered as described on the approved label, for example, a 80 mg / m2injection on day 8, day 15, and day 22 of a first dose cycle, and then on day 1, day 8, day 15, and day 22 of all subsequent dose cycles. Beyond the first dose cycle, dosage at day 22 may be optional.

[0275] An “immune checkpoint inhibitor” refers to a molecule that inhibits the function of an immune checkpoint protein. 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.

[0276] An “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 mTORinhibitor is everolimus. In some embodiments, the mTOR inhibitor is RMC-5552.

[0277] A “tyrosine kinase inhibitor” refers to a molecule that inhibits a 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.

[0278] A “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.

[0279] An “antiandrogen” refers to a molecule that inhibits androgen hormones or androgen- regulated molecules. In some embodiments, the antiandrogen is abiraterone, enzalutamide, nilutamide, or flutamide. In some embodiments, the antiandrogen is abiraterone. In some embodiments, the antiandrogen is enzalutamide. In some embodiments, the antiandrogen is nilutamide. In some embodiments, the antiandrogen is flutamide.

[0280] An “anti-HER2 monoclonal antibody” refers to a recombinant humanized anti-HER2 monoclonal antibody used for the treatment of 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.

[0281] An “anti-HER2 antibody-drug conjugate” refers to a recombinant humanized anti- HER2 monoclonal antibody linked to a biologically active payload or drug, where the anti- HER2 antibody-drug conjugate is used for the treatment of HER2 positive cancer. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab emtansine.

[0282] An “anthracycline” generally refers to a type of antineoplastic antibiotic that come from certain types of Streptomyces bacteria. In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin or idarubicin. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the anthracycline is daunorubicin. In some embodiments, the anthracycline is epirubicin. In some embodiments, the anthracycline is idarubicin.

[0283] A “KRAS inhibitor” refers to a molecule that inhibits a “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.

[0284] An “MEK inhibitor” refers to a molecule that inhibits a mitogen-activated protein kinase kinase. In some embodiments, the MEK inhibitor is trametinib.

[0285] An “ERK inhibitor” refers to a molecule that inhibits an extracellular signal-regulated kinase.

[0286] A “topoisomerase inhibitor” refers to a molecule that inhibits topoisomerases, such as type I topoisomerases or type II topoisomerases. In some embodiments, the topoisomerase inhibitor is etoposide.

[0287] A “SERM” refers to a selective estrogen receptor modulator that blocks estrogen from attaching 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.

[0288] A “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.

[0289] As used herein, the terms “treating”, “to treat”, or “treatment” refer to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

[0290] As used herein, the term “patient” refers to a mammal, preferably, a human.

[0291] As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.

[0292] As used herein, the term "advanced" or "metastatic" means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.

[0293] As used herein, the term “effective amount” refers to the amount or dose of a therapeutic agent, or a pharmaceutically acceptable salt thereof, for example Compound A or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment.

[0294] As used herein, the term “effective response” of a patient or a patient’s “responsiveness” to treatment with a therapeutic agent, or a pharmaceutically acceptable salt thereof, refers to the clinical or therapeutic benefit imparted to a patient upon administrationof the therapeutic agent, or pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof.

[0295] As used herein, the term “in combination with” refers to the administration of a therapeutic agent, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, either separately, simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.

[0296] As used herein, “prior therapy” refers to treatment that was previously administered or used in an effort to treat the cancer (e.g., prior treatment with medications, surgery, or radiation to treat the cancer). In some embodiments, a patient has previously had endocrine therapy to treat the cancer.

[0297] As used herein, the term “tromethamine” may otherwise be referred to as tris(hydroxymethyl)aminomethane or tris.

[0298] As used herein, the term “erbumine” may otherwise be referred to as tert-butylamine.

[0299] As used herein, the term “endocrine therapy” refers to hormone therapy that is used to treat cancer. Exemplary endocrine therapies include tamoxifen or a pharmaceutically acceptable salt thereof, and aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane). Exemplary Aspects

[0300] Various aspects of the invention are set forth in the following numbered clauses.

[0301] Clause 1. A compound that is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid; or a pharmaceutically acceptable salt thereof.

[0302] Clause 2. A compound that is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid.

[0303] Clause 3. A compound that is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl- chromen-8-yl)ethyl]amino]benzoic acid.

[0304] Clause 4. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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°.

[0305] Clause 5. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0306] Clause 6. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0307] Clause 7. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0308] Clause 8. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.1° ± 0.2° in combination with the peaks 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2°, and 20.7° ± 0.2°.

[0309] Clause 9. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta 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°.

[0310] Clause 10. The compound of any one of clauses 1-3, having an X-ray powder diffraction pattern substantially as shown in FIG.1.

[0311] Clause 11. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2°, and 17.4° ± 0.2°.

[0312] Clause 12. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0313] Clause 13. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0314] Clause 14. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0315] Clause 15. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2°, and 17.4° ± 0.2°.

[0316] Clause 16. The compound of any one of clauses 1-3, having an X-ray powder diffraction pattern substantially as shown in FIG.2.

[0317] Clause 17. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 7.4° ± 0.2°, 8.5° ± 0.2°, 10.6° ± 0.2°, 13.4° ± 0.2°, and 15.7° ± 0.2°.

[0318] Clause 18. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0319] Clause 19. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0320] Clause 20. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0321] Clause 21. The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 7.4° ± 0.2°, 8.5° ± 0.2°, 10.6° ± 0.2°, 13.4° ± 0.2°, and 15.7° ± 0.2°.

[0322] Clause 22. The compound of any one of clauses 1-3, having an X-ray powder diffraction pattern substantially as shown in FIG.3.

[0323] Clause 23. A tromethamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.

[0324] Clause 24. The tromethamine salt of clause 23, that is crystalline.

[0325] Clause 25. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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°.

[0326] Clause 26. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0327] Clause 27. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0328] Clause 28. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0329] Clause 29. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 6.4° ± 0.2° in combination with the peaks 8.4° ± 0.2°, 10.9° ± 0.2°, 16.9° ± 0.2°, and 22.1° ± 0.2°.

[0330] Clause 30. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta 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°.

[0331] Clause 31. The tromethamine salt of clause 23 or clause 24, having an X-ray powder diffraction pattern substantially as shown in FIG.4.

[0332] Clause 32. The tromethamine salt of any one of clauses 23-31, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

[0333] Clause 33. The tromethamine salt of any one of clauses 23-31, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively).

[0334] Clause 34. The tromethamine salt of any one of clauses 23-31, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively).

[0335] Clause 35. The tromethamine salt of any one of clauses 23-31, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises 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 (± 0.2 ppm, respectively).

[0336] Clause 36. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2°, and 17.4° ± 0.2°.

[0337] Clause 37. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0338] Clause 38. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0339] Clause 39. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0340] Clause 40. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2°, and 17.4° ± 0.2°.

[0341] Clause 41. The tromethamine salt of clause 23 or clause 24, having an X-ray powder diffraction pattern substantially as shown in FIG.5.

[0342] Clause 42. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2°, and 18.9° ± 0.2°.

