Targeting allosteric and orthosteric pockets of phosphoinositide 3-kinase (PI3k) for the treatment of disease

Abstract

The disclosure relates to the use of inhibitors of phosphoinositide 3-kinase (PI3K) that target allosteric and orthosteric pockets of PI3K in methods of treating, preventing, or ameliorating a disease, or disorder, (or uses in the treatment, prevention, or amelioration of a disease, or disorder), in which PI3K plays a role. The PI3K inhibitors may be utilized in combination and may target allosteric or orthosteric pockets of PI3Kα simultaneously, separately, or sequentially. In some aspects of the disclosed methods, a PI3Kα inhibitor may target an allosteric or an orthosteric pocket of a PI3Kα mutant which is resistant to treatment with another PI3Kα inhibitor that targets a different pocket of PI3Kα.

Description

Cross-Reference to Related Patent Applications [1] The present application claims the benefit of priority to U.S. Provisional Application No., 63 / 501,614, filed on May 11, 2023; U.S. Provisional Application No. 63 / 382,980, filed on November 9, 2022; and U.S. Provisional Application No. 63 / 382,029, filed on November 1, 2022; the contents of which are incorporated herein by reference in their entireties. Reference to a Sequence Listing [2] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “30449SequenceListing.xml” created October 30, 2023 and is 2,777 bytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety. Field [3] The present invention is directed to inhibitors of phosphoinositide 3-kinase (PI3K) and combinations thereof which are useful in the treatment of diseases, or disorders associated with PI3K modulation. The present invention also is directed to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases, or disorders associated with PI3K modulation, and the use of allosteric chromenone inhibitors in combination with other allosteric or orthosteric inhibitors of PI3K useful in the treatment of diseases, or disorders associated with PI3K modulation. The present invention also is directed toward inhibitors of PI3K and combination thereof, methods of (or uses for) treating a disease, or disorder associated with PI3K (e g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), 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), and using, or methods of using, PI3K inhibitors in combination with one or more additional cancer therapies. Background [4] The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling also is involved in other disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome. [5] PI3Ks are members of a unique, and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. The class I PI3Ks (pl 10a, pl 10p, pl 105, and pl 10y) are typically activated by tyrosine kinases, or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt / PDKl, mTOR, the Tec family kinases, and the Rho family GTPases. The class II, and III PI3Ks play a key role in intracellular trafficking through the synthesis of PI(3)P, and PI(3,4)P2. [6] The PI3K isoforms have been implicated, for example, in a variety of human cancers, and disorders. The alpha (a) isoform of PI3K has been implicated, for example, in a variety of human cancers. Angiogenesis has been shown to selectively require the a isoform of PI3K in the control of endothelial cell migration. Mutations in the gene coding for PI3Ka, or mutations which lead to upregulation of PI3Ka are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the gene coding for PI3Ka are point mutations clustered within several hotspots in helical, and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be -3 - oncogenic gain-of-function mutations. Because of the high rate of PI3Ka mutations, targeting of this pathway may provide valuable therapeutic opportunities. While other PI3K isoforms such as PI3K5, or PI3Ky are expressed primarily in hematopoietic cells, PI3Ka, along with PI3KP, is expressed constitutively. [7] Due to the central role of PI3Ka in regulating organismal glucose homeostasis, PI3K inhibition in patients often gives rise to adverse events which include hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin could potentially be mitogenic and / or antiapoptotic for cancer cells, and thus negate the antiproliferative effects of PI3K inhibitors. In the setting of cancer with mutated PI3Ka, one way to overcome the problem of compensatory production of insulin and / or glucose upon systemic PI3Ka inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3Ka over wild-type PI3Ka. This would create an increased window for drug dosing to selectively inhibit the pathologic signaling of mutant PI3Ka in the cancer cells without affecting the wild-type PI3Ka in the host tissues that control systemic metabolism, thus limiting toxicities, and permitting higher doses, and more complete inhibition of the drug target. [8] PI3Ka has an ATP-binding pocket which may be targeted in order to modulate PI3Ka activity. PI3Ka must bind ATP in order to catalyze the transfer of a phosphate group from ATP to the 3’-OH group on phosphatidylinositols or phosphoinositides. Almost all PI3K inhibitors tested in clinical trials are antagonists that interact within the PI3Ka ATP-binding pocket and compete with ATP as orthosteric inhibitors. The PI3Ka ATP-binding pocket may alternatively be referred to as ‘The PI3Ka orthosteric binding pocket.” [9] Current PI3Ka inhibitors are nearly equipotent to wild-type and mutant PI3Ka Mutant selective inhibitors have been elusive due to the fact that the most common PI3Ka mutations (E542K, E545K, and H1047R) are located far from the PBKa orthosteric binding pocket. As such, inhibitors which target a second, peripheral binding pocket near a known mutation (e.g., H1047R) may provide a route to selective PI3Ka inhibition.

[10] The present invention provides a new class of kinase inhibitors that target a non-ATP binding pocket of PI3Ka which is referred to herein as “the PI3Ka allosteric pocket 1” and may interact with amino acid residues of PI3Ka including RI047. The disclosed kinase inhibitors target PI3Ka allosteric pocket 1 and may be utilized in combination therapies, for example, combination therapies in which the disclosed PI3Ka inhibitors are used in combination with PI3Ka inhibitors that target other pockets of PI3Ka, such as the PI3Ka orthosteric pocket.

[11] The present invention also provides a characterization of another non-ATP binding pocket of PI3Ka, which is referred to as “the PI3Ka allosteric pocket 2,” and the interaction of inhibitors of PI3Ka with the PI3Ka allosteric pocket 2. The disclosed kinase inhibitors which target PI3Ka allosteric pocket 1 may be used in combination therapies with PI3Ka inhibitors that target the PI3Ka allosteric pocket 2. Summary

[12] The disclosure relates to the use of inhibitors of phosphoinositide 3-kinase (PI3K) that target allosteric and orthosteric pockets of PI3K in methods of treating, preventing, or ameliorating a disease, or disorder, (or uses in the treatment, prevention, or amelioration of a disease, or disorder), in which PI3K plays a role. The PI3K inhibitors may be utilized in combination and may target an allosteric pocket of phosphatidylinositol 3-kinase alpha (PI3Ka) referred to herein as “PI3Ka allosteric pocket 1„” an allosteric pocket of PI3Ka referred to herein as “PI3Ka allosteric pocket 2,” or the PI3Ka orthosteric pocket. (See Fig. 1). In some aspects of the disclosed methods, a PI3Ka inhibitor may target the PI3Ka allosteric pocket 1, the PI3Ka allosteric pocket 2, or the PI3Ka orthosteric pocket of a PI3Ka mutant that is resistant to treatment with another PI3Ka inhibitor, for example a PI3Ka inhibitor that targets a different pocket of PI3Ka.

[13] The methods may include administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the present invention or combinations of PI3K inhibitors of the present invention and other PI3K inhibitors, which may include other allosteric inhibitors of PI3K and orthosteric inhibitors of PI3K. The methods and PI3K inhibitors of the present invention can be used in the treatment of a variety of PI3K-dependent or PI3K-associated diseases, and disorders.

[14] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka. The methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first -5 - PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to the PI3Ka orthosteric pocket.

[15] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ku. The methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 2; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to the PI3Ka orthosteric pocket.

[16] In some aspects, the disclosed methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds to PI3Ka allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to PI3Ka allosteric pocket 2.

[17] In some aspects, the disclosed methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds to PI3Kot allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor which is different from the first PI3Ka selective inhibitor, wherein the second different PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 1. In some aspects, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor competitively bind to PI3Ka allosteric pocket 1.

[18] In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor are administered simultaneously, separately, or sequentially. In some embodiments, the second PI3Ka selective inhibitor is administered to the patient if the patient has a disease or disorder that is resistant to treatment with the first PI3Ka selective inhibitor. In some embodiments, the second PI3Ka selective inhibitor is administered to the patient after the disease or disorder of the patient has acquired resistance to treatment with the first PI3Ka selective inhibitor.

[19] In some aspects of the disclosed methods which comprise administering a therapeutically effective amount of a first PI3Ka selective inhibitor and a therapeutically effective amount of a second PI3Ka selective inhibitor, an additive effect or synergistic effect may be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Ka selective inhibitor administered in the disclosed methods may be less than a therapeutically effective amount of the first PI3Ka selective inhibitor that is required in a treatment method where the second PI3Ka selective inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the second PI3Ka selective inhibitor administered in the disclosed methods may be less than a therapeutically effective amount of the second PI3Ka selective inhibitor that is required in a treatment method where the first PI3Ka selective inhibitor is not administered.

[20] In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Ka selective inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, the therapeutically effective amount of the second PI3Ka selective inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events. Adverse events may include, but are not limited to hyperglycemia, hyperinsulinemia, diarrhea, dehydration, skin rash, lymphopenia, increased alanine transaminase, fatigue, anemia, elevated serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemic disorder, alopecia, prolonged activated partial thromboplastin time, kidney disease with reduction in glomerular filtration rate (GFR), acute abdominal pain, and abnormal hepatic function tests.

[21] In some aspects, the disclosed methods relate to methods for treating a disease or disorder that is associated with modulation of PI3Ka in a patient that has a disease or disorder that is resistant to treatment with a PI3Ka selective inhibitor, which may be a PI3Ka selective allosteric inhibitor or a PI3Ka selective orthosteric inhibitor. The methods may comprise administering to the patient a different PI3Ka selective inhibitor to which the disease or disorder is not resistant, such as a PI3Ka selective allosteric inhibitor or a PI3Ka selective orthosteric inhibitor.

[22] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient that has a disease or disorder that is resistant to -7 - treatment with a PI3Ka selective orthosteric inhibitor. In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3Ka in a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3Ka selective orthosteric inhibitor or in a patient that is identified as having a disease or disorder which exhibits an incomplete response to treatment with a PI3Kot selective orthosteric inhibitor. In some aspects, the methods may comprise administering to a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3Ka selective orthosteric inhibitor or that is identified as having a disease or disorder that exhibits an incomplete response to treatment with a PI3Ka selective orthosteric inhibitor, a therapeutically effective amount of a PI3Ka selective allosteric inhibitor, wherein the PI3Ka selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1. In some aspects, the methods may comprise administering to a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3Ka selective orthosteric inhibitor or that is identified as having a disease or disorder which exhibits an incomplete response to treatment with a PI3Ka selective orthosteric inhibitor, a therapeutically effective amount of a PI3Ka selective allosteric inhibitor, wherein the PI3Kot selective allosteric inhibitor binds to the PI3Ka allosteric pocket 2.

[23] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a first PI3Ka selective allosteric inhibitor, wherein the first PI3Ka selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3Ka selective inhibitor that binds to the PI3Ka orthosteric pocket.

[24] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a first PI3Ka selective allosteric inhibitor, wherein the first PI3Ka selective allosteric inhibitor binds to PI3Ka allosteric pocket 2. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3Ka selective inhibitor that binds to the PI3Ka orthosteric pocket.

[25] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, wherein the patient has been treated previously with a therapeutically effective amount of a PI3Ka selective inhibitor, and the disease or disorder of the patient has acquired resistance to treatment with the PI3Ka selective inhibitor. The method may include administered to the patient a different PI3Ka selective inhibitor to which the disease or disorder is not resistant.

[26] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, wherein the patient previously has been treated with a therapeutically effective amount of a PI3Ka selective allosteric inhibitor, wherein the PI3Kot selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1 or the PI3Ka allosteric pocket 2. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1.

[27] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ku in a patient in need thereof, wherein the patient previously has been treated with a therapeutically effective amount of a PI3Ka selective allosteric inhibitor, wherein the PI3Ka selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1 or the PI3Ka allosteric pocket 2. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1. In the disclosed methods, the disease or disorder of the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1.

[28] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, wherein the patient has a disease or disorder comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation). The methods may comprise administering to the patient having the disease or disorder a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor. The methods may comprise - 10- administering to the patient having the disease or disorder comprising an Ml 043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation) a therapeutically effective amount of a PI3Ka allosteric inhibitor, wherein the PI3Ka allosteric inhibitor binds to the PI3Ka allosteric pocket 1. The methods may comprise administering to the patient having the disease or disorder comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation) a therapeutically effective amount of a PI3Ka selective allosteric inhibitor that binds the PI3Ka allosteric pocket 2.

[29] In some aspects, the methods related to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, such as a patient having a disease or disorder comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation). The methods may comprise determining that the patient has a disease or disorder comprising the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), for example, by ordering or performing a genomic analysis. If the patient is found to have a disease or disorder comprising the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), the methods further may comprise administering treatment to the patient, which may include administering one or more PI3Ka selective inhibitors to the patient, which may include allosteric inhibitors (e.g., an allosteric inhibitor that binds to the PI3Ka allosteric pocket 1 and / or an allosteric inhibitor that binds to the PI3Ka allosteric pocket 2), orthosteric inhibitors, or combinations thereof as disclosed herein.

[30] In some aspects, the disclosed methods comprise selecting a patient for treatment with one or more PI3Ka selective inhibitors. In some aspects, the patient is selected based on the patient having disease or disorder comprising a M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with the H1047R mutation). Optionally, a selected patient may be administered treatment, which may include administering one or more PI3Ka selective inhibitors to the patient, which may include allosteric inhibitors (e.g., - 11 - allosteric inhibitor that binds to the PI3Ka allosteric pocket 1 or an allosteric inhibitor that binds to the PI3Ka allosteric pocket 2), orthosteric inhibitors, or combinations thereof as disclosed herein.

[31] In the disclosed methods, a patient in need thereof may have cancer. In some aspects, the patient in need thereof may have breast cancer. In some aspects, the patient in need thereof may have PIK3CA-mutated, advanced, or metastatic breast cancer. In some aspects, the patient in need thereof may have PIK3CA H1047R-mutant advanced, or metastatic breast cancer that is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[32] In the disclosed methods, a patient in need thereof may have cancer and may have been previously administered one or more therapeutic agents for treating the cancer, which may include a PI3Ka selective inhibitor. In some aspects, the patient may have a cancer which exhibits de novo resistance or acquired resistance to treatment with a therapeutic agent, which may include a PI3Ka selective inhibitor, and the patient may be administered a different therapeutic agent, which may include a different PI3Ka selective inhibitor.

[33] In the disclosed methods, the patient may have not been previously administered a therapeutic agent for treating the cancer, which may include a PI3Ka selective inhibitor. In some aspects, the patient may be characterized as naive to treatment with a PI3Ka selective inhibitor. Brief Description of the Figures

[34] Fig. 1. Schematic illustration of PI3Ka (H1047R) showing Orthosteric pocket, Allosteric pocket 1, and Allosteric pocket 2.

[35] Fig. 2. Dose response curve for alpelisib in a T47D (M1043I+H1047R) (double, in cis, 6x) cell proliferation assay.

[36] Fig. 3. Dose response curve for Compound 21 in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay.

[37] Fig. 4. Dose response curve for Compound N1 in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay.

[38] Fig. 5. Dose response curve for Compound N2 in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay. - 12-

[39] Fig. 6. Dose response curve for Compound 1 in a T47D (M1043I+H1047R) (double, in cis, 6x) cell proliferation assay.

[40] Fig. 7. Dose response curve for Compound HP1 in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay.

[41] Fig. 8. Dose response curve for alpelisib in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay.