[0343] Clause 43. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0344] Clause 44. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0345] Clause 45. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0346] Clause 46. The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2°, and 18.9° ± 0.2°.

[0347] Clause 47. The tromethamine salt of clause 23 or clause 24, having an X-ray powder diffraction pattern substantially as shown in FIG.6.

[0348] Clause 48. An erbumine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid.

[0349] Clause 49. The erbumine salt of clause 48, that is crystalline.

[0350] Clause 50. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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°.

[0351] Clause 51. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of11.1 ° ± 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°.

[0352] Clause 52. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0353] Clause 53. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

[0354] Clause 54. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 11.1 ° ± 0.2° in combination with the peaks 10.5° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, and 19.3° ± 0.2°.

[0355] Clause 55. The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta 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°.

[0356] Clause 56. The erbumine salt of clause 48 or clause 49, having an X-ray powder diffraction pattern substantially as shown in FIG.7.

[0357] Clause 57. The erbumine salt of any one of clauses 48-56, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

[0358] Clause 58. The erbumine salt of any one of clauses 48-56, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (± 0.2 ppm, respectively).

[0359] Clause 59. The erbumine salt of any one of clauses 48-56, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (externalreference at 176.5 ppm) at: 177.4, 132.6, 27.4, 21.3, and 11.3 ppm (± 0.2 ppm, respectively).

[0360] Clause 60. The erbumine salt of any one of clauses 48-56, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises 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 (± 0.2 ppm, respectively).

[0361] 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.

[0362] Clause 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 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.

[0363] Clause 63. A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a 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.

[0364] Clause 64. The method of clause 62 or clause 63, wherein the PI3K is PI3Kα.

[0365] Clause 65. The method of any one of clauses 62-64, wherein the PI3K has a H1047R mutation.

[0366] Clause 66. The method of any one of clauses 63-65, wherein the disease is a cancer.

[0367] 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.

[0368] Clause 68. The method of clause 66, wherein the cancer is breast cancer.

[0369] 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.

[0370] Clause 70. The method of any one of clauses 63-65, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0371] Clause 71. A method of treating a patient with PIK3CA-mutated 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.

[0372] Clause 72. A method of treating a patient with a PIK3CA-mutated 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.

[0373] Clause 73. A method of treating a patient with PIK3CA-mutated 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.

[0374] 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.

[0375] Clause 75. A method of treating a patient with PIK3CA-mutated 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, 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; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, 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; an 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 apharmaceutically acceptable salt thereof; or any combination thereof.

[0376] Clause 76. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0377] Clause 77. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0378] Clause 78. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0379] 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 erbumine 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.

[0380] Clause 80. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0381] Clause 81. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0382] Clause 82. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0383] 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 erbumine 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.

[0384] Clause 84. A method of treating a patient with PIK3CA-mutated 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, 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.

[0385] Clause 85. A method of treating a patient with a PIK3CA-mutated 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, 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.

[0386] Clause 86. A method of treating a patient with PIK3CA-mutated 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, 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.

[0387] 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, anerbumine 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.

[0388] Clause 88. A method of treating a patient with PIK3CA-mutated 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, 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.

[0389] Clause 89. A method of treating a patient with a PIK3CA-mutated 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, 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.

[0390] Clause 90. A method of treating a patient with PIK3CA-mutated 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, 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.

[0391] Clause 91. 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, 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.

[0392] Clause 92. A method of treating a patient with PIK3CA-mutated cancer, comprisingadministering 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, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0393] Clause 93. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0394] Clause 94. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0395] 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 erbumine 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.

[0396] Clause 96. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0397] Clause 97. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0398] Clause 98. A method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, atromethamine 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, in combination with an effective amount of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0399] Clause 99. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0400] Clause 100. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a platinum agent.

[0401] Clause 101. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a platinum agent.

[0402] Clause 102. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0403] Clause 103. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0404] Clause 104. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an antiandrogen, or a pharmaceutically acceptable salt thereof.

[0405] Clause 105. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an antiandrogen, or a pharmaceutically acceptable salt thereof.

[0406] Clause 106. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0407] Clause 107. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.

[0408] Clause 108. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an anthracycline, or a pharmaceutically acceptable salt thereof.

[0409] Clause 109. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an anthracycline, or a pharmaceutically acceptable salt thereof.

[0410] Clause 110. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of aKRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0411] Clause 111. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0412] Clause 112. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an MEK inhibitor, or a pharmaceutically acceptable salt thereof.

[0413] Clause 113. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an MEK inhibitor, or a pharmaceutically acceptable salt thereof.

[0414] Clause 114. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

[0415] Clause 115. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

[0416] Clause 116. A method of treating a patient with PIK3CA-mutated 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, 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.

[0417] Clause 117. A method of treating a patient with a PIK3CA-mutated 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, 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.

[0418] Clause 118. A method of treating a patient with PIK3CA-mutated 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, 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.

[0419] Clause 119. A method of treating a patient with a PIK3CA-mutated 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, 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.

[0420] Clause 120. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0421] Clause 121. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0422] Clause 122. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a SERM, or a pharmaceutically acceptable salt thereof.

[0423] Clause 123. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a SERM, or a pharmaceutically acceptable salt thereof.

[0424] Clause 124. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

[0425] Clause 125. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

[0426] Clause 126. A method of treating a patient with PIK3CA-mutated 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, 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.

[0427] Clause 127. A method of treating a patient with a PIK3CA-mutated 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, 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.

[0428] Clause 128. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0429] Clause 129. A method of treating a patient with a PIK3CA-mutated 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, in combination with an effective amount of an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0430] Clause 130. A method of treating a patient with PIK3CA-mutated 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, in combination with an effective amount of an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0431] 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 erbumine 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.

[0432] 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-mutated cancer is PIK3CA H1047R-mutant cancer.

[0433] 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-mutated 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.

[0434] Clause 134. The method of clause 133, wherein the PIK3CA-mutated cancer is endometrial cancer.

[0435] Clause 135. The method of clause 133, wherein the PIK3CA-mutated cancer is gastric cancer.

[0436] Clause 136. The method of clause 133, wherein the PIK3CA-mutated cancer is leukemia.

[0437] Clause 137. The method of clause 133, wherein the PIK3CA-mutated cancer is lymphoma.

[0438] Clause 138. The method of clause 133, wherein the PIK3CA-mutated cancer is sarcoma.

[0439] Clause 139. The method of clause 133, wherein the PIK3CA-mutated cancer is colorectal cancer.

[0440] Clause 140. The method of clause 133, wherein the PIK3CA-mutated cancer is lung cancer.

[0441] Clause 141. The method of clause 133, wherein the PIK3CA-mutated cancer is ovarian cancer.

[0442] Clause 142. The method of clause 133, wherein the PIK3CA-mutated cancer is skin cancer.

[0443] Clause 143. The method of clause 133, wherein the PIK3CA-mutated cancer is head and neck cancer.

[0444] Clause 144. The method of clause 133, wherein the PIK3CA-mutated cancer is breast cancer.

[0445] Clause 145. The method of clause 133, wherein the PIK3CA-mutated cancer is brain cancer.

[0446] Clause 146. The method of clause 133, wherein the PIK3CA-mutated cancer is prostate cancer.

[0447] 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-mutated solid tumor is a PIK3CA H1047R- mutant solid tumor.

[0448] 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-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0449] Clause 149. The method of clause 148, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0450] Clause 150. The method of clause 148, wherein the PIK3CA-mutated solid tumor is head and neck cancer.

[0451] Clause 151. The method of clause 148, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0452] Clause 152. The method according to clause 73, clause 78, clause 82, clause 86, clause 90, clause 94, or clause 130, wherein the PIK3CA-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0453] Clause 153. The 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 PIK3CA H1047R-mutant advanced or metastatic breast cancer.

[0454] Clause 154. The 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, preferablyestrogen receptor-positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0455] Clause 155. The 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-mutant, advanced or metastatic breast cancer, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0456] Clause 156. The method according to any one of clauses 62-155, wherein the patient is a postmenopausal female.

[0457] Clause 157. The method according to any one of clauses 62-156, wherein the patient has type I diabetes mellitus.

[0458] Clause 158. The method according to any one of clauses 62-156, wherein the patient has type II diabetes mellitus.

[0459] Clause 159. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 200 mg to 2400 mg.

[0460] Clause 160. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 400 mg to 2000 mg.

[0461] Clause 161. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 600 mg to 1200 mg.

[0462] Clause 162. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 400 mg.

[0463] Clause 163. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 450 mg.

[0464] Clause 164. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 500 mg.

[0465] Clause 165. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 550 mg.

[0466] Clause 166. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 600 mg.

[0467] Clause 167. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 650 mg.

[0468] Clause 168. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 700 mg.

[0469] Clause 169. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of750 mg.

[0470] Clause 170. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 800 mg.

[0471] Clause 171. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 850 mg.

[0472] Clause 172. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 900 mg.

[0473] Clause 173. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 950 mg.

[0474] Clause 174. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1000 mg.

[0475] Clause 175. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1050 mg.

[0476] Clause 176. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1100 mg.

[0477] Clause 177. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1150 mg.

[0478] Clause 178. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1200 mg.

[0479] Clause 179. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1250 mg.

[0480] Clause 180. The method according to any one of clauses 62-158, wherein thecompound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1300 mg.

[0481] Clause 181. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1350 mg.

[0482] Clause 182. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1400 mg.

[0483] Clause 183. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1450 mg.

[0484] Clause 184. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1500 mg.

[0485] Clause 185. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1550 mg.

[0486] Clause 186. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1600 mg.

[0487] Clause 187. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1650 mg.

[0488] Clause 188. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1700 mg.

[0489] Clause 189. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1750 mg.

[0490] Clause 190. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1800 mg.

[0491] Clause 191. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1850 mg.

[0492] Clause 192. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1900 mg.

[0493] Clause 193. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1950 mg.

[0494] Clause 194. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2000 mg.

[0495] Clause 195. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2050 mg.

[0496] Clause 196. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2100 mg.

[0497] Clause 197. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2150 mg.

[0498] Clause 198. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2200 mg.

[0499] Clause 199. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2250 mg.

[0500] Clause 200. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2300 mg.

[0501] Clause 201. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of2350 mg.

[0502] Clause 202. The method according to any one of clauses 62-158, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 2400 mg.

[0503] Clause 203. 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 2400 mg once a day.

[0504] Clause 204. 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 to 2000 mg once a day.

[0505] Clause 205. 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 to 1200 mg once a day.

[0506] Clause 206. 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 once a day.

[0507] Clause 207. 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 250 mg once a day.

[0508] Clause 208. 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 once a day.

[0509] Clause 209. 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 350 mg once a day.

[0510] Clause 210. 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 once a day.

[0511] Clause 211. 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 once a day.

[0512] Clause 212. The method according to any one of clauses 62-158, wherein thecompound, the tromethamine salt, or the erbumine salt, is administered at a dose of 500 mg once a day.

[0513] Clause 213. 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 once a day.

[0514] Clause 214. 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 once a day.

[0515] Clause 215. 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 once a day.

[0516] 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.

[0517] Clause 217. 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 once a day.

[0518] Clause 218. 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 800 mg once a day.

[0519] Clause 219. The method according to any one of clauses 62-158, the compound, the tromethamine salt, or the erbumine salt, is administered at a dose of 850 mg once a day.

[0520] Clause 220. 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 900 mg once a day.

[0521] Clause 221. 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 950 mg once a day.

[0522] Clause 222. 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 1000 mg once a day.

[0523] Clause 223. The method according to any one of clauses 62-158, wherein thecompound, the tromethamine salt, or the erbumine salt, is administered at a dose of 1050 mg once a day.

[0524] Clause 224. 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 1100 mg once a day.

[0525] Clause 225. 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 1150 mg once a day.

[0526] Clause 226. 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 1200 mg once a day.

[0527] Clause 227. 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 1250 mg once a day.

[0528] Clause 228. 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 1300 mg once a day.

[0529] Clause 229. 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 1350 mg once a day.

[0530] Clause 230. 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 1400 mg once a day.

[0531] Clause 231. 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 1450 mg once a day.

[0532] Clause 232. 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 1500 mg once a day.

[0533] Clause 233. 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 1550 mg once a day.

[0534] Clause 234. 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 1600 mg once a day.

[0535] Clause 235. 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 1650 mg once a day.

[0536] Clause 236. 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 1700 mg once a day.

[0537] Clause 237. 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 1750 mg once a day.

[0538] Clause 238. 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 1800 mg once a day.

[0539] Clause 239. 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 1850 mg once a day.

[0540] Clause 240. 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 1900 mg once a day.

[0541] Clause 241. 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 1950 mg once a day.

[0542] Clause 242. 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 2000 mg once a day.

[0543] Clause 243. 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 2050 mg once a day.

[0544] Clause 244. 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 2100 mgonce a day.

[0545] Clause 245. 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 2150 mg once a day.

[0546] Clause 246. 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 2200 mg once a day.

[0547] Clause 247. 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 2250 mg once a day.

[0548] Clause 248. 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 2300 mg once a day.

[0549] Clause 249. 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 2350 mg once a day.

[0550] Clause 250. 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 2400 mg once a day.

[0551] Clause 251. 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 to 1200 mg twice a day.

[0552] 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.

[0553] 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.

[0554] 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.

[0555] Clause 255. The method according to any one of clauses 62-158, wherein thecompound, the tromethamine salt, or the erbumine salt, is administered at a dose of 150 mg twice a day.

[0556] Clause 256. 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 twice a day.

[0557] Clause 257. 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 250 mg twice a day.

[0558] Clause 258. 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 twice a day.

[0559] Clause 259. 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 350 mg twice a day.

[0560] 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.

[0561] 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.

[0562] 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.

[0563] 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.

[0564] 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.

[0565] 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.

[0566] Clause 266. 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 twice a day.

[0567] 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.

[0568] Clause 268. 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 800 mg twice a day.

[0569] 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.

[0570] Clause 270. 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 900 mg twice a day.