[42] Fig. 9. Dose response curve for Compound HP1 in a T47D (M1043I+H1047R) (double, in cis, 6*) cell proliferation assay.

[43] Fig. 10. Dose response curve for Compound 1 in a T47D (M1043I+H1047R) (double, in cis, 6x) cell proliferation assay.

[44] Fig. 11. Dose response curve for Compound 21 in a T47D (M1043I+H1047R) (double, in cis, 6x) cell proliferation assay.

[45] Fig. 12. Combination Index plot for Compound 21 and alpelisib in T47D naive cells based on growth inhibition assay (CTG).

[46] Fig. 13. Combination Index plot for Compound 21 and alpelisib in T47D (M1043I+H1047R) (double, in cis, 6x) cells based on growth inhibition assay (CTG).

[47] Fig. 14. Combination Index plot for Compound 21 and Compound HP1 in T47D naive cells based on growth inhibition assay (CTG).

[48] Fig. 15. Combination Index plot for Compound 21 and Compound HP1 in T47D (M1043I+H1047R) (double, in cis, 6x) cells based on growth inhibition assay (CTG).

[49] Fig. 16. Combination Index plot for Compound 21 and alpelisib in MDA453 naive cells based on growth inhibition assay (CTG).

[50] Fig. 17. Combination Index plot for Compound 21 and alpelisib in MDA453 (Cpd 21-R) (double, in cis, 6x) cells based on growth inhibition assay (CTG).

[51] Fig. 18. Combination Index plot for Compound 21 and Compound HP1 in MDA453 naive cells based on growth inhibition assay (CTG).

[52] Fig. 19. Combination Index plot for Compound 21 and Compound HP1 in MDA453 (Cpd 21-R) cells based on growth inhibition assay (CTG). - 13 -

[53] Fig. 20. Graphic illustration of the interaction of PIKa_H1047R and Compound 21 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound 21 and the side chains of RI 047 and Q981; hydrogen bonding between the carboxy acid group of Compound 21, a bridging water molecule, and the side chain of Y985; hydrogen bonding between the chromenone exocyclic ketone group of Compound 21, a bridging water molecule, and the side chain of H931 (and between the exocyclic ketone group of Compound 21, a bridging water molecule and the carbonyl backbone group of C901 (not shown)).

[54] Fig. 21. Graphic illustration of the interaction of PIKa_H1047R and Compound 172 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound 172 and the side chains of RI 047 and Q981; hydrogen bonding between the chromenone exocyclic ketone group of Compound 172, a bridging water molecule, and the side chain of H931; hydrogen bonding between the cyano group of Compound 172 and the side chain of Y1021; core pi-pi stacking between the chromenone core of Compound 172 and the side chain of F954; and pi-pi T-stacking between the 4-cyano-phenyl group of Compound 172 and the side chain ofF909.

[55] Fig. 22. Graphic illustration of the interaction of PIKa_H1047R and Compound N3 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound N3 and the side chains of R1047 and Q981; core pi-pi stacking between the chromenone core of Compound N3 and the side chain of F954 in addition to pi-pi T-stacking between the phenyl group of Compound N3 and the side chain of F954.

[56] Fig. 23. Graphic illustration of the interaction of PIKa_H1047R and Compound N4 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound N4 and the side chains of RI 047 and Q981; and hydrogen bonding between the chromenone exocyclic ketone group of Compound N4, a bridging water molecule, and the side chain ofH931.

[57] Fig. 24. Graphic illustration of the interaction of PIKa_H1047R and Compound N5 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound N5 and the side chains of RI 047 and Q981; direct hydrogen bonding between - 14- the isoxazole group of Compound N5 and side chain of H931; and core pi-pi stacking between the isoxazole core of Compound N5 and the side chain of F954.

[58] Fig. 25. Graphic illustration of the interaction of PIKa_M1043I_H1047R and Compound HP1 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-l-one core of Compound HP1 and the carbonyl backbone group of D1018; core pi-pi stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of Compound HP1 and the side chain of F937 in addition to pi-pi T-stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of Compound HP1 and the side chain of F1002.

[59] Fig. 26. Graphic illustration of the interaction of PIKa_M1043I_H1047R and Compound HP2 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-l-one core of Compound HP2 and the carbonyl backbone group of D1018; core pi-pi T-stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of Compound HP2 and the side chain of Fl002; and a chlorine-carbonyl interaction between the chlorine atom of the 2-chloro, 5-fluorophenyl group of Compound HP2 and the side chain carbonyl ofE1012.

[60] Fig. 27. Graphic illustration of the interaction of PIKa_H1047R, Compound N6, and Compound HP2 in their respective allosteric pockets based on an X-ray structure analysis.

[61] Fig. 28. Effect of Compound 21 (37.5mg / kg), alpelisib (12.5 mg / kg), and fulvestrant(5mg / animal) in a T47D xenograft (Hl047+ / 1, ER+, PR+, HER2-).

[62] Fig. 29. Effect of Compound 21 (37.5mg / kg), alpelisib (6.25mg / kg), and fulvestrant(5mg / animal) in a T47D xenograft (H1047+ / 1, ER+, PR+, HER2-).

[63] Fig. 30. Naive and Compound 21 resistant MDA453 cells (having an M1043I 2nd site mutation) were treated with Compound 21, alpelisib, or Compound HP1.

[64] Fig. 31. Naive and Engineered T47D Cells (having 6x M104312nd site mutations) were treated with Compound 21, alpelisib, or Compound HP1.

[65] Fig. 32. Parental SUM185PE cells and Compound 21 resistant SUM185PE cells were treated with Compound 21, Compound 1, alpelisib, or Compound HP1

[66] Fig. 33. MDA453 naive cells were treated with Compound 21 in combination with alpelisib. - 15 -

[67] Fig. 34. Synergy plot of MDA453 naive cells treated with Compound 21 in combination with alpelisib.

[68] Fig. 35. MDA453 naive cells were treated with Compound 21 in combination with Compound HP1.

[69] Fig. 36. Synergy plot of MDA453 naive cells treated with Compound 21 in combination with Compound HP1.

[70] Fig. 37. MDA453 naive cells were treated with alpelisib in combination with Compound HP1.

[71] Fig. 38. MDA453 naive cells were treated with alpelisib in combination with Compound HP1.

[72] Fig. 39. H1047R homozygous SUM185PE cells were treated with Compound 21 in combination with alpelisib.

[73] Fig. 40. Compound 21 resistant SUM185PE cells treated with a combination of Compound 21 and alpelisib.

[74] Fig. 41. H1047R homozygous SUM185PE cells were treated with Compound 21 in combination with Compound HP1.

[75] Fig. 42. H1047R homozygous SUM185PE cells were treated with alpelisib in combination with Compound HP1.

[76] Fig. 43. T47D cells treated with Compound 21 in combination with alpelisib.

[77] Fig. 44. T47D cells treated with Compound 21 in combination with Compound HP 1.

[78] Fig. 45. T47D cells treated with alpelisib in combination with Compound HP 1.

[79] Fig. 46. T47D naive cells treated with Compound 21 in combination with alpelisib.

[80] Fig. 47. T47D 6x H1043I cells treated with Compound 21 in combination with alpelisib.

[81] Fig. 48. Parental SUM185PE cells and Cpd-21-R SUM185PE cells treated with Compound 21, alpelisib, Compound HP 1, Compound HP4, Compound HP5, or Compound HP6.

[82] Fig. 49. T47D cells (5xH1047R / lxWT) or engineered T47D cells having 2nd site mutations (5xH1047R / 6xC901F or 6xH1047R / M1043I) treated with Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.

[83] Fig. 50. T47D cells treated with Compound 21 in combination with Compound HP6.

[84] Fig. 51. T47D cells treated with Compound 21 in combination with Compound HP6. - 16

[85] Fig. 52. Combination Index plot for Compound 21 in combination with Compound HP6 in T47D cells.

[86] Fig. 53. SUM185PE cells treated with Compound 21 in combination with Compound HP6.

[87] Fig. 54. Combination Index plot for Compound 21 in combination with Compound HP6 in SUM185PE cells.

[88] Fig. 55. T47D cells treated with Compound 21 in combination with Compound HP5.

[89] Fig. 56. Combination Index plot for Compound 21 in combination with Compound HP5 in T47D cells.

[90] Fig. 57. SUM185PE cells treated with Compound 21 in combination with Compound HP5.

[91] Fig. 58. Combination Index plot for Compound 21 in combination with Compound HP5 in SUM185PE cells. Detailed Description

[92] The present invention provides methods of treating, preventing, or ameliorating a disease or disorder, or uses of PI3K inhibitors in the treatment, prevention, or amelioration of a disease or disorder, where the disease or disorder is dependent or associated with PI3K activity. In the disclosed methods and uses, a patient in need thereof is administered a therapeutically effective amount of a PI3K inhibitor or a combination of PI3K inhibitors, which may include allosteric inhibitors and orthosteric inhibitors. The methods and uses disclosed herein may be performed in the treatment of a variety of PI3K-dependent or PI3K-associated diseases, and disorders.

[93] In some embodiments of the disclosed methods and uses, the disease, or disorder is a cancer, such as breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. In some embodiments, the disease, or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamouscell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, - 17- 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, and encapsulated glioma.

[94] The details of the invention are set forth in the accompanying description below. Although methods, and materials similar, or equivalent to those described herein can be used in the practice, or testing of the present disclosure, illustrative methods, and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims. In the specification, and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical, and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, and publications cited in this specification are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Kot inhibitor compounds disclosed therein. Definitions

[95] The articles “a”, and “an” refer to one, or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element, or more than one element.

[96] The term “and / or” means either “and”, or “or” unless indicated otherwise.

[97] The term “administer”, “administering”, or “administration” refers to either directly or indirectly administering to a patient a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition. “Administering” or “administration” may be performed by a caregiver, for example, by a medical professional or other caregiver where the medical professional or other caregiver administers to a patient a disclosed compound, or pharmaceutically - 18 - acceptable salt of the disclosed compound, or a composition. “Administering” or “administration” may be performed by a patient, for example, where a patient administers to themselves a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition.

[98] The term “alkenyl” refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated, or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

[99] The term “alkoxy” refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[100] The term “alkyl” refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms, preferably 1-6 carbon atoms. Examples of a (Ci-Ce) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[101] The term “alkynyl” refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

[102] The term “aromatic” means a planar ring having An + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[103] The term “aryl” unless otherwise specifically defined refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic, or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). Furthermore, when containing two fused rings the aryl groups herein defined may have one, or more saturated, or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl. - 19-

[104] The term “carrier” encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid, or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying, or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a patient.

[105] The term “cyano” means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C=N.

[106] The term “cycloalkyl” means mono, or polycyclic saturated carbon rings containing 3-18 carbon atoms, preferably 3-10 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.

[107] The term “disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[108] The term “haloalkoxy” refers to an alkoxy group, as defined herein, which is substituted with one, or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[109] The term “haloalkyl” refers to an alkyl group, as defined herein, which is substituted with one, or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and tri chloromethyl.

[110] The term “halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine. [Ill] The term “heteroaryl” unless otherwise specifically defined means a monovalent monocyclic, or a polycyclic aromatic radical of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. A polycyclic aromatic radical includes two, or more fused rings, and may further include two, or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Examples of heteroaromatic groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-l-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[ 1,2,3 ]triazolyl, imidazo[ 1,2-a]pyrimidinyl, [ 1,2,4]triazolo[4,3 -b]pyridazinyl, benzo[c] [ 1,2,5]thiadiazolyl, benzo[c] [ 1,2,5]oxadiazole, 1,3 -dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and 3H-indolyl. Furthermore, when containing two, or more fused rings, the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring fused with one, or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated, or partially unsaturated ring may further be fused with a saturated, or partially unsaturated ring described herein. Furthermore, when containing three, or more fused rings, the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring spiro-fused. Any -21 - saturated, or partially unsaturated ring described herein is optionally substituted with one, or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[l,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[ 1,2-a]indol-1 (2H)-onyl, benzofc][ 1,2]oxaborol-1 (377)-olyl, 6,6a,7,8-tetrahydro-97 / -pyrido[2,3- / >]pyrrolo[l,2-d][l,4]oxazin-9-onyl, and 6a’,7’-dihydro-6’H,9’H-spiro[cyclopropane-l,8’-pyrido[2,3- / >]pyrrolo[l,2-<7][l,4]oxazin]-9’-onyl.

[112] The term “heterocyclyl”, “heterocycle”, or “heterocycloalkyl” means mono, or polycyclic rings containing 3-24 atoms, preferably 3-10 atoms, which include carbon, and one, or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the rings are not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[113] The term “hydroxyalkyl” refers to an alkyl group, as defined herein, which is substituted with a hydroxy group.

[114] The term “in cis’" when referring to two different mutations means that the two different mutations are located on the same chromosome.

[115] The term “isomers” refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[116] The term “modulate”, “modulation”, or “modulating” refers to a biological activity of a compound, or substrate that inhibits and / or activates PI3K. Modulation may include inhibition.

[117] The terms “patient” and “subject” may be utilized interchangeably herein and mean a mammal such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. Preferably, the mammal is human.

[118] The term “therapeutically effective amount” when used in connection with a compound refers to the amount or dose of the compound which upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.

[119] An effective amount can be determined by one skilled in the art by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[120] The term “treating” with regard to a patient, includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. The term “treating” with regard to a patient, may include prescribing for a patient a therapeutic agent to be administered to the patient or a treatment regimen for the patient. The term “treating” with regard to a patient, may include ordering a diagnostic test for the patient. Diagnostic tests may include genomic analyses that identify mutations present in PI3Ka, such as mutations in C901 (e.g., C901F), M1043 (e.g.. -23 - M1043I / L), and / or H1047 (e.g., H1047R) which mutations may be in cis (i.e., on the same allele), as disclosed herein.

[121] The term “preventing” with regard to a patient, may mean preventing a disease or disorder and / or preventing a symptom of a disease or disorder. A patient in need thereof may include a patient at risk for developing a disease or disorder wherein the disclosed methods may performed in order to prevent the patient from developing the disease or disorder. A patient in need thereof may include a patient in remission wherein the disclosed methods may performed in order to prevent the disease or disorder from recurring in the patient.

[122] In regard to cancer, treating may mean administering a therapeutic agent to a patient and observing a decrease in tumor growth, a reduction in tumor size, and / or an increase in mean survival time for the patient after treatment.