[0571] Clause 271. 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 950 mg twice a day.

[0572] Clause 272. 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 1000 mg twice a day.

[0573] Clause 273. 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 1050 mg twice a day.

[0574] Clause 274. 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 1100 mg twice a day.

[0575] Clause 275. 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 1150 mg twice a day.

[0576] Clause 276. 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 1200 mgtwice a day.

[0577] Clause 277. The method according to any one of clauses 62-276, wherein the compound, the tromethamine salt, or the erbumine salt, is administered via an oral dosage form.

[0578] Clause 278. The method according to clause 277, wherein the oral dosage form is a tablet.

[0579] 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 pharmaceutically acceptable salt thereof, is palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof.

[0580] 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 pharmaceutically acceptable salt thereof, is abemaciclib.

[0581] Clause 281. The method according to clause 280, wherein abemaciclib is administered as a 50-200 mg oral dose twice a day.

[0582] Clause 282. The method according to clause 280, wherein abemaciclib is administered as a 50 mg oral dose twice a day.

[0583] Clause 283. The method according to clause 280, wherein abemaciclib is administered as a 100 mg oral dose twice a day.

[0584] Clause 284. The method according to clause 280, wherein abemaciclib is administered as a 150 mg oral dose twice a day.

[0585] Clause 285. The method according to clause 280, wherein abemaciclib is administered as a 200 mg oral dose twice a day.

[0586] Clause 286. The method according to any one of clauses 75, 80-87, 116, 117, or 132- 285, wherein the SERD, or pharmaceutically acceptable salt thereof, is fulvestrant, imlunestrant, giredestrant, amcenestrant, rintodestrant, AZD9833, or LSZ102.

[0587] Clause 287. The method according to any one of clauses 75, 80-87, 116, 117, or 132- 285, wherein the SERD, or pharmaceutically acceptable salt thereof, is fulvestrant.

[0588] Clause 288. The method according to clause 287, wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).

[0589] Clause 289. The method according to any one of clauses 75, 80-87, 116, 117, or 132- 285, wherein the SERD, or pharmaceutically acceptable salt thereof, is imlunestrant.

[0590] Clause 290. The method according to clause 289, wherein imlunestrant is administered as a 400 mg oral dose once daily.

[0591] Clause 291. The method according to any one of clauses 75, 88-91, or 128-285, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole, letrozole, or exemestane.

[0592] Clause 292. The method according to clause 291, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole.

[0593] Clause 293. The method according to clause 292, wherein anastrozole is administered as a 1 mg oral dose once daily.

[0594] Clause 294. The method according to clause 291, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is letrozole.

[0595] Clause 295. The method according to clause 294, wherein letrozole is administered as a 2.5 mg oral dose once daily, or as a 2.5 mg oral dose once every other day for patients with cirrhosis or severe hepatic impairment.

[0596] Clause 296. The method according to clause 291, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is exemestane.

[0597] Clause 297. The method according to clause 296, wherein exemestane is administered as a 25 mg oral dose once daily.

[0598] Clause 298. The method according to any one of clauses 75, 92-95, or 132-278, wherein the taxane, or pharmaceutically acceptable salt thereof, is paclitaxel or docetaxel.

[0599] 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.

[0600] Clause 300. The method according to clause 299, wherein paclitaxel is administered as a 80 mg / m2 injection on day 8, day 15, and day 22 of a first dose cycle, and then on day 1, day 8, day 15, and day 22 of all subsequent dose cycles.

[0601] 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 pharmaceutically acceptable salt thereof, is sirolimus, temsirolimus, everolimus, or RMC-5552.

[0602] Clause 302. The method according to clause 301, wherein the mTOR inhibitor, or pharmaceutically acceptable salt thereof, is everolimus.

[0603] Clause 303. The method according to clause 302, wherein the everolimus is administered as a 10 mg oral dose once daily.

[0604] Clause 304. The method according to clause 301, wherein the mTOR inhibitor, or pharmaceutically acceptable salt thereof, is RMC-5552.

[0605] Clause 305. The method according to any one of clauses 75, 98, 99, or 132-278, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is neratinib or afatinib.

[0606] Clause 306. The method according to clause 305, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is neratinib.

[0607] Clause 307. The method according to clause 306, wherein the neratinib is administered as a 240 mg oral dose once daily.

[0608] Clause 308. The method according to clause 305, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is afatinib.

[0609] Clause 309. The method according to clause 308, wherein the afatinib is administered as a 40 mg oral dose once daily, or 30 mg oral dose once daily in patients with severe renal impairment.

[0610] 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.

[0611] Clause 311. The method according to clause 310, wherein the platinum agent is cisplatin.

[0612] Clause 312. The method according to any one of clauses 75, 108, 109, or 132-278, wherein the anthracycline, or pharmaceutically acceptable salt thereof, is doxorubicin, daunorubicin, epirubicin or idarubicin.

[0613] Clause 313. The method according to any one of clauses 75, 102, 103, 118, 119, or 132-285, wherein the immune checkpoint inhibitor, or pharmaceutically acceptable salt thereof, is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

[0614] Clause 314. The method according to clause 313, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0615] Clause 315. The method according to clause 314, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.

[0616] Clause 316. The method according to clause 313, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

[0617] Clause 317. The method according to clause 316, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab.

[0618] Clause 318. The method according to clause 313, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

[0619] Clause 319. The method according to clause 318, wherein the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.

[0620] Clause 320. The method according to any one of clauses 75, 104, 105, or 132-278, wherein the antiandrogen, or pharmaceutically acceptable salt thereof, is abiraterone, enzalutamide, nilutamide, flutamide, or darolutamide, preferably abiraterone, enzalutamide, nilutamide, or flutamide.

[0621] Clause 321. The method according to clause 320, wherein the antiandrogen, or pharmaceutically acceptable salt thereof, is enzalutamide.

[0622] Clause 322. The method according to clause 321, wherein the enzalutamide is administered as a 160 mg oral dose once daily.

[0623] Clause 323. The method according to any one of clauses 75, 106, 107, or 132-278, wherein the anti-HER2 monoclonal antibody is trastuzumab, margetuximab, or pertuzumab.

[0624] Clause 324. The method according to clause 323, wherein the anti-HER2 monoclonal antibody is trastuzumab.

[0625] 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 deruxtecan or trastuzumab emtansine.

[0626] Clause 326. The method according to clause 325, wherein the anti-HER2 antibody- drug conjugate is trastuzumab deruxtecan.

[0627] Clause 327. The method according to any one of clauses 75, 110, 111, or 132-278, wherein the KRAS inhibitor, or pharmaceutically acceptable salt thereof, is sotorasib, or adagrasib.

[0628] Clause 328. The method according to any one of clauses 75, 112, 113, or 132-278, wherein the MEK inhibitor, or pharmaceutically acceptable salt thereof, is trametinib.

[0629] 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 pharmaceutically acceptable salt thereof, is etoposide.

[0630] Clause 330. The method according to any one of clauses 75, 122, 123, or 132-278, wherein the SERM, or pharmaceutically acceptable salt thereof, is tamoxifen or toremifene.