[123] The term “PI3K” means “Phosphoinositide 3-Kinase.” The term “PI3Ka” means the Phosphoinositide 3-Kinase alpha, which is a Class IPI3K that comprises the PI3k, catalytic, alpha polypeptide (pl10-a) encoded by the gene PIK3CA. The pl10-a polypeptide alternatively may be referred to as “PIK3CA.” The pl 10-a polypeptide comprises 1068 amino acids and has the amino acid sequence of SEQ ID NO: 1: p!10-a(SEQ ID NO:1) 1 mpprpssgel wgihlmppri Ivecllpngm ivtleclrea tlitikhelf kearkyplhq 61 llqdessyif vsvtqeaere effdetrrlc dlrlfqpflk viepvgnree kilnreigfa 121 igmpvcefdm vkdpevqdfr rnilnvckea vdlrdlnsph sramyvyppn vesspelpkh 181 iynkldkgqi ivviwvivsp nndkqkytlk inhdcvpeqv iaeairkktr smllsseqlk 241 Icvleyqgky llkvcgcdey flekyplsqy kyirscimlg rmpnlmlmak eslysqlpmd 301 cftmpsysrr istatpymng etstkslwvi nsalrikilc atyvnvnird idkiyvrtgi 361 yhggeplcdn vntqrvpcsn prwnewlnyd iyipdlpraa rlclsicsvk grkgakeehc 421 plawgninlf dytdtlvsgk malnlwpvph gledllnpig vtgsnpnket pclelefdwf 481 ssvvkfpdms vieehanwsv sreagfsysh aglsnrlard nelrendkeq Ikaistrdpl 541 seiteqekdf Iwshrhycvt ipeilpklll svkwnsrdev aqmyclvkdw ppikpeqame 601 lldcnypdpm vrgfavrcle kyltddklsq yliqlvqvlk yeqyldnllv rfllkkaltn 661 qrighfffwh Iksemhnktv sqrfgllles ycracgmylk hlnrqveame klinltdilk 721 qekkdetqkv qmkflveqmr rpdfmdalqg flsplnpahq Ignlrleecr imssakrplw 781 Inwenpdims ellfqnneii fkngddlrqd mltlqiirim eniwqnqgld Irmlpygcls 841 igdcvgliev vrnshtimqi qckgglkgal qfnshtlhqw Ikdknkgeiy daaidlftrs 901 cagycvatfi Igigdrhnsn imvkddgqlf hidfghfldh kkkkfgykre rvpfvltqdf 961 liviskgaqe ctktreferf qemcykayla irqhanlfin Ifsmmlgsgm pelqsfddia 1021 yirktlaldk teqealeyfm kqmndahhgg wttkmdwifh tikqhaln

[124] The Enzyme Commission (EC) number for the catalytic activity of PI3Ka is 2.7.1.153. The catalytic activity of PI3Ka includes phosphatidylinositol-4,5-bisphosphate 3-kinase activity, whereby a phosphate group from adenosine triphosphate (ATP) is transferred to phosphatidylinositol-4,5-bisphosphate (PIP2) to create phosphatidylinositol-3,4,5-trisphosphate (PIP3). PI3Ka catalyzes the addition of a 3-phosphate group from ATP to PIP2 by binding ATP in an ATP-binding pocket within the kinase catalytic domain in the pl00a subunit of PI3Ka.

[125] The PI3Ka inhibitors disclosed herein inhibit the phosphatidylinositol-4,5-bisphosphate 3-kinase activity of PI3Ka. The disclosed inhibitors may inhibit PI3Ka activity by binding at or near the ATP-binding pocket of PI3Ka, which may be referred to as an “the PI3Ka orthosteric pocket.” The disclosed inhibitors may prevent ATP from binding at the ATP-binding pocket as antagonists and / or the disclosed inhibitors may displace ATP from the ATP-binding pocket. The disclosed inhibitors may include orthosteric inhibitors that compete with ATP for binding at the ATP-binding site of PI3Ka. The ATP-binding pocket of PI3Ka has been studied and characterized via X-ray crystallography. (Gkeka et al., Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Ka, J. Phys. Chem. B 2015, 119, 1002-1016, published Oct. 9, 2014; and Fairhurst et al., Identification and optimisation of 4,5-dihydrobenzo [l,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors , Biorg. & Medic. Chem. Lett. 25 (2015) 3575-3581, published June 26, 2015). The ATP-binding pocket is located in a cleft between the N-terminal and C-terminal lobes of the kinase catalytic domain of pl00a. The ATP-binding pocket may comprise one or more amino acid residues selected from R770, M772, P778, W780,1800, K802, D810, Y836,1848, V850, V851, S854, Q859, N920, -25 - M922, F930,1932, and D933.

[126] Orthosteric inhibitors of PI3Ka may bind to PI3Ka at or near the ATP-binding pocket of PI3Ka and may form interactions with one or more amino acids selected from R770, M772, P778, W780,1800, K802, D810, Y836,1848, V850, V851, S854, Q859, N920, M922, F930,1932, and D933. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking. Orthosteric inhibitors of PI3Ka are known and may include, but are not limited to, alpelisib, inavolisib, and serabelisib, which are PI3Kot selective inhibitors.

[127] The disclosed inhibitors may inhibit PI3Ka by binding at or near a pocket of PI3Ka which is not the ATP-binding pocket of PI3Ka, which may be referred to as an “allosteric pocket.” The disclosed inhibitors may function as allosteric inhibitors of PI3Ka. Allosteric inhibitors of PI3Ka which may be utilized in the disclosed methods are disclosed in WO2021 / 202964 (Petra), WO2021 / 222556, WO2022 / 235574, WO2022 / 235575, WO2022 / 251482, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 056407, WO2023 / 060262, WO2023 / 288242, WO2023 / 081209, WO2023 / 081757, WO2023 / 081759, WO2023 / 078401, WO2023 / 104111, WO2023 / 109870, WO2023 / 159155, WO2023 / 168378, WO2023 / 173124, and WO2023 / 192416, and WO2023 / 288242, the contents of which are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein.

[128] In some aspects, the allosteric inhibitors disclosed herein may bind to PI3Ka at or near an allosteric pocket of PI3Ka referred to herein as “the PI3Ka allosteric pocket 1.” In some aspects, allosteric inhibitors of PI3Ka may bind the PI3Ka allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and RI047. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking. Particular interactions may include one or more of the following interactions: direct hydrogen bonding between a carboxy acid group of the inhibitor and the side chains of RI 047 and Q981; hydrogen bonding between a carboxy acid group of inhibitor, a bridging water molecule, and the side chain of Y985; hydrogen bonding between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the side chain of H931; hydrogen bonding between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the carbonyl backbone group of C901; hydrogen bonding between a cyano group of the inhibitor and the side chain of Y1021; core pi-pi stacking between the chromenone core of the inhibitor and the side chain of F954; pi-pi T-stacking between a phenyl core group of the inhibitor (e.g., a core in a substituent at position C2 of the chromenone core) and the side chain of F909; direct hydrogen bonding between a C3 substituent on the chromenone core of the inhibitor and side chain of H931; and core pi-pi stacking between a core of the inhibitor (e.g., a core in a substituent at position C3 of the chromenone core) and the side chain of F954. Allosteric inhibitors of PI3Ka that bind to the PI3Ka allosteric pocket 1 are disclosed in WO2021 / 202964, WO2022 / 235574, WO2022 / 235575, WO2022 / 251482, WO2023 / 056407, WO2023 / 060262, and WO2023 / 078401, the contents of which are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein.

[129] In some aspects, the allosteric inhibitors disclosed herein may bind to PI3Ka at or near an allosteric pocket of PI3Ka referred to herein as “the PI3Ka allosteric pocket 2.” In some aspects, allosteric inhibitors of PI3Ka may bind the PI3Ka allosteric pocket 2 and may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking. Particular interactions may include one or more of the following interactions: direct hydrogen bonding between the nitrogen atom in an isoindolin- l-one core of the inhibitor and the carbonyl backbone group of D1018; core pi-pi stacking between the core of a 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of F937; pi-pi T-stacking between the core of a 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of Fl 002; and a chlorine-carbonyl interaction between the chlorine atom of a 2-chloro, 5-fluorophenyl group of the compound and the side chain carbonyl of E1012.

[130] Allosteric inhibitors of PI3Ka are disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, and WO2023 / 081759, the -27 - contents of which are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein. In some embodiments, the disclosed methods may utilize a PI3Ka allosteric specific inhibitor disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, which optionally may bind to the PI3Ka allosteric pocket 2.

[131] In some embodiments of the methods disclosed herein, the methods may utilize a PI3Ka allosteric specific inhibitor disclosed in WO2021 / 222556, at Table 1, pages 162-855, and referred to as Compounds 1-1 through 1-2704 or a pharmaceutically acceptable salt thereof.

[132] In some embodiments, the methods may utilize a PI3Ka allosteric specific inhibitor selected from: Compound Name Structure N-(l-Oxo-3-(o-tolyl)isoindolin-4-yl)benzo[b]thiophene-3-carboxamide (1-1) P J MH T \ $ N-(l-Oxo-3-(o-tolyl)isoindolin-4-yl)bicyclo[2.2.2]octane-l-carboxamide (I-179)            ' 0 h < nh . x 5 x pc* o N-( 1 -Oxo-3-(o-tolyl)isoindolin-4-yl)-[l,2,4]triazolo[4,3-a]pyridine-3-carboxamide (1-328)                 ' & IM / -y J- \- 7-Chloro-N-[3-(2-methylphenyl)-l-oxo-2,3-dihydro-l H-isoindol-4-yl]imidazo[1,5-a]pyridine-1 -carboxamide (1-258) a: V    / —Z / J ‘ y o 7-Chloro-N-(l-oxo-3-(o-tolyl)isoindolin-4- yl)-3-methylimidazo[l,5-a]pyridine-l-carboxamide (1-277) T <5 o VW / ««\ x 6,8-Difluoro-N-(l-oxo-3-(o-tolyl)isoindolin-4-yl)imidazo[l,5-a]pyridine-3-carboxamide (1-180)      ’ ¢3   & \ V IX N-(l-Oxo-3-(o-tolyl)isoindolin-4-yl)-l,2,3,4-tetrahydro-1,4-methanonaphthalene-1 -carboxamide (1-226) p J JSH T v 00 N-(1-oxo-3-(o-toly!)isoindoHn-4-yl)benzo[d]isothiazole-3-carboxamide (I-13) T i / N-[3-(2-methylphenyl)-l-oxo-2,3-dihydro-IH-i soindol-4-yl]-2,3-dihydro-1 H-indoie-1 -carboxamide (1-43) Q » 'J ; Z N-[6-bromo-3-(2-methylphenyl)-l~oxo-2,3-dihydro-lH-isoindol-4-yl]-l-benzothiophene-3-carboxamide (1-29) ft p X N-[6-( 1 -methyl-IH-pyrazol -4-yl)-3-(2-methylphenyl)-1 -oxo-2,3 -dihydro- 1H-isoindol-4-yi]-l-benzothiophene-3-carboxamide (1-115) ft J V'l ..... 3-Fluoro-N-[3-(2-methylphenyl)-6- (isopropyl)-l-oxo-2,3-dihydro- lH-isoindol-4-yl]-5- (trifluoromethyl)benzamide (1-266) -n                            x. \ /     Z”" \ ft      “ ¥-4 N-(6-Bromo-3-(2-chloro-5-fluorophenyl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl (benzamide Vh, °ynh ¢5 N-[4-Chloro-l-(2-methylphenyl)-3-oxo-1 H,2H,3 H-pyrrol o[3,4-cjpyri di n-7-yl ]-3 -fluoro- 5~(trifluoromethyl)benzamide (1-232) Cs a YH Y Xl F-^-^CFs N-(4-Ammo-3~oxo-l-(o-tolyl)-2,3-dihydro~ lH-pyrrolo[3,4-c]pyridin-7-yI)-3-fluoro-5-(tri fl uoromethy 1 )benzami de (I -262) J .....o LL N-[3-(2-Methylphenyl)-1 -oxo-1 H,2H,3 H-pyrrolo[3,4-c]pyridin-4-yl]-l,2-benzothiazole-3- carboxamide (1-176) 0 Jo N-[5-(2-Chlorophenyl)-2-(methylsulfanyl)-7-oxo-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide 1           p J NH O<rNH P'. 'F 3-Fluoro-N-[l-(l-methylcyclohexyl)-3-oxo- 2,3-dihydro-lH-indazol-7-yl]-5-(trifluoromethyl)benzarnide O F 6 N-( 1,1 -Dioxido-3-(o-tolyl)-2,3-dihydrobenzo[d]isothiazol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide A O iTS^nh o'° (Z)-N-[3 -(2-Chloro-5-fluorophenyl)~ 1 -sulfanylidene-2,3-dihydro-lH-isoindol-4-yl]- 3- fluoro-N'-hydroxy-5- (trifluoromethyl)benzimidamide p If p F 5-Bromo-4-(2-methylphenyl)-3,4-dihydro-2H-1,3 -benzoxazin-2-one Br o N-(4-(2-Chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide H N-[ 1 -(2-Chiorophenyl)-3-oxo-1,2,3,4-te trahy droi soqui nol in-8 -y 1 ]-3 -fluoro-5 -(trifluoromethyl)benzamide / a.... / .......x 9 cw a a N-[5-(2-Chloro-5-fluorophenyl)-1 -methyl-2,7-dioxo-lH,2H,5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]-3-fluoro-5-(trifluoroniethyl)benzamide 4-Ami no-3 -methoxyi soindolin-1 -one 0 OMe 6-([ 1,2,4]Triazolo[ 1,5-a]pyridin-6-yl)-4-brom o-3 -(2-chl oro-5-fl aoropheny 1)-2-(4-methoxybenzyl)isoindolin-l-one h j / W iC-'O d a \ N-(3-(2-Chloro-5-fluorophenyl)-1 -oxo-6-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan-2-y l)isoin dolin-4-yl)-3-fluoro-5-(tritluoromethyl)benzamide F r~'O     Y - cf3 VyY™ J wo J—NH / O       Gi N-(3-(2-Chloro-5-fluorophenyl)-6-hydroxy-1 -oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide F z?—MH    / oz        Cl Methyl l-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoi soi ndol i n e-5 -carboxy 1 ate Q / N-(6-(Bromomethyl)-3-(2-chloro-5~ fluorophenyl)-1 -oxoisoindolin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide ., o ’ Uc rf     CJ *"CF: (1 -(2-Chl oro-5 -fl uoroph enyl)-7-(3 -fl uoro-5-(trifluoromethyl)benzamido)-3- oxoisoindolin-5-yl)methanesulfonyl chloride a 1 o - 33 - N-(3-(2-Chloro-5-fluorophenyl)-6~formyl-l-oxoisoindolin-4-yl)-3-fluoro-5- (tri fl uoromethy 1 )ben zami de (I -3 3 3 ) F Wd NH / Cl N-(2-([l,2,4]Triazolo[l,5-a]pyridin-6-yl)-5-(2-chloro-5-fluorophenyl)-7-oxo-6,7-dihydro-5H-py rrol o[3,4 -b ] py ri din-4-y 1 )-3 -fluoro-5 -(trifluoromethyl )benzamide A : S            P OyNH PstAdd N-[3-(2-Chloro-5-fluorophenyl)-6~(lH-indol-2-yl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]- 3-fluoro-5-(trifluoromethyl)benzamide * v p N-[3-(2-Chloro-5-fluorophenyl)-6-[3-(difluoromethyl)imidazo[l,2-a]pyridin-6-yI]-1-oxo- 2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide jCO 7 F A                 ! NH f     vS1 « T A ,ci XP F N-[3-(2-Chloro-5-fluorophenyl)-6-[(oxetan-2-yl)methyl]-l-oxo-2,3-dihydro-lH-isoindol- 4-yl]-3-fluoro-5-(trifluoromethyl)benzamide p / yU A K J zNH ci O^NH Pp 1          V \ 1 xp d A F F I F N-[3-(2-Chloro-5-fluorophenyl)-l~oxo-6-(5-oxo-5,6-dihydro-l,6-naphthyridin-6-yl)-2,3-dihydro-1 H-isoi ndol -4-y 1 ]-3 -fluoro-5 -(trifluoromethyl)benzamide T r      o I T14H TV £1 NH / "Y fl F? N-[3-(2-Chloro-5-fluorophenyl)-1 -oxo-6-[(pyrimidin-5-yl)methoxy]-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide i       NH o^jh Jv X N-[3-(2-Chloro-5-fluorophenyl)-1 -oxo-6-{[(1 r* ,3r* *)-3 -hydroxy cyclobutyl] amino} -2,3- dihydro-lH-isoindol-4-yl]-3-fluoro-5-(tri fluorom ethyl )benzamide H      P .— L 1 HO T \ X's °Y^ fC JX F F N-(6-(Aminomethyl)-1 -oxo-3 -(o-tolyl)isoindolin-4-yl)benzo[b]thiophene-3-carboxamide (I-8S) 0 XXX Hy l* V XX N-[6-Amino-3-(2-methylphenyl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-l,2-benzothiazole-3-carboxamide (1-50) o § >1 I L) - 35 - N-[6-Ethenyl-3-(2-methylphenyl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-l- benzothiophene-3-carboxamide (1-100) p N-[6-(2-Hydroxyethyl)-3-(2-methyiphenyl)-1-oxo-2,3-dihydro-lH-isoindol-4-yl]-l-benzothiophene-3-carboxamide (1-181) Q HQ. i 1 MH s L N-[6-( 1,2-Dihydroxyethyl)-3-(2-methylphenyl)-1 -oxo-2,3 -dihydro- 1H-isoindol-4-yi]-l- benzothiophene-3 -carboxamide (1-139) Vv / N-[6-(Hydroxymethyl)-3-(2-methylphenyl)-1 -oxo-2,3-dihydro-1 H-isoindol-4-yl]-l ,2-benzothi azole-3-carboxamide (I-131) O     } )             ,_____Z N-(6-((Methylsulfonyl)methyl)-1 -oxo-3 -(o- tolyl)isoindolin-4-y[)benzo[d]isothiazole-3-carboxamide (1-202) O O' "b | J V'R Y y a N-(6-(Methoxymethyl)- 1 -oxo-3 -(o- tolyl)i soindolin-4-yl)- N- methylbenzo[d]isothiazoIe-3- carboxamide (I-134)" r y ,• W'"® N-(6-(Methoxymethy 1)-1 -oxo-3 -(o-tolyl)isoindolin-4-yl)benzo[d]isothiazole-3-carboxamide (1-146) 0 °' i / / I 7-(Benzo[b]thiophene-3 -carboxami do)-N-methyl-3-oxo-1 -(o-tolyl)i soindoline-5 -carboxamide (1-6) H | - X (R)-7-(Benzo[b]thiophene-3-carboxamido)-N -methyl -3 -oxo-1 -(o-tolyl)i soi ndoline-5-carboxamide (1-75) O     p H NH S (S)-7-(Benzo[b]thiophene-3-carboxamido)-N-methyl-3-oxo-l-(o-toiyl)isoindoline-5-carboxamide (1-76) 9      o 0<yNH N-[6-( 1 -hydroxy cyclopropyl)-3-(2-methylphenyl)-1 -oxo-2,3 -dihydro- 1H-isoindol-4-yl]- l,2-benzothiazole-3-carboxamide (1-315) p .KH / "X T Y $ A      ---5: / M"5 -37 - Methy1 7-(benzo[d]i sothi azole-3 - carboxamido)-3-oxo-l-(o-tolyl)isoindoline-5-carb oxy late Ct          ZJ . Ji F o’ a-a I A T A z cp * N-(7-Cyano-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[b]thiophene-3-carboxamide (I-132) X-f X .-. A, A N-[7-Etheny1-3 -(2-methylphenyl)-1 -oxo-2,3 -dihydro- lH-isoindol-4-yl]-l- benzothiophene-3-carboxamide (1-2157) A* I X > 'VA AX rt 7-(Benzo[b]thiophene-3-carboxanudo)-3-oxo-l-(o-tolyl)isoindoline-4-carboxamide (I- 149) r           e - i 4'"'% N-(7-Methyl-1 -oxo-3-(o-tolyl)isoindolin-4- yl)benzo[b]thiophene-3-carboxamide (1-153) A'S'X «      KH A -ssA / Y \ X % / WZ“S - 38 - N-(6-Acetyl-3-(2-chl oro-5-fluorophenyl)-1 -oxoisoindolin-4-yl)-3-fluoro-5-(tri fluoromethy 1 )benzami de (I-127) 0      0 A (| 1 m VP oi A / Y x I           r N-(3-(2-chloro-5-fluorophenyl)-6-(2-hydroxy propan-2 -y 1)-1 -oxoi soindolin-4-yl)-3 -fluoro- 5-(trifluoromethyl)benzamide (1-128) f HO" V J p XI / N-(3-(2-chloro-5-fluorophenyl)-1 -oxo-6-(2,2,2-trifluoro-1 -hydroxy ethyl)! soindolin-4-yl)- 3-fluoro-5-(trifluoromethyl)benzamide (I-270)                        " 1        \ % A £' LF' N-(3-(2-Chloro-5-fluorophenyl)-6-((3,3-difluoroazeti din-1 -yl)methyl)-1 -oxoisoindolin-4- yl)-3 -fluoro-5 -(trifluoromethyl)benzamide (1-348) D F                      JGI 1 f- N-[3-(2-chl oro-5 -fl uorophenyl )-6-(1-hy droxycyclopropyl)-1 -oxo-2,3-dihydro- 1H-isoindoI-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-374) V?      p T \ Y  < $ Methyl I -(2-chloro-5-fluorophenyl)-7-[3-fluoro-5-(trifluoromethyf)benzamido]-3-oxo-2,3 -di hydro-1 H-i soi ndol e-5-carb oxylate X A ci Ai) N-(3-Cyclohexyl-1 -oxoisoindolin-4-yl)benzo[d]isothiazole-3-carboxamide (1-204) '•f ; r z - X N-(7-oxo-5-(o-tolyl)-6,7-di hydro-5H-pyirolo[3,4-b]pyridin-4-yl)indoline-l-carboxamide (1-147) O ..-jy A 1 1 T     *  7 / / 7 K / N-(5-(2,3-Difluorophenyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)benzo[b]thiophene-3-carboxamide (I-15) °' 3-Fluoro-N-(4-methyl-3-oxo-l-(o-tolyr)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-7-yl)-5- (trifluoromethyi)benzamide (1-244) X-f IX l V / a^.mi / «=< I w Cl F       CFj N-(l-Chloro-l-(2-chloro-5-f!uorophenyl)-4-(3,3-difluoroazetidin-1 -yl)-3-ox 0-2,3 -dihydro- lH-pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-274) Y © A. J & J f VC! rs .o p- N-[4-Chl oro-1 ~(2-chloro-5-f!uorophenyl)-3 -oxo-lH,2H,3H-pyrrolo[3,4-c]pyridin-7-yl]-3- fluoro-5 -(tri fl uor om ethy l)b enzam i de 1 -F $ V'   a N-(3-(2-(Difluoromethyl)-5-fluorophenyl)-5-fluoro-1 -oxoi soi ndoiin-4-y 1)-3 -fluoro-5 -(trifluoromethyl)benzamide (1-283) a 1 4 £M £1 / ' F'        'GFj N-(3-Methyl~ 1 -oxo-3-(o-tolyl)i soindolin-4-yl)benzo[b]thiophene-3-carboxamide (1-80) ,. \ - \ J ...... /                     s ■O w N-(l-(2-chlorophenyl)-6-methoxy-3-oxo-2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-335) 9 1 J IwV \ 1 w £1 F     "CFj 6-([ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl)-3 -(2-chioro-5-fluorophenyl)-4-(piperidin-3-ylamino)i soindolin-1 -one (1-215 8) (A rS LTF ar ci -41 - (S)-N~[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihy dro-1 H-isoi ndol -4-y 1 ] - 3 -fluoro-5 -(trifluoromethyl)benzamide (1-943) F A F AAA A 0 Cl (R)- N-[3-(2-chloro-5-fluorophenyl)- 1 -oxo-6-{[ 1,2,4]tri azolof 1,5-a]pyridin-6-yl} -2,3 -dihydro- 1H- isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (1-945) F p ,...1.... p z ' 4 T F ¢0 0 Cf (S)-N-( 3-(2-chl oro-5-fluorop heny 1 )-6-(5 -cyano- [ 1,2,4] tri azol o[ 1,5 -a]pyri di n-6-yl)-1 - oxoisoindolin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide (1-1647) ,   *___ /   \           U ^-■"1—k d     i 1 V; / f 1   < x Af #--2 It ¢ / ) \— / o (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cy ano-[ 1,2,4]triazolo[l,5-a]pyridin-6-y 1)-1-oxoisoindolin-4- y 1)-3 -fluoro-5 - (trifluoromethyl)benzamide (1-1648) F . x J" CN T >‘'G O      Cf (S)-N-(3-(2-chloro-5-fluorophenyi)-6-(l -(difluoromethyl)- lH-pyrazol-4-yl)-1 -oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1739) F F      <yV<F f LX x rv J~nh ; a     Cl (R.)-N-(3-(2- chloro-5-fluorophenyl)-6-( 1 -(difluoromethyl)- lH-pyrazol-4-yl)-1 -oxoisoindolin-4-yl)-3- fluoro-5-(tritluoromethyl)benzamide (1-1740) F F-4-F F w O      Ct N-(3-(2-chloro-5-fluorophenyl)-6-(5-cy anofl,2,4]triazo1o[1,5-a]pyridin-6-yl)-1 -oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide F f. yx '   1 J A G   © (S)-N-(3-(2-chl oro-5 -fluorophenyl)-6-( 1 -methyl -6-oxo- 1,6-dihydropyri di n-3 -y 1)-1 -oxoisoindolin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide (1-701) F F—f—F Yvd X-NH / O' Cl (R)-N-(3-(2- chloro-5-fluorophenyl)-6-(l-m ethyl -6-oxo-1,6-dihydropyridin-3-yl)-l -oxoisoindolin-4- yl)-3~fluoro-5-(trifluoromethyl)benzamide (1-702) y y-NH y O      Cf 4-Amino-2-chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one OMe O / S xl w -43 - N-(5-(2-Chlorophenyl)-7-oxo-2-(lH-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)benzo[d]isothiazole-3-carboxamide (I-94) J hu I V / cP N-[2-Chloro-5~(2-chlorophenyl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]-l,2-benzothiazole-3-carboxamide (1-93) o 1 J P'! Ct 7 O N-(5-(2-Chlorophenyl)-7-oxo-2-(lH-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 4-yl)benzo[d]isothiazole-3-carboxamide (I- 94) 0 I T A F I N-[5-(2-C hl oro-5 -fl u oropheny 1)-2-(3,3-difl u oroazeti din-1 -yl)- 7-oxo- 5H, 6H, 7H-py rr ol o [3,4-b]py ridi n-4 -yl ] -3 -fluoro- 5 -(trifluoromethyl)benzamide (1-286) F—V'-t        0 A / Ox Methyl 4-(1,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridine-2-carboxylate (1-222) ¢) X ,N,  # \ / 4 0,.. .W 1 V / LX* or a pharmaceutically acceptable salt thereof.

[133] In some embodiments, the methods may utilize a PI3Ka allosteric specific inhibitor as disclosed in WO2021 / 222556, Table 1, selected from: or a pharmaceutically acceptable salt thereof.

[134] In some aspects of the methods disclosed herein, the methods may utilize a PI3Ka allosteric specific inhibitor disclosed in WO2022 / 265993, at Tables A-D, pages 175-259. In some embodiments, the methods may utilize a PI3Ka allosteric specific inhibitor disclosed in WO2022 / 265993 selected from: or a pharmaceutically acceptable salt thereof.

[135] In some aspects, the PI3Ka inhibitors utilized in the disclosed methods may bind to PI3Ka concurrently. In some aspects, the disclosed combinations of inhibitors may bind to one or more -45 - allosteric pockets (e.g., PI3Ka allosteric pocket 1 and / or PI3Ka allosteric pocket 2) and the disclosed combinations of inhibitors may bind to the PI3Ka orthosteric pocket, concurrently. In some aspects, the disclosed combination of inhibitors may bind to a first allosteric pocket (e.g., one of PI3Ka allosteric pocket 1 and PI3Ka allosteric pocket 1) and the disclosed combinations of inhibitors may bind to a second allosteric pocket (e.g., the other of PI3Ka allosteric pocket 1 and PI3Ka allosteric pocket 2), concurrently. In some aspects, the disclosed combinations of inhibitors may bind to a first allosteric pocket (e.g., PI3Ka allosteric pocket 1), the disclosed combinations of inhibitors may bind to a second or allosteric pocket (e.g., PI3Ka allosteric pocket 2), and the disclosed combinations of inhibitors may bind to the PI3Ka orthosteric pocket, concurrently.

[136] In some aspects, the PI3Ka inhibitors utilized in the disclosed methods may bind to PI3Ka competitively. In some aspects, the disclosed combinations of inhibitors bind to one or more allosteric pockets (e.g., PI3Ka allosteric pocket 1 and / or PI3Ka allosteric pocket 2) competitively.

[137] In some aspects, PI3Ka selective inhibitors, which may include PI3Ka selective allosteric inhibitors and PI3Ka selective orthosteric inhibitors, may inhibit activity of PI3Ka, such as phosphorylation activity of PI3Ka. Phosphorylation activity may be assayed by methods including the methods disclosed herein. In some aspects, PI3Ka selective inhibitors disclosed herein have an ICso in an in vitro phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM. In some aspects, PI3Ka selective inhibitors disclosed herein have an EC50 in an in vitro cell phosphorylation assay (e.g., a phosphorylation assay which measures phosphorylation of a substrate of PI3Ka such as p-AKT, p-S6, or F0XM1) which is less than about 100 nM, 50 nM, 10 nM, or 1 nM. In some embodiments, PI3Ka selective inhibitors, which may include PI3Ka selective allosteric inhibitors and PI3Ka selective orthosteric inhibitors, may inhibit the growth of cancer cells whose growth is dependent on PI3Ka activity. Growth inhibition may be assayed using methods including methods disclosed herein including the use of cell titer glow reagents (CTGs). In some aspects, PI3Ka selective inhibitors disclosed herein have an EC50 in a growth inhibition assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.

[138] In some aspects, the disclosed subject matter relates to methods of using multiple inhibitors of PI3Ka or combinations of inhibitors of PI3Ka for treating diseases and disorders associated with PI3Ka modulation. The term “multiple inhibitors of PI3Ka” or “combination of inhibitors of PI3Ka” as used herein, should be interpreted to mean “two or more different inhibitors of PI3Ka.” The multiple inhibitors of PI3Ka may inhibit PI3Ka by binding at or near the same pocket of PI3Ka (e.g., at or near an allosteric pocket of PI3Ka), or the multiple inhibitors of PI3Ka may inhibit PI3Ka by binding at or near different pockets of PI3Koi (e.g., where one inhibitor binds at or near an allosteric pocket of PI3Ka and the other inhibitor binds at or near an orthosteric pocket of PI3Ka, or where one inhibitor binds at or near an allosteric pocket of PI3Ka and the other inhibitor binds at or near a different allosteric pocket of PI3Ka).