[0631] Clause 331. The method according to any one of clauses 75, 124, 125, or 132-278,wherein the PARP inhibitor, or pharmaceutically acceptable salt thereof, is olaparib or talazoparib.

[0632] Clause 332. The method according to any one of clauses 62-331, wherein the patient has not received prior therapy with a PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0633] Clause 333. The method according to any one of clauses 62-331, wherein the patient received prior therapy with a PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0634] Clause 334. The method according to clause 333, wherein the PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof, was alpelisib or inavolisib.

[0635] Clause 335. The method according to clause 334, wherein the PI3K / AKT / mTOR inhibitor, or a pharmaceutically acceptable salt thereof, was alpelisib.

[0636] Clause 336. The method according to any one of clauses 62-335, wherein the patient has not received prior therapy with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0637] Clause 337. The method according to any one of clauses 62-335, wherein the patient received prior therapy with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0638] Clause 338. The method according to any one of clauses 62-335, wherein the patient received prior therapy with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with endocrine therapy.

[0639] Clause 339. The method according to any one of clauses 62-338, wherein the patient has not received prior therapy with a SERD, or a pharmaceutically acceptable salt thereof.

[0640] Clause 340. The method according to any one of clauses 62-338, wherein the patient received prior therapy with a SERD, or a pharmaceutically acceptable salt thereof.

[0641] Clause 341. The method according to any one of clauses 62-340, wherein the patient has not received prior therapy with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0642] Clause 342. The method according to any one of clauses 62-340, wherein the patient received prior therapy with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0643] Clause 343. The method according to any one of clauses 62-342, wherein the patienthas not received prior therapy with a taxane, or a pharmaceutically acceptable salt thereof.

[0644] Clause 344. The method according to any one of clauses 62-342, wherein the patient received prior therapy with a taxane, or a pharmaceutically acceptable salt thereof.

[0645] 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.

[0646] Clause 346. 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 treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0647] Clause 347. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to clause 346, wherein the PI3K is PI3Kα.

[0648] Clause 348. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to clause 346 or 347, wherein the PI3K has a H1047R mutation.

[0649] Clause 349. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to any one of clauses 346-348, wherein the disease is a cancer.

[0650] Clause 350. The compound, tromethamine salt, erbumine 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.

[0651] Clause 351. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to clause 349, wherein the cancer is breast cancer.

[0652] Clause 352. The compound, tromethamine salt, erbumine 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.

[0653] Clause 353. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to any one of clauses 346-348, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome(PROS).

[0654] Clause 354. 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 the treatment of PIK3CA-mutated cancer.

[0655] Clause 355. 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 the treatment of a PIK3CA-mutated solid tumor.

[0656] Clause 356. 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 the treatment of PIK3CA-mutated breast cancer.

[0657] Clause 357. 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 the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0658] Clause 358. 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 simultaneous, separate, or sequential 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; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, 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; an 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; in the treatment of PIK3CA-mutated cancer.

[0659] Clause 359. 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 compositionof clause 61, for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0660] Clause 360. 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 simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0661] Clause 361. 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 simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0662] Clause 362. 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 simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0663] Clause 363. 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 simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0664] Clause 364. 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 simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0665] Clause 365. 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 simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0666] Clause 366. 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 compositionof clause 61, for use in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0667] Clause 367. 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 simultaneous, separate, or sequential 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-mutated cancer.

[0668] Clause 368. 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 simultaneous, separate, or sequential 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 a PIK3CA-mutated solid tumor.

[0669] Clause 369. 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 simultaneous, separate, or sequential 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-mutated breast cancer.

[0670] Clause 370. 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 simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

[0671] Clause 371. 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 simultaneous, separate, or sequential 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-mutated cancer.

[0672] Clause 372. 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 simultaneous, separate, or sequential combination with (i) a CDK4and 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-mutated solid tumor.

[0673] Clause 373. 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 simultaneous, separate, or sequential 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-mutated breast cancer.

[0674] Clause 374. 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 simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

[0675] Clause 375. 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 simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0676] Clause 376. 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 simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0677] Clause 377. 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 simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0678] Clause 378. 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 simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0679] Clause 379. 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 simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0680] Clause 380. 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 simultaneous, separate, or sequential combination with an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0681] Clause 381. 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 simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA- mutated cancer.

[0682] Clause 382. 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 simultaneous, separate, or sequential combination with a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0683] Clause 383. 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 simultaneous, separate, or sequential combination with a platinum agent, in the treatment of PIK3CA-mutated cancer.

[0684] Clause 384. 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 simultaneous, separate, or sequential combination with a platinum agent, in the treatment of a PIK3CA-mutated solid tumor.

[0685] Clause 385. 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 simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment ofPIK3CA-mutated cancer.

[0686] Clause 386. 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 simultaneous, separate, or sequential combination with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0687] Clause 387. 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 simultaneous, separate, or sequential combination with an antiandrogen, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA- mutated cancer.

[0688] Clause 388. 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 simultaneous, separate, or sequential combination with an antiandrogen, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0689] Clause 389. 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 simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate, in the treatment of PIK3CA- mutated cancer.

[0690] Clause 390. 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 simultaneous, separate, or sequential combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate, in the treatment of a PIK3CA-mutated solid tumor.

[0691] Clause 391. 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 simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA- mutated cancer.

[0692] Clause 392. A compound of any one of clauses 1-22, a tromethamine salt of any one ofclauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in simultaneous, separate, or sequential combination with an anthracycline, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0693] Clause 393. 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 simultaneous, separate, or sequential combination with a KRAS inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0694] Clause 394. 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 simultaneous, separate, or sequential combination with a KRAS inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0695] Clause 395. 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 simultaneous, separate, or sequential combination with an MEK inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0696] Clause 396. 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 simultaneous, separate, or sequential combination with an MEK inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0697] Clause 397. 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 simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0698] Clause 398. 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 simultaneous, separate, or sequential combination with an ERKinhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0699] Clause 399. 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 simultaneous, separate, or sequential 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-mutated cancer.

[0700] Clause 400. 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 simultaneous, separate, or sequential 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-mutated solid tumor.

[0701] Clause 401. 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 simultaneous, separate, or sequential 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-mutated cancer.

[0702] Clause 402. 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 simultaneous, separate, or sequential 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 a PIK3CA- mutated solid tumor.

[0703] Clause 403. 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 simultaneous, separate, or sequential combination with a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0704] Clause 404. 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 simultaneous, separate, or sequential combination with atopoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0705] Clause 405. 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 simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0706] Clause 406. 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 simultaneous, separate, or sequential combination with a SERM, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0707] Clause 407. 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 simultaneous, separate, or sequential combination with a PARP inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0708] Clause 408. 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 simultaneous, separate, or sequential combination with a PARP inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0709] Clause 409. 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 simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0710] Clause 410. 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 simultaneous, separate, or sequential combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA-mutated solid tumor.

[0711] Clause 411. 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 compositionof clause 61, for use in simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated cancer.

[0712] Clause 412. 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 simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of a PIK3CA- mutated solid tumor.