[139] The disclosed methods may include administered a PI3Ka selective inhibitor. A PI3Ka selective inhibitor may be defined as an inhibitor of PI3Ka which has an inhibitory activity for PI3Ka which is greater than an inhibitory activity for one or more of PI3KP, PI3Ky, and PI3K8. In some aspects, a PI3Ka selective inhibitor may have an ICso value or an ECso value for PI3Ka in a phosphorylation assay which is lower than an ICso value or an ECso value, respectively, for one or more of PI3KP, PI3Ky, and PI3K5 in the phosphorylation assay. Suitable phosphorylation assays for determining ICso values for PI3Ka, PI3KP, PI3Ky, and PI3K8, may include, but are not limited to in vitro biochemical or cell-based phosphorylation assays. In some aspects, a PI3Ka selective inhibitor has an ICso value or an ECso value for PI3Ka in a phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM. In some aspects, a PI3Ka selective inhibitor has an ICso value or an ECso value for one or more of PI3KP, PI3Ky, and PI3K8 in a phosphorylation assay which is greater than about 100 nM, 200 nM, 500 nM, or 1000 nM. In some aspects, a PI3Ka selective inhibitor has an ICso value or an ECso value for PI3Ka in a phosphorylation assay which is at least 5\ 10*, 20*, 30*, 40*, 50*, 100*, 500*, or 1000* less than an ICso value or an ECso value, respectively, for one or more of PI3KP, PI3Ky, and PI3K8 in the phosphorylation assay.

[140] The disclosed PI3Ka selective inhibitors may exhibit selectivity for mutant forms of PI3Ka relative to wild-type forms of PI3Ka. In some aspects, the disclosed PI3Ka selective inhibitors may exhibit selectivity for H1047R mutant PI3Ka relative to wild-type PI3Ka. In some aspects, a PI3Ka selective inhibitor has an ICso value or an ECso value for H1047R mutant PI3Ka in a phosphorylation assay which is less than an ICso value or an ECso value, respectively for wild-type PI3Ka in the phosphorylation assay. In some aspects, a PI3Ka selective inhibitor has an IC50 value or an ECso value for H1047R mutant PI3Ka in a phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM. In some aspects, a PI3Ka selective inhibitor has an IC50 value or an EC50 value for wild-type PI3Ka in a phosphorylation assay which is greater than about 100 nM, 200 nM, 500 nM, or 1000 nM. In some aspects, a PI3Ka selective inhibitor has an IC50 value or an EC50 value for H1047R mutant PI3Ka in a phosphorylation assay which is at least 5*, 10x, 20*, 30*, 40*, 50*, 100*, 500*, or 1000* less than an IC50 value or an EC50 value for wild-type PI3Ka in the phosphorylation assay. Suitable phosphorylation assays for determining IC50 values or EC50 values for H1047R mutant PI3Ka relative to wild-type PI3Ka, may include, but are not limited to in vitro biochemical or cell-based phosphorylation assays.

[141] The methods disclosed herein may recite a “first PI3Ka selective inhibitor” and a “second PI3Ka selective inhibitor.” This should not be interpreted as requiring that the first PI3Ka selective inhibitor is administered prior (e.g., temporally) to the second PI3Ka selective inhibitor in the disclosed methods. In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor may be administered simultaneously or substantially simultaneously (e.g. within less than about 12, 6, 2, 1, 0.5, 0.25, or 0.1 hours of each other), separately or at substantially different times (e.g., more than 12, 24, 48, or 72 hours apart, or more than 1, 2, 3, or 4 weeks apart, or more than 1, 2, 3, or 4 months apart), or sequentially (e.g., where the first PI3Ka selective inhibitor is administered before the second PI3Ka selective inhibitor, or where the second PI3Ka selective inhibitor is administered before the first PI3Ka selective inhibitor).

[142] In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor may be administered by the same actor. In some aspects, a caretaker (e.g., a patient’s physician or a patient’s non-physician caretaker) administers both of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor to the patient. In some aspects, a patient administers both of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor to themself. In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor may be administered by separate actors. In some aspects, a caretaker administers one of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor, and a different caretaker administers the other of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor. In some aspects, a caretaker administers one of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor to the patient, and a patient administers the other of the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor to themself.

[143] In some aspects of the disclosed methods, the therapeutically effective amount of the PI3Ka selective inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events. Adverse events may include, but are not limited to hyperglycemia, which may be defined as blood glucose greater than about 100, 105, 110, 115, 120, or 125 mg / dL while fasting (e.g., after not eating for at least 8 hours), or blood glucose greater than about 155, 160, 165, 170, 175, or 180 mg / dL one to two hours after eating. Adverse events may include but are not limited to hyperinsulinemia, diarrhea, dehydration, skin rash, lymphopenia, Increased alanine transaminase, fatigue, anemia, elevated serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemic disorder, alopecia, prolonged activated partial thromboplastin time, kidney disease with reduction in glomerular filtration rate (GFR), acute abdominal pain, and abnormal hepatic function tests.

[144] In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Ka selective inhibitor is administered to the patient in need thereof, and the PI3Ka selective inhibitor functions as an allosteric inhibitor. In some aspects, the therapeutically effective amount of a PI3Ka selective allosteric inhibitor administered to the patient is a 100-1200 mg oral dose (e.g., BID (administered two times daily)). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose (e.g., 37.5 mg / kg oral dose BID).

[145] The PI3Ka selective allosteric inhibitors disclosed herein, or a pharmaceutically acceptable salts 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.

[146] In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg to 2400 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg to 2000 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg to 1200 mg.

[147] In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg. In an embodiment, aPI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 500 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 800 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1000 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1200 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1400 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1600 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1900 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2000 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2300 mg. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2400 mg.

[148] In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 500 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 800 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1000 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1200 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1400 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1600 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1900 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2000 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2300 mg in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2400 mg in a 28-day cycle.

[149] In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 100 mg to 1200 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg to 1000 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 300 mg to 600 mg twice a day.

[150] In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 100 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 500 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 550 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 700 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 900 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1100 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1200 mg twice a day.

[151] In an embodiment, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 100 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 500 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is - 54- administered at a dose of 550 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 700 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 900 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1100 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day in a 28-day cycle. In an embodiment, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1200 mg twice a day in a 28-day cycle.

[152] In a preferred embodiment, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, 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, a PI3Ka selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day in a 28-day cycle.

[153] In some aspects, the therapeutically effective amount of the a PI3Ka selective allosteric inhibitor administered to the patient is a 9, 15, 20, 25, 30, 35, 37.5, 40, 45, 50, 55, 60, 65, 70, or 75 mg / kg oral dose (e.g., QD or BID), or a dose within a range bounded by any of these values. In some aspects, the therapeutically effective amount of the a PI3Ka selective allosteric inhibitor administered to the patient is a 9-75 mg / kg oral dose (e.g., QD or BID 37.5 mg / kg). In some aspects, the therapeutically effective amount of the a PI3Ka selective allosteric inhibitor administered to the patient is less than about 75, 70, 65, 60, 55, 50, 45, 40, 37.5, 30, 35, 30, 25, 30 15, 9, 8, 7, 6, or 5 mg / kg oral dose (e.g., QD or BID).

[154] In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Ka selective inhibitor is administered to the patient in need thereof, and the PI3Ka selective inhibitor functions as an orthosteric inhibitor. In some aspects, the therapeutically effective amount of the PI3Ka selective orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD, such as less than about 250, 200, 150, 100, or 50 mg QD. In some aspects, the therapeutically effective amount of the PI3Ka selective orthosteric inhibitor administered to the patient is a 50 mg / kg oral dose QD (i.e., administered once a day) or less than about a 50 mg / kg oral dose QD, such as less than about 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, for example when the PI3Ka selective orthosteric inhibitor is administered with a PI3Ka selective allosteric inhibitor (e.g., a PI3Ka selective allosteric inhibitor that binds the PI3Ka allosteric pocket 1 or the PI3Ka allosteric pocket 2), simultaneously, separately, or sequentially.

[155] The disclosed methods may relate to treating a patient having a disease or disorder which is resistant to treatment with a PI3Ka selective inhibitor. Resistance may include “acquired resistance” where a patient has a disease or disorder which has developed resistance to treatment with the PI3Ka selective inhibitor after having been treated previously with the PI3Ka selective inhibitor. - 56- Resistance may include “de novo resistance” where a patient has a disease or disorder that is resistant to treatment with the PI3Ka selective inhibitor and the patient was not treated previously with the PI3Ka selective inhibitor.

[156] The disclosed methods may relate to a patient having a disease or disorder which has acquired resistance to a PI3Ka selective inhibitor. Acquired resistance may be characterized in vitro by methods that include, but are not limited to: an ECso shift in growth inhibition, for example as measured by a cell viability assay; changes in phosphorylation inhibition, for example as assayed by Western blot and quantification of phosphorylated bands, or as assayed by determining an ICso value in a phosphorylation assay; and stability of cell colonies in a sei ection-free condition. Acquired resistance may be characterized in vivo or clinically by observing recurrence in a patient after the patient was treated with the PI3Ka selective inhibitor and the patient previously exhibited remission. For a patient having cancer, acquired resistance may be characterized clinically by observing recurrence after having previously observed remission in the patient when the patient was treated with the PI3Ka selective inhibitor. For a patient having cancer, acquired resistance may be characterized clinically by observing an increase in growth of cancer after having previously observed a decline in growth of the cancer after treatment with the PI3Ka selective inhibitor. For a patient having cancer, acquired resistance may be characterized clinically by observing recurrence of the cancer in a different part of the patient’s body than where the cancer was first observed prior to treatment with the PI3Ka selective inhibitor.

[157] In the disclosed methods, a patient may be administered a therapeutically effective amount of one or more PI3Ka selective inhibitors, which may include a combination of allosteric inhibitors and / or orthosteric inhibitors. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of another therapeutic agent. In some aspects of the disclosed methods, the patient further is administered a therapeutically effective amount of a selective estrogen receptor degrader (SERD). Suitable SERDs may include, but are not limited to imlunestrant, fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502. In some aspects of the disclosed methods, the therapeutically effective amount of the SERD is a dose of 500 mg, which may be administered on days 1, 15, and 29 or a treatment regimen.

[158] In the disclosed methods, a patient in need thereof may have cancer. In some aspects, the patient in need thereof may have breast cancer. In some aspects, the patient in need thereof may have PIK3CA-mutated, advanced, or metastatic breast cancer. PIK3CA-mutated cancer may include cancer having one or more mutations selected from, but not limited to E542K, E545K, E453Q / K, E726K, C901F, M1043I / L, and H1047R, optionally wherein the one or more mutations are in cis (i.e., on the same allele). In some aspects, the patient in need thereof may have PIK3CACA H1047R-mutant advanced, or metastatic breast cancer which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[159] In some aspects of the disclosed methods, the patient in need thereof is a postmenopausal female.

[160] In some aspects of the disclosed methods, the patient has type II diabetes mellitus.

[161] LA, Use of a Combination of an Allosteric Inhibitor and an Orthosteric Inhibitor of Phosphoinositide 3-Kinase (PI3K) for Treating Diseases and Disorders Associated with PI3K Modulation

[162] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka. The methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to the PI3Ka orthosteric pocket. The disclosed methods may comprise administering a first PI3Ka selective inhibitor which is a PI3Ka selective allosteric inhibitor and a second PI3Ka selective inhibitor which is a PI3Ka selective orthosteric inhibitor. In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ka selective inhibitor may be administered simultaneously, separately, or sequentially.

[163] In some aspects of the disclosed methods, the first PI3Ka selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: ; or R2 is a group of the formula: Rs is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, C1-C6 hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted - 59- heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[164] In some aspects of the disclosed methods, the allosteric inhibitor is of a formula: -60- O HOO or a pharmaceutically acceptable salt thereof.

[165] The second PI3Ka selective inhibitor utilized in the disclosed methods binds to the PI3Ka orthosteric pocket and may function as an orthosteric inhibitor. In some aspects, the orthosteric inhibitor is alpelisib or a pharmaceutically acceptable salt thereof. In some aspects, the orthosteric inhibitor is inavolisib or a pharmaceutically acceptable salt thereof. In some aspects, the orthosteric inhibitor is serabelisib or a pharmaceutically acceptable salt thereof.

[166] In some aspects of the disclosed methods, a therapeutically effective amount of the first PI3Ka selective inhibitor is administered to the patient in need thereof, and the first PI3Ka selective inhibitor functions as an allosteric inhibitor. In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily). In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg or less than about 37 mg / kg).

[167] In some aspects of the disclosed methods, a therapeutically effective amount of the second PI3Ka selective inhibitor administered to the patient in need thereof, and the PI3Ka selective inhibitor functions as an orthosteric inhibitor. In some aspects, the therapeutically effective amount of the orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD.

[168] In some aspects of the disclosed methods, a synergistic effect may be observed after administering a therapeutically effective amount of the allosteric inhibitor and a therapeutically effective amount of the orthosteric inhibitor. In some aspects of the disclosed methods, the therapeutically effective amount of the allosteric inhibitor administered to the patient may be less than a therapeutically effective amount of the allosteric inhibitor that is required in a treatment method where the orthosteric inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the orthosteric inhibitor that is administered to the patient may be less than a therapeutically effective amount of the orthosteric inhibitor that is required in a treatment method where the allosteric inhibitor is not administered.

[169] In some aspects of the disclosed methods, the therapeutically effective amount of the allosteric inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, the therapeutically effective amount of the orthosteric inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.

[170] In some aspects of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously, separately, or sequentially. In some aspects of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously or substantially simultaneously. In some aspects of the disclosed methods, the dose of the orthosteric inhibitor which is administered to the patient is less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, optionally where the orthosteric inhibitor is alpelisib.

[171] In the disclosed methods, the first PI3Ka selective inhibitor and the second PI3Ku selective inhibitor may be administered sequentially. In some aspects, the methods comprise administering the second PI3Ka selective inhibitor after the disease or disorder has developed resistance to the first PI3Ka selective inhibitor. In some aspects, the second PI3Ka selective inhibitor is administered initially after the disease or disorder has developed resistance to the first PI3Ka selective inhibitor. In some aspects, the second PI3Ka selective inhibitor is not administered until after the disease or disorder has developed resistance to the first PI3Ka selective inhibitor. In some aspects, resistance is characterized by occurrence of a M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). A patient exhibiting resistance may have a disease or disorder comprising the M1043I / L mutation and / or the C901F mutation together with the H1047R mutation (optionally wherein the M1043I / L mutation and the C901F mutation are in cis on the same allele with the H1047R mutation). -62-

[172] IB, Use of a Combination of a First Allosteric Inhibitor and a Second Allosteric Inhibitor of Phosphoinositide 3-Kinase (PI3K) for Treating Diseases and Disorders Associated with PI3K Modulation, Where the First Allosteric Inhibitor and the Second Allosteric Inhibitor Bind to Different Allosteric Pockets

[173] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof. The methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047; and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to a different allosteric pocket of PI3Ka, such as the PI3Ka allosteric pocket 2, and the second PI3Ka selective inhibitor optionally may form an interaction with one or more amino acids selected from L911, F937, Fl002, E1012, and D1018. The disclosed methods may comprise administering a PI3Ka selective allosteric inhibitor (i.e., a first allosteric inhibitor) and a different PI3Ka selective allosteric inhibitor (i.e., a second allosteric inhibitor), where the first allosteric inhibitor and the second allosteric inhibitor bind to different allosteric pockets (e g., the PI3Ka allosteric pocket 1 and the PI3Ka allosteric pocket 2, respectively), and the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially.

[174] In the disclosed methods, the first PI3Ka selective inhibitor may be an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: ; or R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or Ci-Ce haloalkyl; -64- Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, C1-C6 haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[175] In some aspects of the disclosed methods, the first PI3Ka selective inhibitor is an allosteric inhibitor of a formula: HO^O or a pharmaceutically acceptable salt thereof.

[176] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein.

[177] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor of a Formula IV: IV or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(Re)2-, -C(Re)2C(Re)2-, -C(S)-, -S(O)2-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(Re)2C(O)~; Qis CH, C(Rq), orN; X is CH, C(RX), or N; YisCH, C(Ry), orN; ZisCH, C(RZ), orN; R1 is -Ll-R1A; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; Rq is -LQ-RQA; Rx is J NR Ry is -Ly-Rya; Rz is -Lz-Rza; or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REeC; R$ and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or -66- partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C; RY and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYzt; each of L1, L“, LE, LQ, Lx, L\ and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, Cb-6 cvcloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, ~N(R)C(NR)~, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; RiA is Ra or Rb substituted by r1 instances of RiC; R2A is RA or Rs substituted by r2 instances of R2C, Rea is Ra or Rb substituted by r3 instances of REC; Rqa is Ra or Rb substituted by r4 instances of RQC; RaA is Ra or Rb substituted by r3 instances of Rxc; Rya is Ra or Rb substituted by r6 instances of RYC; rza ra or rb substituted by r instances of RZc; Rl is Ra or Rb substituted by r8 instances of RLC; each instance of RA is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, •StOKXCNIR. -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR?., -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, or -B(OR)2; each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyk a. 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially -67 - unsaturated monocyclic carbocyclic ring; a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each instance of RIC, R2C, REC, RQC, Rxc, RYC, Rzc, RLC, RQiC, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NRz, -S(O)2R -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)R -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from C1-6 aliphatic (wherein the Cue aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, Cu? haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic (wherein the C1-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, Ci-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r1, r2, r3, r4, r3, r6, r7, and r8 is independently 0, 1,2, 3, 4, or 5.

[178] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor of a Formula XXVIII:

[179] R2 R1 Y 1 / NH

[180] 0 XXVIII

[181] or a pharmaceutically acceptable salt thereof.

[182] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor of a Formula: RYA O

[183]

[184] or a pharmaceutically acceptable salt thereof.

[185] In some aspects, the second PI3Ka selective inhibitor is of a formula in which R R1C

[186] Rl is

[187] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of R!c is independently halogen, -CN, -O-(Cn6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[188] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of RiC is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[189] In some aspects, the second PI3Ka selective inhibitor is of a formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-R2A, -N(H)-R2A, -S(O)2CH2-R2A, -CH2S(O)2-R2A, or -C(H)(CHj)OH.

[190] In some aspects, the second PI3Ka selective inhibitor is of a formula in which R2A is phenyl optionally substituted at one or more positions C1.3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen. -69-

[191] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of R2C is independently halogen, -CN, -O-(Ci-e aliphatic), or Cue aliphatic; wherein each Ci-e aliphatic is optionally substituted with one or more halogen atoms.

[192] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of R2C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[193] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r6 instances of Rvc.

[194] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is

[195] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of Ryc is independently oxo, halogen, -CN, -OH, -O-(Ci-3 aliphatic), or C1-3 aliphatic, wherein each Cl- 3 aliphatic is optionally substituted with one or more halogen atoms.

[196] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor has a formula selected from: -70- or a pharmaceutically acceptable salt thereof.

[197] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.

[198] In the disclosed methods, a therapeutically effective amount of the first PI3Ka selective inhibitor is administered to the patient in need thereof, and the first PI3Ka selective inhibitor functions as an allosteric inhibitor (i.e., the first allosteric inhibitor). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg).

[199] In some aspects of the disclosed methods which comprise administering a therapeutically effective amount of a first allosteric inhibitor and a therapeutically effective amount of a second allosteric inhibitor, a synergistic effect may be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first allosteric inhibitor administered to the patient may be less than a therapeutically effective amount of the first allosteric inhibitor that is required in a method where the second allosteric inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the second allosteric inhibitor that is administered to the patient may be less than a therapeutically effective amount of the second allosteric inhibitor that is required in a method where the first allosteric inhibitor is not administered.

[200] In some aspects of the disclosed methods, the therapeutically effective amount of the first allosteric inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, the therapeutically effective amount of the second allosteric inhibitor is effective for reducing PI3Ka activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.

[201] In the disclosed methods, the first allosteric inhibitor and the second allosteric inhibitor may be administered sequentially. In some aspects, the methods comprise administering the second allosteric inhibitor after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, the second allosteric inhibitor is administered initially after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, the second allosteric inhibitor is not administered until after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, resistance is characterized by occurrence of a Ml 043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). In some aspects, a patient has a disease or disorder comprising a M1043I / L mutation and / or a C901F mutation together with a H1047R mutation (optionally wherein the M1043I / L mutation and the C901F mutation are in cis on the same allele with the H1047R mutation). -72-

[202] LC. Use of a Combination of a First Allosteric Inhibitor and a Second Allosteric Inhibitor of Phosphoinositide 3-Kinase (PI3K) for Treating Diseases and Disorders Associated with PI3K Modulation, Where the First Allosteric Inhibitor and the Second Allosteric Inhibitor Bind to the Same Allosteric Pocket

[203] The disclosed methods may relate to methods for treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof. The methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Ka selective inhibitor, wherein the first PI3Ka selective inhibitor binds the PI3Ka allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047 and (ii) a therapeutically effective amount of a second PI3Ka selective inhibitor, wherein the second PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and RI 047. The disclosed methods may comprise administering a PI3Ka selective allosteric inhibitor (e.g., the first allosteric inhibitor) and a different PI3Ka selective allosteric inhibitor (e.g., the second allosteric inhibitor), where the PI3Kot selective allosteric inhibitors bind to the PI3Kot allosteric pocket 1. In the disclosed methods, the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially.

[204] In some aspects of the disclosed methods, the first PI3Ka selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or Ci-Ce haloalkyl; -74- Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[205] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs -76- cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[206] In some aspects of the disclosed methods, the first allosteric inhibitor of Formula I and the second allosteric inhibitor of Formula I are different.

[207] In some aspects of the disclosed methods, the first allosteric inhibitor is of a Formula: HO^O or a pharmaceutically acceptable salt thereof.

[208] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is not of a formula: -77 - or a pharmaceutically acceptable salt thereof.

[209] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is an allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.

[210] In some aspects of the disclosed methods, the second allosteric inhibitor is of a formula selected from: or a pharmaceutically acceptable salt thereof.

[211] In the disclosed methods, a therapeutically effective amount of the first PI3Ka selective inhibitor is administered to the patient in need thereof, and the first PI3Ka selective inhibitor functions as an allosteric inhibitor. In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg).

[212] In the disclosed methods, a first allosteric inhibitor and a second allosteric inhibitor may be administered sequentially. In some aspects, the methods comprise administering the second allosteric inhibitor after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, the second allosteric inhibitor is administered initially after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, the second allosteric inhibitor is not administered until after the disease or disorder has developed resistance to the first allosteric inhibitor. In some aspects, resistance is characterized by occurrence of a Ml 043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). In some aspects, a patient may have a disease or disorder comprising a M1043I / L mutation and / or a C901F mutation together with a H1047R mutation (optionally wherein the M1043I / L mutation the C901F mutation -79- are in cis on the same allele with the H1047R mutation).

[213] I,D(i). Use of Allosteric Inhibitors for Treating Diseases or Disorders that are Resistant to Treatment with Orthosteric Inhibitors

[214] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a PI3Ka selective orthosteric inhibitor. The methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of aPI3Ka selective allosteric inhibitor, wherein the PI3Ka selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, andR1047.

[215] In some aspects of the disclosed methods, the patient has a disease or disorder which has developed resistance to treatment with the orthosteric inhibitor after the patient previously was treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder exhibiting de novo resistance to treatment with the orthosteric inhibitor, where the patient was not treated previously with the orthosteric inhibitor.

[216] In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with alpelisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with inavolisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with serabelisib or a pharmaceutically acceptable salt thereof.

[217] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula I: - 80- or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, C1-C6 alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[218] In some aspects of the disclosed methods, the allosteric inhibitor is not of a formula: HO^O or a pharmaceutically acceptable salt thereof.

[219] In some aspects of the disclosed methods, the allosteric inhibitor is of a formula: - 82- or a pharmaceutically acceptable salt thereof.

[220] In some aspects of the disclosed methods, the allosteric inhibitor is of a formula selected from: or a pharmaceutically acceptable salt thereof.

[221] The disclosed methods may include administered a therapeutically effective amount of a PI3Ka selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[222] I D(ii). Use of Other Allosteric Inhibitors for Treating Diseases or Disorders that have Resistance to Orthosteric Inhibitors

[223] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a PI3Ka selective orthosteric inhibitor. The methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2 and optionally may form one or more interactions with one or more amino acids selected from L911, F937, Fl002, El012, and D1018.

[224] In some aspects of the disclosed methods, the patient has developed a disease or disorder that is resistant to treatment with the orthosteric inhibitor after the patient previously was treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder exhibiting de novo resistance to treatment with the orthosteric inhibitor, where the patient was not treated previously with the orthosteric inhibitor.

[225] In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with alpelisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with inavolisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with serabelisib or a pharmaceutically acceptable salt thereof.

[226] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor is an allosteric inhibitor disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein.

[227] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula IV: - 84- IV or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(Re)2-, -C(Re)2C(Re)2-, -C(S)-, -S(O)2-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(RE)2C(O)-; Qis CH, C(Rq), orN; Xis CH, C(RX), orN; Yis CH, C(Ry), orN; ZisCH, C(RZ), orN; R1 is -LEr^; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; Rq is -Lq-Rqa; Rx is -Lx-Rxa; Ry is -Ly-Rya; Rz is -Lz-Rza; or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REEC;

[228] Rq and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C;

[229] Ry and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, Lx, LY, and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[230] R1A is Ra or RB substituted by r1 instances of R1C;

[231] R2A is Ra or RB substituted by r2 instances of R2C;

[232] Rea is Ra or RB substituted by r3 instances of REC;

[233] Rqa is Ra or RB substituted by r4 instances of RQC;

[234] Rxa is Ra or RB substituted by r instances of Rxc;

[235] Rya is Ra or RB substituted by r6 instances of RYC;

[236] Rza is Ra or RB substituted by r7 instances of Rzc;

[237] RL is Ra or RB substituted by r8 instances of RLC;

[238] each instance of RA is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(0)0R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, or -B(OR)2;

[239] each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; - 86- or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[240] each instance of R1C, R2C, REC, RQC, Rxc, RYC, Rzc, RLC, REEC, RQ1C, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from Ci-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from Ci-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r1, r2, r3, r4, r5, r6, r7, and r8 is independently 0, 1, 2, 3, 4, or 5.

[241] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula XXVIII: - 87- XXVIII or a pharmaceutically acceptable salt thereof.

[242] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.

[243] In some aspects, the allosteric inhibitor is of a Formula in which R1 is

[244] In some aspects, the allosteric inhibitor is of a Formula in which each instance of RIC is independently halogen, -CN, -O-(Ci-6 aliphatic), or Cm aliphatic, wherein each Cue aliphatic is optionally substituted with one or more halogen atoms.

[245] In some aspects, the allosteric inhibitor is of a Formula in which each instance of R1C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[246] In some aspects, the allosteric inhibitor is of a Formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-R2A, -N(H)-R2A, -S(O)2(1 F-R' -CH2S(O)2-R2A, or -C(H)(CHs)OH.

[247] In some aspects, the allosteric inhibitor is of a Formula in which R2A is phenyl optionally substituted at one or more positions C1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.

[248] In some aspects, the allosteric inhibitor is of a Formula in which each instance of R2C is independently halogen, -CN, -O-(Ci-6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[249] In some aspects, the allosteric inhibitor is of a Formula in which each instance of R2C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[250] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r° instances of RlC. In some aspects, the allosteric inhibitor is of a Formula in which RYA is

[251] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of R?c is independently oxo, halogen, -CN, -OH, -O-(Cio aliphatic), or Cj-3 aliphatic, wherein each Cl - 3 aliphatic is optionally substituted with one or more halogen atoms.

[252] In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from:

[253] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor has a formula selected from: - 89- or a pharmaceutically acceptable salt thereof.

[254] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.

[255] The disclosed methods may include administered a therapeutically effective amount of a PI3Ka selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor -90- degrader (SERD).

[256] LD(iii} Use of Allosteric Inhibitors for Treating Diseases or Disorders that have Resistance to Another Allosteric Inhibitor

[257] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a first PI3Ka selective allosteric inhibitor, wherein the first PI3Ka selective allosteric inhibitor binds to the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a second different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 1 and optionally form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[258] In some aspects of the disclosed methods, the patient has a disease or disorder which has developed resistance to treatment with the first allosteric inhibitor after the patient previously was treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder exhibiting de novo resistance to treatment with the first allosteric inhibitor, where the patient was not treated previously with the first allosteric inhibitor.

[259] In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, Ci-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Rs is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; -92- each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted Ch-O cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[260] In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with an allosteric inhibitor of a formula: HO^O or a pharmaceutically acceptable salt thereof.

[261] In some aspects of the disclosed methods, the patient that is resistant to treatment with the first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Cs haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from -94- N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, C1-C6 alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Cs alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[262] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient is of a formula: or a pharmaceutically acceptable salt thereof.

[263] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient is of a formula selected from: or a pharmaceutically acceptable salt thereof.

[264] The disclosed methods may include administered a therapeutically effective amount of a PI3Ka selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with a different PI3Ka selective allosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). -96-

[265] I.D.(iv) Use of Allosteric Inhibitors for Treating Diseases or Disorders that have Acquired Resistance to Another Allosteric Inhibitor

[266] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka that is resistant to treatment with a first PI3Ka selective allosteric inhibitor, wherein the first PI3Ka selective allosteric inhibitor binds the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and RI047. The methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a second different PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2 and optionally may form an interaction with one or more amino acids selected from L911, F937, Fl002, E1012, andD1018.

[267] In some aspects of the disclosed methods, the patient has a disease or disorder which has developed resistance to treatment with the first allosteric inhibitor after the patient previously was treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder exhibiting de novo resistance to treatment with the first allosteric inhibitor, where the patient was not treated previously with the first allosteric inhibitor.

[268] In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: -97 - R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and

[269] each Rn is independently -H or C1-C3 alkyl.

[270] In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with an allosteric inhibitor of a formula: HO^O or a pharmaceutically acceptable salt thereof.