[0713] Clause 413. 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 simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated breast cancer.

[0714] Clause 414. 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 simultaneous, separate, or sequential combination with an aromatase inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated advanced or metastatic breast cancer.

[0715] Clause 415. The compound, tromethamine salt, erbumine 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, or clause 411, wherein the PIK3CA-mutated cancer is PIK3CA H1047R-mutant cancer.

[0716] Clause 416. The compound, tromethamine salt, erbumine 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-mutated 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.

[0717] Clause 417. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is endometrial cancer.

[0718] Clause 418. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is gastric cancer.

[0719] Clause 419. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is leukemia.

[0720] Clause 420. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is lymphoma.

[0721] Clause 421. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is sarcoma.

[0722] Clause 422. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is colorectal cancer.

[0723] Clause 423. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is lung cancer.

[0724] Clause 424. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is ovarian cancer.

[0725] Clause 425. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is skin cancer.

[0726] Clause 426. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is head and neck cancer.

[0727] Clause 427. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is breastcancer.

[0728] Clause 428. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is brain cancer.

[0729] Clause 429. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 416, wherein the PIK3CA-mutated cancer is prostate cancer.

[0730] Clause 430. The compound, tromethamine salt, erbumine 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-mutated solid tumor is a PIK3CA H1047R-mutant solid tumor.

[0731] Clause 431. The compound, tromethamine salt, erbumine 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-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0732] Clause 432. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 431, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0733] Clause 433. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 431, wherein the PIK3CA-mutated solid tumor is head and neck cancer.

[0734] Clause 434. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 431, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0735] Clause 435. The compound, tromethamine salt, erbumine 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-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0736] Clause 436. The compound, tromethamine salt, erbumine 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-mutant advanced or metastatic breast cancer.

[0737] Clause 437. The compound, tromethamine salt, erbumine 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.

[0738] Clause 438. The compound, tromethamine salt, erbumine 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-mutant, advanced or metastatic breast cancer, preferably estrogen receptor-positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0739] Clause 439. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-438, wherein the patient is a postmenopausal female.

[0740] Clause 440. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient has type I diabetes mellitus.

[0741] Clause 441. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient has type II diabetes mellitus.

[0742] Clause 442. 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 total daily dose of 200 mg to 2400 mg.

[0743] Clause 443. 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 total daily dose of 400 mg to 2000 mg.

[0744] Clause 444. 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 total daily dose of 600 mg to 1200 mg.

[0745] Clause 445. 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 total daily dose of 400 mg.

[0746] Clause 446. 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 total daily dose of 450 mg.

[0747] Clause 447. 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 total daily dose of 500 mg.

[0748] Clause 448. 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 total daily dose of 550 mg.

[0749] Clause 449. 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 total daily dose of 600 mg.

[0750] Clause 450. 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 total daily dose of 650 mg.

[0751] Clause 451. 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 total daily dose of 700 mg.

[0752] Clause 452. 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 total daily dose of 750 mg.

[0753] Clause 453. 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 total daily dose of 800 mg.

[0754] Clause 454. 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 total daily dose of 850 mg.

[0755] Clause 455. 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 total daily dose of 900 mg.

[0756] Clause 456. 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 total daily dose of 950 mg.

[0757] 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 at a total daily dose of 1000 mg.

[0758] Clause 458. 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 total daily dose of 1050 mg.

[0759] Clause 459. 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 total daily dose of 1100 mg.

[0760] Clause 460. 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 total daily dose of 1150 mg.

[0761] Clause 461. 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 total daily dose of 1200 mg.

[0762] Clause 462. 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 total daily dose of 1250 mg.

[0763] Clause 463. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, thetromethamine salt, or the erbumine salt, is administered at a total daily dose of 1300 mg.

[0764] Clause 464. 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 total daily dose of 1350 mg.

[0765] Clause 465. 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 total daily dose of 1400 mg.

[0766] Clause 466. 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 total daily dose of 1450 mg.

[0767] 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 at a total daily dose of 1500 mg.

[0768] Clause 468. 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 total daily dose of 1550 mg.

[0769] Clause 469. 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 total daily dose of 1600 mg.

[0770] Clause 470. 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 total daily dose of 1650 mg.

[0771] Clause 471. 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 total daily dose of 1700 mg.

[0772] Clause 472. 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 total daily dose of 1750 mg.

[0773] Clause 473. 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 total daily dose of 1800 mg.

[0774] Clause 474. The compound, tromethamine salt, erbumine salt, or pharmaceuticalcomposition for use according to any one of clauses 345-441, wherein the compound, the tromethamine salt, or the erbumine salt, is administered at a total daily dose of 1850 mg.

[0775] Clause 475. 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 total daily dose of 1900 mg.

[0776] Clause 476. 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 total daily dose of 1950 mg.

[0777] Clause 477. 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 total daily dose of 2000 mg.

[0778] Clause 478. 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 total daily dose of 2050 mg.

[0779] Clause 479. 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 total daily dose of 2100 mg.

[0780] Clause 480. 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 total daily dose of 2150 mg.

[0781] Clause 481. 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 total daily dose of 2200 mg.

[0782] Clause 482. 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 total daily dose of 2250 mg.

[0783] Clause 483. 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 total daily dose of 2300 mg.

[0784] Clause 484. 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 total daily dose of 2350 mg.

[0785] Clause 485. 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 total daily dose of 2400 mg.

[0786] Clause 486. 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 200 mg to 2400 mg once a day.

[0787] Clause 487. 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 400 mg to 2000 mg once a day.

[0788] Clause 488. 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 to 1200 mg once a day.

[0789] Clause 489. 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 200 mg once a day.

[0790] Clause 490. 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 250 mg once a day.

[0791] Clause 491. 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 300 mg once a day.

[0792] Clause 492. 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 350 mg once a day.

[0793] Clause 493. 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 400 mg once a day.

[0794] Clause 494. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, thetromethamine salt, or the erbumine salt, is administered at a dose of 450 mg once a day.

[0795] Clause 495. 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 500 mg once a day.

[0796] Clause 496. 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 550 mg once a day.

[0797] 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.

[0798] Clause 498. 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 650 mg once a day.

[0799] Clause 499. 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 700 mg once a day.

[0800] Clause 500. 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 once a day.

[0801] Clause 501. 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 800 mg once a day.

[0802] Clause 502. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, the compound, the tromethamine salt, or the erbumine salt, is administered at a dose of 850 mg once a day.

[0803] Clause 503. 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 900 mg once a day.

[0804] Clause 504. 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 950 mg once a day.

[0805] Clause 505. The compound, tromethamine salt, erbumine salt, or pharmaceuticalcomposition 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 1000 mg once a day.

[0806] Clause 506. 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 1050 mg once a day.

[0807] Clause 507. 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 once a day.

[0808] Clause 508. 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 once a day.

[0809] Clause 509. 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 once a day.

[0810] Clause 510. 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 1250 mg once a day.

[0811] 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.

[0812] Clause 512. 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 1350 mg once a day.

[0813] 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.

[0814] Clause 514. 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 1450 mg once a day.