[271] In some aspects of the disclosed methods, the patient that is resistant to treatment with the first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor as disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, the contents of which are incorporated -99- herein by reference in their entireties with respect to the PI3Ka inhibitor compounds and methods of making and using the PI3Ka inhibitor compounds disclosed therein. In some aspects of the disclosed methods, the second allosteric inhibitor is of a Formula IV: IV or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(Re)2-, -C(Re)2C(Re)2-, -C(S)-, -S(O)2-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(Re)2C(O)-; Qis CH, C(Rq), orN; Xis CH, C(RX), orN; Yis CH, C(Ry), orN; ZisCH, C(RZ), orN; R1 is -LCr^; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; Rq is -Lq-Rqa; Rx is -Lx-Rxa; Ry is -Ly-Rya; Rz is -Lz-Rza; or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REEC;

[272] Rq and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C;

[273] Ry and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, Lx, LY, and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[274] R1A is Ra or RB substituted by r1 instances of R1C;

[275] R2A is Ra or RB substituted by r2 instances of R2C;

[276] Rea is Ra or RB substituted by r3 instances of REC;

[277] Rqa is Ra or RB substituted by r4 instances of RQC;

[278] Rxa is Ra or RB substituted by r5 instances of Rxc;

[279] Rya is Ra or RB substituted by r6 instances of RYC;

[280] Rza is Ra or RB substituted by r7 instances of Rzc;

[281] Rl is Ra or RB substituted by r8 instances of RLC;

[282] each instance of RA is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, or -B(OR)2;

[283] each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[284] each instance of R1C, R2C, REC, RQC, Rxc, RYC, Rzc, RLC, REEC, RQ1C, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from Ci-6 aliphatic (wherein the C1-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic (wherein the C1-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, Ci-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r1, r2, r3, r4, r5, r6, r7, and r8 is independently 0, 1, 2, 3, 4, or 5.

[285] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof.

[286] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.

[287] In some aspects, the allosteric inhibitor is of a formula in which R1 is                        .

[288] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen, -CN, -0-(Cw aliphatic), or Cm aliphatic, wherein each Cm aliphatic is optionally substituted with one or more halogen atoms.

[289] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[290] In some aspects, the allosteric inhibitor is of a formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-Rm, A(H)-R2a -S(O)2CH2“R2A, -CH2S(O)2-R2A, or -C(H)(CHs)OH.

[291] In some aspects, the allosteric inhibitor is of a formula in which R2A is phenyl optionally-substituted at one or more positions C1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.

[292] In some aspects, the allosteric inhibitor is of a formula in which each instance of R2C is independently halogen, -CN, -O-(Ci-6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[293] In some aspects, the allosteric inhibitor is of a formula in which each instance of R2C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[294] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r° instances of RlC.

[295] In some aspects, the allosteric inhibitor is of a formula in which Rya is

[296] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of RYC is independently oxo, halogen, -CN, -OH, -O-(Ci-3 aliphatic), or C1-3 aliphatic, wherein each Cl- 3 aliphatic is optionally substituted with one or more halogen atoms.

[297] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from: or a pharmaceutically acceptable salt thereof.

[298] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.

[299] The disclosed methods may include administered a therapeutically effective amount of a PI3Ka selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with another PI3Ka selective allosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[300] EE, Orthosteric Inhibitors for Treating M1043I / L + H1047R Cancer

[301] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, wherein the patient has cancer comprising a M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), optionally after the patient was treated previously with a therapeutically effective amount a PI3Ka selective allosteric inhibitor. In the disclosed methods, the PI3Ka selective allosteric inhibitor may bind to the PI3Ka allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. In the disclosed methods, the patient may have a cancer exhibiting acquired resistance to treatment with the PI3Ka selective allosteric inhibitor or the patient may have a cancer exhibiting de novo resistance to treatment with the PI3Ka selective allosteric inhibitor; and in the disclosed methods, the patient may be administered a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor.

[302] In some aspects of the disclosed methods, the patient was previously treated with a PI3Ka selective allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[303] In some aspects of the disclosed methods, the patient was treated previously with a therapeutically effective amount of a PI3Ka selective allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.

[304] In some aspects of the disclosed methods, the therapeutically effective amount of the PI3Ka selective allosteric inhibitor that was administered to the patient was a 100-1200 mg oral dose administered two times daily. In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Ka selective inhibitor that was administered to the patient was a 9-75 mg / kg oral dose administered two times daily (e.g., 37.5 mg / kg oral dose administered two times daily). In the disclosed methods, the patient may have acquired resistance to treatment with the PI3Ka selective allosteric inhibitor which was administered at the indicated dose.

[305] In the disclosed methods, a therapeutically effective amount of the PI3Ka selective orthosteric inhibitor is administered to the patient in need thereof. In some aspects, the therapeutically effective amount of the PI3Ka selective orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD, such as less than about 250, 200, 150, 100, or 50 mg oral dose QD.

[306] In some aspects, the disclosed methods comprise administering a patient a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, the administered PI3Ka selective orthosteric inhibitor is selected from alpelisib, inavolisib, serabelisib, or pharmaceutically acceptable salts thereof.

[307] LF(i). Allosteric Inhibitors for Treating M1043I / L + H1047R Cancer

[308] In some aspects, the disclosed methods relate to method for treating a disease or disorder associated with modulation of PI3Ko. in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis) with an H1047R mutation and / or a C901 mutation (e.g., C901F optionally in cis) with an H1047R mutation. The methods comprise administering to the patient a therapeutically effective amount of a PI3Ka selective allosteric inhibitor that binds to the PI3Ka allosteric pocket 2 and optionally may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[309] In some aspects, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a Formula IV: IV or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(Re)2-, -C(Re)2C(Re)2-, -C(S)-, -S(O)2-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(RE)2C(O)-; Qis CH, C(Rq), orN; Xis CH, C(RX), orN; Yis CH, C(Ry), orN; ZisCH, C(RZ), orN; R1 is -LEr^; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; Rq is -Lq-Rqa; Rx is -Lx-Rxa; Ry is -Ly-Rya; Rz is -Lz-Rza; or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REEC; R° and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C; Ry and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, Lx, LY, and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; ria js ra or rb substituted by r1 instances of R1C; r2a rA or rb substituted by r2 instances of R2C; Rea is Ra or Rb substituted by r3 instances of REC; Rqa is Ra or Rb substituted by r4 instances of RQC; Rxa is Ra or Rb substituted by r5 instances of Rxc; Rya is Ra or Rb substituted by r6 instances of RYC; Rza is Ra or Rb substituted by r7 instances of Rzc; RL is Ra or RB substituted by r8 instances of RLC; each instance of RA is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, or -B(OR)2; each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 - Ill - membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R1C, R2C, REC, RQC, Rxc, RYC, Rzc, RLC, REEC, RQ1C, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, - S(O)NR2, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from C1-6 aliphatic (wherein the C1-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from Ci-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r1, r2, r3, r4, r5, r6, r7, and r8 is independently 0, 1, 2, 3, 4, or 5.

[310] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof.

[311] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.

[312] In some aspects, the allosteric inhibitor is of a formula in which R1 is                        .

[313] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen, -CN, -0-(Cm aliphatic), or Cm aliphatic, wherein each Cm aliphatic is optionally substituted with one or more halogen atoms.

[314] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[315] In some aspects, the allosteric inhibitor is of a formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-Rm, A(H)-R2a -S(O)2CH2“R2A, -CH2S(O)2-R2A, or -C(H)(CHs)OH.

[316] In some aspects, the allosteric inhibitor is of a formula in which R2A is phenyl optionally-substituted at one or more positions C1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.

[317] In some aspects, the allosteric inhibitor is of a formula in which each instance of R2C is independently halogen, -CN, -O-(Ci-6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[318] In some aspects, the allosteric inhibitor is of a formula in which each instance ofR2C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[319] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r° instances of RlC.

[320] In some aspects, the allosteric inhibitor is of a formula in which RYA is

[321] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of Ryc is independently oxo, halogen, -CN, -OH, -O-(Ci-3 aliphatic), or C1-3 aliphatic, wherein each Cl- 3 aliphatic is optionally substituted with one or more halogen atoms.

[322] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a formula selected from: or a pharmaceutically acceptable salt thereof.

[323] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof

[324] In some aspects of the disclosed methods, the patient has a cancer which has acquired the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g, C901F optionally in cis with the H1047R mutation), after the patient was treated previously with a therapeutically effective amount of a first PI3Ka selective allosteric inhibitor that binds to the PI3Ka pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. In some aspects of the disclosed methods, the patient has a cancer comprising the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047 R mutation) and / or the C901 mutation (e.g, C901F optionally in cis with the H1047R mutation) without the patient having been treated previously with a therapeutically effective amount of a first PI3Ka selective allosteric inhibitor that binds to the PI3Ka pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[325] In some aspects of the disclosed methods, the patient has a cancer which has acquired the M1043I / L mutation (optionally in cis with the H1047R mutation) after the patient was treated previously with a therapeutically effective amount of a first PI3Ka selective allosteric inhibitor of a Formula I or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: ; or R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, Ci-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and R6 is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, C1-C6 alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NRu-C02Rn, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-Cs cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[326] In some aspects of the disclosed methods, the therapeutically effective amount of the PI3Ka selective allosteric inhibitor of Formula I that was administered to the patient was a 100-1200 mg oral dose administered two times daily. In some aspects of the disclosed methods, the therapeutically effective amount of the PI3Ka selective allosteric inhibitor of Formula I that was administered to the patient was a 9-75 mg / kg oral dose administered two times daily (e.g., 37.5 mg / kg oral dose administered two times daily). In the disclosed methods, the patient may have a cancer which acquired resistance after the patient was administered the PI3Ka selective allosteric inhibitor at the indicated dose.

[327] In some aspects of the disclosed methods, the patient was treated previously with a therapeutically effective amount of a PI3Ka selective inhibitor of a formula: HO O or a pharmaceutically acceptable salt thereof.

[328] In the disclosed methods, the patient may have a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g, C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, the patient in need thereof may have advanced, or metastatic breast cancer that is estrogen receptorpositive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[329] In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Ka selective allosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[330] LF(ii). Other Allosteric Inhibitors for Treating M1043I / L + H1047R Cancer

[331] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation). The methods comprise administering to the patient a therapeutically effective amount of a PI3Ka selective inhibitor that binds to the PI3Ka pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, andR1047.

[332] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[333] In some aspects of the disclosed methods, the PI3Kot selective allosteric inhibitor that is administered to the patient is not of a formula: HO^O or a pharmaceutically acceptable salt thereof.

[334] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor of Formula I that is administered to the patient is of a formula: or a pharmaceutically acceptable salt thereof.

[335] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor of Formula I that is administered to the patient is selected from: or a pharmaceutically acceptable salt thereof.

[336] In the disclosed methods, the patient may have a cancer comprising a mutation M1043I / L (optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g, C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, the patient in need thereof may have advanced, or metastatic breast cancer which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[337] In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Ka selective allosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[338] LG. Diagnosis and Treatment of Patients that Have M1043X+H1047R Cancer or C901X +H1047R Cancer

[339] In some aspects, the methods related to methods for treating a disease or disorder associated with modulation of PI3Ka in a patient in need thereof, such as a patient having a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation). The methods may comprise determining that the patient has a cancer comprising the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), for example, by ordering or performing a genomic analysis that identifies mutations in the patient’s cancer (e.g., M1043I / L and / or C901F and / or H1047R, optionally in cis). Suitable genomic analysis may include one or more steps such as: ordering a genomic analysis that identifies the M1043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis}, performing PCR amplification of the allele comprising the M1043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis\, sequencing of the allele comprising the Ml 043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis), probing of the allele comprising the Ml043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis)', identifying or detecting the allele comprising the M1043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis)', and determining that a patient has a cancer comprising the M1043 mutation, the C901 mutation, and / or the H1047R mutation (optionally in cis). After having determined that the patient has a cancer comprising the M1043 mutation (e.g., M1043I / L optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), the methods further may comprise administering treatment to the patient, which may include administering to the patient one or more PI3Ka selective inhibitors to the patient.

[340] In some aspects of the disclosed methods, if the patient has a cancer comprising an M1043 mutation (e.g., 1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective inhibitor. In some aspects, the PI3Kot selective inhibitor is not of a formula: HO O or a pharmaceutically acceptable salt thereof.

[341] In some aspects of the disclosed methods, if the patient has a cancer comprising an Ml 043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective orthosteric inhibitor. In some aspects, the PI3Ka selective orthosteric inhibitor is selected from alpelisib, inavolisib, serabelisib, or pharmaceutically acceptable salts thereof.

[342] In some aspects of the disclosed methods, if the patient has a cancer comprising an Ml 043 mutation (M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective inhibitor, wherein the PI3Ka selective inhibitor binds to the PI3Ka allosteric pocket 2 and may form an interaction with one or more amino acids selected from L911, F937, Fl002, El012, and D1018. In some aspects, the PI3Ka selective allosteric inhibitor is a compound disclosed in WO2021 / 222556 (e.g., any of Compounds I-1 through 1-2704 in Table 1, pages 162-855). In some aspects, the PI3Ka selective allosteric inhibitor is a compound disclosed in WO2022 / 265993, Tables A-D, pages 175-259).

[343] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a Formula IV: or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(Re>, -C(Re)2C(Re)2-, -C(S)-, -S(O)z-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(Re)2C(O)-, Q is CH, C(RQ), orN; Xis CH, C(RX), orN, Y is CH, C(RY), orN; ZisCH, C(RZ), orN; R1 is -Lf-RlA; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; RQ is -LV-rQa; Rx is -LX-RXA; Ry is -LY-RYA; Rz is -LZ-RZA; or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of R^*2; Rq and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C; R? and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with q instances of R^ / c; each of L1, Lz, LE, LQ, Lx, LY, and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, cycloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O>, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2~, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O>; R1A is Ra or R3 substituted by r1 instances of RiC; R2a is Ra or Rb substituted by r2 instances of R2C; Rea is Ra or RB substituted by r3 instances of REC, Rqa is Ra or Rb substituted by r4 instances of RQC; Rxa is Ra or RB substituted by r5 instances of Rxc; R> a is Ra or R3 substituted by r6 instances of R^c; RZA is RA or R3 substituted by r' instances of RzC; RL is Ra or Rb substituted by r8 instances of RLC; each instance of Ra is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, AmSiO)2NR2, -N(R)S(O)?R, -P(O)R2, -P(O)(R)OR, or -B(OR)2; each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatonis independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R1C, R2C, REC, RQC, Rxc, RYC, Rzc, RLC, REEC, RQ1C, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -SONIb. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from Ci-6 aliphatic (wherein the Ct-e aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from Ci-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, rf, r2, r’, r4, r, r°, r7, and r8 is independently 0, 1, 2, 3, 4, or 5.

[344] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof.

[345] In some aspects of the disclosed methods, the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.

[346] In some aspects, the allosteric inhibitor is of a formula in which R1 is                        .

[347] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen, -CN, -0-(Cm aliphatic), or Cm aliphatic, wherein each Cm aliphatic is optionally substituted with one or more halogen atoms.

[348] In some aspects, the allosteric inhibitor is of a formula in which each instance of R1C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[349] In some aspects, the allosteric inhibitor is of a formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-R2A, A(H)-R2a, -S(O)2CH2“R2A, -CH2S(O)2-R2A, or -C(H)(CHs)OH.

[350] In some aspects, the allosteric inhibitor is of a formula in which R2A is phenyl optionally-substituted at one or more positions C1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.

[351] In some aspects, the allosteric inhibitor is of a formula in which each instance of R2C is independently halogen, -CN, -O-(Ci-6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[352] In some aspects, the allosteric inhibitor is of a formula in which each instance of R2C is independently halogen or C1-3 aliphatic optionally substituted with 1-3 halogen.

[353] In some aspects, the second PI3Ka selective inhibitor is of a formula in which RYA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r° instances of RlC.

[354] In some aspects, the allosteric inhibitor is of a formula in which Rya is

[355] In some aspects, the second PI3Ka selective inhibitor is of a formula in which each instance of RYC is independently oxo, halogen, -CN, -OH, -O-(Ci-3 aliphatic), or C1-3 aliphatic, wherein each Cl- 3 aliphatic is optionally substituted with one or more halogen atoms.