[0815] Clause 515. 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 1500 mg once a day.

[0816] Clause 516. 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 1550 mg once a day.

[0817] Clause 517. 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 1600 mg once a day.

[0818] Clause 518. 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 1650 mg once a day.

[0819] Clause 519. 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 1700 mg once a day.

[0820] Clause 520. 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 1750 mg once a day.

[0821] Clause 521. 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 1800 mg once a day.

[0822] Clause 522. 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 1850 mg once a day.

[0823] 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.

[0824] Clause 524. 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 1950 mg once a day.

[0825] Clause 525. 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 2000 mg once a day.

[0826] Clause 526. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, thetromethamine salt, or the erbumine salt, is administered at a dose of 2050 mg once a day.

[0827] Clause 527. 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 2100 mg once a day.

[0828] Clause 528. 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 2150 mg once a day.

[0829] Clause 529. 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 2200 mg once a day.

[0830] Clause 530. 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 2250 mg once a day.

[0831] Clause 531. 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 2300 mg once a day.

[0832] Clause 532. 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 2350 mg once a day.

[0833] Clause 533. 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 2400 mg once a day.

[0834] Clause 534. 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 100 mg to 1200 mg twice a day.

[0835] Clause 535. 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 200 mg to 1000 mg twice a day.

[0836] Clause 536. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, thetromethamine salt, or the erbumine salt, is administered at a dose of 300 mg to 600 mg twice a day.

[0837] Clause 537. 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 100 mg twice a day.

[0838] Clause 538. 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 150 mg twice a day.

[0839] Clause 539. 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 200 mg twice a day.

[0840] Clause 540. 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 250 mg twice a day.

[0841] Clause 541. 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 300 mg twice a day.

[0842] Clause 542. 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 350 mg twice a day.

[0843] Clause 543. 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 400 mg twice a day.

[0844] Clause 544. 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 450 mg twice a day.

[0845] Clause 545. 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 500 mg twice a day.

[0846] Clause 546. 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 550 mg twice a day.

[0847] Clause 547. 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 twice a day.

[0848] Clause 548. 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 650 mg twice a day.

[0849] Clause 549. 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 700 mg twice a day.

[0850] 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.

[0851] Clause 551. 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 800 mg twice a day.

[0852] Clause 552. 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 850 mg twice a day.

[0853] Clause 553. 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 900 mg twice a day.

[0854] Clause 554. 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 950 mg twice a day.

[0855] Clause 555. 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 1000 mg twice a day.

[0856] Clause 556. 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 1050 mg twice a day.

[0857] Clause 557. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, thetromethamine salt, or the erbumine salt, is administered at a dose of 1100 mg twice a day.

[0858] 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.

[0859] 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.

[0860] Clause 560. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 345-559, wherein the compound, the tromethamine salt, or the erbumine salt, is administered via an oral dosage form.

[0861] Clause 561. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 560, wherein the oral dosage form is a tablet.

[0862] Clause 562. The compound, tromethamine salt, erbumine 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 pharmaceutically acceptable salt thereof, is palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof.

[0863] Clause 563. The compound, tromethamine salt, erbumine 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 pharmaceutically acceptable salt thereof, is abemaciclib.

[0864] Clause 564. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered as a 50- 200 mg oral dose twice a day.

[0865] Clause 565. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered as a 50 mg oral dose twice a day.

[0866] Clause 566. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered as a 100 mg oral dose twice a day.

[0867] Clause 567. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered as a 150 mg oral dose twice a day.

[0868] Clause 568. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered as a 200 mg oral dose twice a day.

[0869] Clause 569. The compound, tromethamine salt, erbumine 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, imlunestrant, giredestrant, amcenestrant, rintodestrant, AZD9833, or LSZ102.

[0870] Clause 570. The compound, tromethamine salt, erbumine 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.

[0871] Clause 571. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 570, wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).

[0872] Clause 572. The compound, tromethamine salt, erbumine 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 imlunestrant.

[0873] Clause 573. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 572, wherein imlunestrant is administered as a 400 mg oral dose once daily.

[0874] Clause 574. The compound, tromethamine salt, erbumine 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.

[0875] Clause 575. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole.

[0876] Clause 576. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 575, wherein anastrozole is administered as a 1 mg oral dose once daily.

[0877] Clause 577. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor, orpharmaceutically acceptable salt thereof, is letrozole.

[0878] Clause 578. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 577, wherein letrozole is administered as a 2.5 mg oral dose once daily, or as a 2.5 mg oral dose once every other day for patients with cirrhosis or severe hepatic impairment.

[0879] Clause 579. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is exemestane.

[0880] Clause 580. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 579, wherein exemestane is administered as a 25 mg oral dose once daily.

[0881] Clause 581. The compound, tromethamine salt, erbumine 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.

[0882] Clause 582. The compound, tromethamine salt, erbumine 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.

[0883] Clause 583. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 582, wherein paclitaxel is administered as a 80 mg / m2 injection on day 8, day 15, and day 22 of a first dose cycle, and then on day 1, day 8, day 15, and day 22 of all subsequent dose cycles.

[0884] Clause 584. The compound, tromethamine salt, erbumine 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.

[0885] Clause 585. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 584, wherein the mTOR inhibitor, or pharmaceutically acceptable salt thereof, is everolimus.

[0886] Clause 586. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 585, wherein the everolimus is administered as a 10 mg oral dose once daily.

[0887] Clause 587. The compound, tromethamine salt, erbumine salt, or pharmaceuticalcomposition for use according to clause 584, wherein the mTOR inhibitor, or pharmaceutically acceptable salt thereof, is RMC-5552.

[0888] Clause 588. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 358, 381, 382, or 415-561, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is neratinib or afatinib.

[0889] Clause 589. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 588, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is neratinib.

[0890] Clause 590. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 589, wherein the neratinib is administered as a 240 mg oral dose once daily.

[0891] Clause 591. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 588, wherein the tyrosine kinase inhibitor, or pharmaceutically acceptable salt thereof, is afatinib.

[0892] Clause 592. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 591, wherein the afatinib is administered as a 40 mg oral dose once daily, or 30 mg oral dose once daily in patients with severe renal impairment.

[0893] Clause 593. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 358, 383, 384, 409, 410, or 415-561, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

[0894] Clause 594. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 593, wherein the platinum agent is cisplatin.

[0895] Clause 595. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 358, 391, 392, or 415-561, wherein the anthracycline, or pharmaceutically acceptable salt thereof, is doxorubicin, daunorubicin, epirubicin or idarubicin.

[0896] Clause 596. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to any one of clauses 358, 385, 386, 401, 402, or 415-568, wherein the immune checkpoint inhibitor, or pharmaceutically acceptable salt thereof, is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.

[0897] Clause 597. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 596, wherein the immune checkpoint inhibitor is aCTLA-4 inhibitor.

[0898] Clause 598. The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 597, wherein the CT...

Claims

WE CLAIM:

1. A method of 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 of 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 of 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 of 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 of 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,Compound A, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

6. The method according to any one of claims 1-5, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

7. The method according to 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 according to 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-mutant, advanced or metastatic breast cancer.

9. The method according to any one of claims 1-8, wherein the patient is a postmenopausal female.

10. The method according to any one of claims 1-9, wherein the patient has type II diabetes mellitus.

11. The method according to any one of claims 1-10, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a total daily dose of 300 mg to 600 mg.

12. The method according to any one of claims 1, 3, 4 or 6-11, wherein the CDK4 and 6 inhibitor, or pharmaceutically acceptable salt thereof, is abemaciclib.

13. The method according to claim 12, wherein abemaciclib is administered as a 50- 200 mg oral dose twice daily.

14. The method according to claim 13, wherein abemaciclib is administered as a 150 mg oral dose twice daily.

15. The method according to any one of claims 2, 3, or 6-14, wherein the SERD, or pharmaceutically acceptable salt thereof, is fulvestrant.

16. The method according to claim 15, wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).

17. The method according to any one of claims 2, 3, or 6-14, wherein the SERD, or pharmaceutically acceptable salt thereof, is imlunestrant.

18. The method according to claim 17, wherein imlunestrant is administered as a 400 mg oral dose once daily.

19. The method according to any one of claims 4 or 6-14, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole, letrozole, or exemestane.

20. The method according to claim 19, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole.

21. The method according to claim 20, wherein anastrozole is administered as a 1 mg oral dose once daily.

22. The method according to claim 19, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is letrozole.

23. The method according to claim 22, wherein letrozole is administered as a 2.5 mg oral dose once daily, or as a 2.5 mg oral dose once every other day for patients with cirrhosis or severe hepatic impairment.

24. The method according to claim 19, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is exemestane.

25. The method according to claim 24, wherein exemestane is administered as a 25 mg oral dose once daily.

26. The method according to any one of claims 5-11, wherein the taxane, or pharmaceutically acceptable salt thereof, is paclitaxel.

27. The method according to claim 26, wherein paclitaxel is administered as a 80 mg / m2injection on day 8, day 15, and day 22 of a first dose cycle, and then on day 1, day 8, day 15, and day 22 of all subsequent dose cycles.

28. The method according to any one of claims 1-27, wherein the Compound A, or a pharmaceutically acceptable salt thereof, is a tromethamine salt of Compound A.

29. The method according to claim 28, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 according to claim 28, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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 according to any one of claims 28-30, wherein the tromethamine salt of Compound A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

32. The method according to any one of claims 28-30, wherein the tromethamine salt of Compound A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively).

33. Compound A, or a pharmaceutically acceptable salt thereof,for use in simultaneous, separate, or sequential combination with a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

34. Compound A, or a pharmaceutically acceptable salt thereof,Compound A, for use in simultaneous, separate, or sequential combination with a SERD, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

35. Compound A, or a pharmaceutically acceptable salt thereof,for use in simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

36. Compound A, or a pharmaceutically acceptable salt thereof,Compound A, for use in simultaneous, separate, or sequential 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-mutated, advanced or metastatic breast cancer.

37. Compound A, or a pharmaceutically acceptable salt thereof,for use in simultaneous, separate, or sequential combination with a taxane, or a pharmaceutically acceptable salt thereof, in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

38. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

39. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

40. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-37, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

41. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-40, wherein the patient is a postmenopausal female.

42. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-41, wherein the patient has type II diabetes mellitus.

43. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-42, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a total daily dose of 300 mg to 600 mg.

44. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33, 35, 36 or 38-43, wherein the CDK4 and 6 inhibitor, or pharmaceutically acceptable salt thereof, is abemaciclib.

45. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 44, wherein abemaciclib is administered as a 50-200 mg oral dose twice daily.

46. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 45, wherein abemaciclib is administered as a 150 mg oral dose twice daily.

47. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 34, 35 or 38-46, wherein the SERD, or pharmaceutically acceptable salt thereof, is fulvestrant.

48. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 47, wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).

49. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 34, 35 or 38-46, wherein the SERD, or pharmaceutically acceptable salt thereof, is imlunestrant.

50. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 49, wherein imlunestrant is administered as a 400 mg oral dose once daily.

51. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 36 or 38-46, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole, letrozole, or exemestane.

52. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 51, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is anastrozole.

53. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 52, wherein anastrozole is administered as a 1 mg oral dose once daily.

54. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 51, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is letrozole.

55. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 54, wherein letrozole is administered as a 2.5 mg oral dose once daily, or as a 2.5 mg oral dose once every other day for patients with cirrhosis or severe hepatic impairment.

56. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 51, wherein the aromatase inhibitor, or pharmaceutically acceptable salt thereof, is exemestane.

57. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 56, wherein exemestane is administered as a 25 mg oral dose once daily.

58. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 37, wherein the taxane, or pharmaceutically acceptable salt thereof, is paclitaxel.

59. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 58, wherein paclitaxel is administered as a 80 mg / m2injection on day 8, day 15, and day 22 of a first dose cycle, and then on day 1, day 8, day 15, and day 22 of all subsequent dose cycles.

60. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 33-59, wherein the Compound A, or a pharmaceutically acceptable salt thereof, is a tromethamine salt of Compound A.

61. The compound, or pharmaceutically acceptable salt thereof, for use according to claim 60, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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, or pharmaceutically acceptable salt thereof, for use according to claim 60, wherein the tromethamine salt of Compound A is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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, or pharmaceutically acceptable salt thereof, for use according to any one of claims 60-62, wherein the tromethamine salt of Compound A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

64. The compound, or pharmaceutically acceptable salt thereof, for use according to any one of claims 60-62, wherein the tromethamine salt of Compound A is characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine(external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively).

65. A 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 having at least one peak at diffraction angle 2-theta selected from 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 having a peak at diffraction angle 2-theta 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 diffraction angle 2-theta of 6.4° ± 0.2° in combination with the peaks 8.4° ± 0.2°, 10.9° ± 0.2°, 16.9° ± 0.2°, and 22.1° ± 0.2°.

69. The tromethamine salt of any one of claims 65-68, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

70. The tromethamine salt of any one of claims 65-68, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm (± 0.2 ppm, respectively).

71. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selectedfrom 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 having a peak at diffraction angle 2-theta 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 angle 2-theta 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 CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 having a peak at diffraction angle 2-theta 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°.

76. The tromethamine salt of claim 65, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2°, and 18.9° ± 0.2°.

77. An erbumine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid.

78. The erbumine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 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 erbumine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta 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°.

80. The erbumine salt of claim 77, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 11.1 ° ± 0.2° in combination with the peaks 10.5° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, and 19.3° ± 0.2°.

81. The erbumine salt of any one of claims 77-80, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 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 (± 0.2 ppm, respectively).

82. The erbumine salt of any one of claims 77-80, characterized by a13C solid state NMR (100.6 MHz) spectrum which comprises 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, respectively).

83. A pharmaceutical composition comprising a tromethamine salt of any one of claims 65-76, or an 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 having at least one peak at diffraction angle 2-theta selected from 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 usingCuKa radiation having at least one peak at diffraction angle 2-theta selected from 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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