[356] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a formula selected from: or pharmaceutically acceptable salts thereof.

[357] In some aspects of the disclosed methods, the second PI3Ka selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.

[358] In some aspects of the disclosed methods, if the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), the methods may comprise administering to the patient a therapeutically effective amount of a PI3Ka selective inhibitor that binds to the PI3Ka allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, andR1047.

[359] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor that is administered to the patient is of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: ; or R2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, C1-C& alkyl, C1-C& haloalkyl, Ci-Ce hydroxyalkyl, C3-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-Cs cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-Ce alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, Ci-C3 alkoxy, or -CONR11R11; the optionally substituted C3-Cs cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[360] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor of Formula I is of a formula: or a pharmaceutically acceptable salt thereof.

[361] In some aspects of the disclosed methods, the PI3Ka selective allosteric inhibitor of Formula I that is administered to the patient is selected from:

[362] In some aspects of the disclosed methods, the patient may have a cancer comprising an M1043 mutation (e.g, M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, the patient in need thereof may have advanced, or metastatic breast cancer that is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[363] Compounds for Use in Treatment

[364] In some aspects, the disclosed subject matter relates to a first PI3Ka specific inhibitor for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka), in simultaneous, separate or sequential combination with a second PI3Ka specific inhibitor. The disclosed compounds for use in treatment may be further illustrated by the following embodiments.

[365] Embodiment 1. A PI3Ku specific inhibitor compound of Formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; Ri is a group of the formula: Ra is -H, halogen, -CN, -N(H)(Ci-C3 alkyl), -N(Ci-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Cs-Cs cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, or Ci-C3 haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R? is independently -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-Cs cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kot), in simultaneous, separate or sequential combination with a second PI3Ka specific inhibitor which is a PI3Ka specific orthosteric inhibitor.

[366] Embodiment 2. A compound for use according to embodiment 1, wherein the second PI3Ka specific inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.

[367] Embodiment 3. A compound for use according to embodiment 1, wherein the second PI3Ka specific inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.

[368] Embodiment 4. A compound for use according to any of embodiments 1-3, wherein the dose of the second PI3Ka specific inhibitor is less than about a 300 mg oral dose administered every day.

[369] Embodiment 5. A compound for use according to any of embodiments 1-4, wherein the first PI3Ka specific inhibitor and the second PI3Ka specific inhibitor are administered simultaneously.

[370] Embodiment 6. A compound for use according to embodiment 5, wherein the dose of the second PI3Ka specific inhibitor is less than about a 50, 30, 12.5, 6.25, or 3.125 mg / kg oral dose administered every day.

[371] Embodiment 7. A PI3Ka specific inhibitor compound of Formula I: r3 r2 I or a pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, R4, Rs, R«, R7, and Rs, are as defined in embodiment 1; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka), in simultaneous, separate or sequential combination with a second PI3Ka specific inhibitor which binds to PI3Ka allosteric pocket 2.

[372] Embodiment 8. The compound for use according to embodiment 7, wherein the second PI3Ka specific inhibitor forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[373] Embodiment 9. The compound for use according to embodiment 7 or 8, wherein the second PI3Ka specific inhibitor is of a formula: or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(RE>, -C(Re)2C(Re)2-, -C(S)-, -S(O)2-, -OC(O)-, -N(Re)C(O)-, -C(O)N(Re)-, or -C(Re)2C(O)-; Qis CH, C(Rq), orN; X is CH, C(RX), or N; Y is CH, C(Ry), or N; Z is CH, C(RZ), or N; Rj is -Ll-R!A; R2 is -L2-R2A; each instance of RE is independently H or -LE-REA; RQ is -LQ-RQA; Rx is -Lx-Rxa, Ry is -Ly-Rya; Rz is -I CR2 ’: or two instances of RE are taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is substituted with n instances of REfcC; R° and R1 are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each ring is substituted with p instances of RQJC; R2 and Rz are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, Lx, LY, and Lz is independently a covalent bond, or a Ci-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(RL)-, -C(RL)2-, C3-6 cycloalkylene, C3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR>, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R1A is RA or R8 substituted by r1 instances of R R2A is Ra or R3 substituted by r2 instances of R2c; Rea is Ra or Rb substituted by ri’ instances of REC; Rqa is Ra or Rb substituted by r4 instances of RQC; RaA is Ra or Rb substituted by r5 instances of Rxc; RYA is Ra or Rb substituted by instances of RYC; Rza is Ra or Rb substituted by r instances of RZc; Rl is Ra or Rb substituted by rs instances of RLC; each instance of RA is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NRz, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, or -B(OR)2; each instance of RB is independently a C1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R1C, R2C, Rtc, RQC, Rxc, RAC, Rzc, RlC, Reec, Rqic, and RYZC is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)zNRz, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NRz, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR, -B(OR)2, or an optionally substituted group selected from C1-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from C1-3 alkyl, C1-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic (wherein the Ci-6 aliphatic group is optionally substituted at one or more positions with substituents selected from Ci-3 alkyl, Ci-3 haloalkyl, and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; and each of n, p, q, r1, r2, r3, r4, r3, r6, r7, and r8 is independently 0, 1, 2, 3, 4, or 5.

[374] Embodiment 10. The compound for use according to any of embodiments 7-9, wherein the second PI3Ka selective inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.

[375] Embodiment 11. The compound for use according to any of embodiments 7-10, wherein the second PI3Ka selective inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.

[376] Embodiment 12. The compound for use according to any of embodiments 7-11, wherein the second PI3Ka selective inhibitor is of a formula in which

[377] Embodiment 13. The compound for use according to any of embodiments 7-12, wherein the second PI3Ka selective inhibitor is of a formula in which each instance of R1C is independently halogen, -CN, -O-(Ci-6 aliphatic), or Ci-6 aliphatic, wherein each Ci-6 aliphatic is optionally-substituted with one or more halogen atoms.

[378] Embodiment 14. The compound for use according to any of embodiments 7-13, wherein the second PI3Ka selective inhibitor is of a formula in which R2 is -N(H)C(O)-R2A, -N(H)C(O)N(H)-R2A, -C(O)N(H)-R2a, -N(H)-R2A, -S(O)2CH2-R2A, -CH2S(O)2-R2A, or -C(H)(CH3)OH.

[379] Embodiment 15. The compound for use according to any of embodiments 7-14, wherein the second PI3Ka selective inhibitor is of a formula in which R2A is phenyl optionally substituted at one or more positions C1-3 aliphatic (e.g., methyl), haloalkyl (e.g., tri fluoromethyl or difluoromethyl), or halogen.

[380] Embodiment 16. The compound for use according to any of embodiments 7-15, wherein the second PI3Ka selective inhibitor is of a formula in which each instance of R2c is independently halogen, -CN, -O~(Ci-6 aliphatic), or Ci-6 aliphatic; wherein each Ci-6 aliphatic is optionally substituted with one or more halogen atoms.

[381] Embodiment 17. The compound for use according to any of embodiments 7-16, wherein the second PI3Ka selective inhibitor is of a formula in which RYAis a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r6 instances of RYC.

[382] Embodiment 18. The compound for use according to any of embodiments 7-17, wherein the second PI3Ka selective inhibitor is of a formula in which RYA is

[383] Embodiment 19. The compound for use according to any of embodiments 7-18, wherein the second PI3Ka selective inhibitor is of a formula in which each instance of Ryc is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C1-3 aliphatic, wherein each Cl-3 aliphatic is optionally substituted with one or more halogen atoms.

[384] Embodiment 20. The compound for use according to embodiment 19, wherein the second PI3Ka selective inhibitor has a formula selected from:

[385] or pharmaceutically acceptable salts thereof, or the second PI3Ka selective inhibitor has a formula selected from: or pharmaceutically acceptable salts thereof.

[386] Embodiment 21. A PI3Ka specific inhibitor compound of Formula I: I R or pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, Ri, Rs, R«, R7, and Rs, are as defined in claim 1; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in simultaneous, separate or sequential combination with a second PI3Ka specific inhibitor of Formula I or pharmaceutically acceptable salt thereof, wherein the first PI3Ka specific inhibitor and the second PI3Ka specific inhibitor are different compounds.

[387] Embodiment 22. A compound for use according to embodiment 21, wherein the second PI3Ka specific inhibitor is not of a formula:

[388] Embodiment 23. A compound for use according to embodiment 21 or 22, wherein the second PI3Ka specific inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.

[389] Embodiment 24. A compound for use according to any of embodiments 21-23, wherein the second PI3Ka specific inhibitor is of a formula selected from: or a pharmaceutically acceptable salt thereof.

[390] Embodiment 25. A compound for use according to any of embodiments 1-24, wherein the therapeutically effective amount of the first PI3Ka specific inhibitor is effective for reducing PI3Ka activity in the patient without inducing hyperglycemia in the patient.

[391] Embodiment 26. A compound for use according to any of embodiments 1-25, wherein the therapeutically effective amount of the second PI3Ka specific inhibitor is effective for reducing PI3Ka activity in the patient without inducing hyperglycemia in the patient.

[392] Embodiment 27. A PI3Ka specific inhibitor compound of a Formula I: or pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, R«, Rs, Re, R7, and Rs, are as defined in embodiment 1; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka), of a patient that is resistant to treatment with alpelisib or inavolisib.

[393] Embodiment 28. A PI3Ka specific inhibitor which binds to an allosteric pocket of PI3Kot and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018 for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka), of a patient that is resistant to treatment with alpelisib or inavolisib.

[394] Embodiment 29. A PI3Ka specific inhibitor for use according to embodiment 28, wherein said inhibitor is a compound of Formula : or a pharmaceutically acceptable salt thereof, wherein Ri, R2, E, Q, X, Y, Z are as defined in embodiment 9, or a PI3Ka specific inhibitor for use according to embodiment 28, wherein said inhibitor is a compound of Formula selected from: or a pharmaceutically acceptable salt thereof.

[395] Embodiment 30. A PI3Ka specific inhibitor which is a PI3Ka specific orthosteric inhibitor for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka), wherein the patient has been treated previously with compound of Formula I or pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, R4, Rs, Re, R7, and Rs, are as defined in embodiment 96, and the patient has a cancer which has acquired an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation.

[396] Embodiment 31. A PI3Ka specific inhibitor that binds to PI3Ka allosteric pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018 for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation.

[397] Embodiment 32. A PI3Ka specific inhibitor compound of Formula E or pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, Rt, Rs, Re, R7, and Rs, are as defined in embodiment 1, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation.

[398] Embodiment 33. A PI3Ka specific inhibitor compound of Formula I: or pharmaceutically acceptable salt thereof, wherein R, Ri, R2, R3, Ri, Rs, Re, R7, and Rs, are as defined in embodiment 1, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, comprising assaying a blood sample from a patient, determining if a patient has a cancer comprising an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047 mutation, and administering a therapeutically effective amount of compound of Formula I or pharmaceutically acceptable salt thereof to the patient if an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an Hl047 mutation is present.

[399] Embodiment 34. A PI3Ka specific inhibitor selected from alpelisib and inavolisib, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, comprising assaying a sample from a patient, determining if a patient has a cancer comprising an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an Hl047 mutation, and administering a therapeutically effective amount of alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof to the patient if an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an Hl 047 mutation is present.

[400] Embodiment 35. A PI3Ka specific inhibitor that binds to PI3Ka allosteric pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, comprising assaying a blood sample from a patient, determining if a patient has a cancer comprising an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an Hl047 mutation, and administering a therapeutically effective amount of the PI3Kot specific inhibitor or pharmaceutically acceptable salt thereof to the patient if an M1043I / L in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047 mutation is present.

[401] Embodiment 36. A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the compound of Formula I is of the formula: or a pharmaceutically acceptable salt thereof.

[402] Embodiment 37. A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the therapeutically effective amount of the compound of Formula I administered to the patient is a 100-1200 mg oral dose administered two times daily.

[403] Embodiment 38. A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the therapeutically effective amount of the first PI3Ka specific inhibitor administered to the patient is a 9-75 mg / kg oral dose administered two times daily.

[404] Embodiment 39. A compound for use according to any of embodiments 1-38, wherein the disease or disorder is cancer.

[405] Embodiment 40. A compound for use according to any of embodiments 1-39, wherein the disease or disorder is breast cancer.

[406] Embodiment 41. A compound for use according to any of embodiments 1-40, wherein the disease or disorder is PIK3CA-mutated, advanced, or metastatic breast cancer.

[407] Embodiment 42. A compound for use according to any of embodiments 1-41, wherein the disease or disorder is PIK3CACA H1047R-mutant advanced, or metastatic breast cancer.

[408] Embodiment 43. A compound for use according to embodiment 42, wherein the PIK3CACA H1047R-mutant advanced, or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[409] Embodiment 44. A compound for use according to any of embodiments 1-43, wherein the patient is a postmenopausal female.

[410] Embodiment 45. A compound for use according to any of embodiments 1-44, wherein the patient has type II diabetes mellitus.

[411] Embodiment 46. A compound for use according to any of embodiments 1-45, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[412] Embodiment 47. A compound for use according to embodiment 46, wherein the SERD is selected from imlunestrant, fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502.

[413] Embodiment 48. A compound for use according to embodiment 46 or 47, wherein the therapeutically effective amount of the SERD is a 500 mg dose administered on days 1,15, and 29.

[414] Embodiment 49. A compound for use according to any one of embodiments 1-48, wherein the second PI3Ka specific inhibitor is administered after the disease or disorder has developed resistance to the first PI3Ka specific inhibitor.

[415] Illustrative Compounds

[416] The following are illustrative compounds that may be used in some aspects of the disclosed subject matter.

[417] In one aspect, the present invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof wherein R, Ri, R2, Rj, Rt, Rs, Re, R7, and Rs, are as defined in the Summary for Formula (I).

[418] In a further aspect, compounds of Formula (I) wherein Rs is H have Formula (II), or pharmaceutically acceptable salts thereof: wherein R, Ri, R2, R3, Ri, Rs, Re, and R7, are as defined in the Summary for Formula (I).

[419] In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R is -H or C1-C3 alkyl; Ri is a group of the formula: R2 is a group of the formula: R10 Ra is -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; each of R4, Rs and Re is independently -H, halogen, C1-C6 alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl

[420] In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R is -H or C1-C3 alkyl; Ri is a group of the formula: R9 HO^O R2 is a group of the formula: R3 is -H, -CN, Ci-Ce alkyl or Ci-Cs haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl

[421] In a compound of Formula (I), or pharmaceutically acceptable salts thereof, R is -H or C1-C3 alkyl; Ri is a group of the formula: R3 is -H, -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; each of R4, Rs and Re is independently -H, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; R7 is -CN, Ci-Ce alkyl or Ci-Ce haloalkyl; Rs is -H or Ci-Ce alkyl; each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONRnRii, -NRuRn, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[422] In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-l,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each optionally substituted with a -CN, -OH, oxetanyl, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN.

[423] In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[424] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: Preferably, each Rm is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SChRn, -CONR11R11, -NRnRn, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[425] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NRnRn, -OH or -CN.

[426] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, -SO2R11, -CONR11R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, or an optionally substituted heteroaryl selected from selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[427] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, -SO2R11, -C(O)OCi-C3 alkyl, -CONR11R11, a Ci-Ce alkyl optionally substituted with -CN or -CONR11R11 (preferably each Rn is C1-C3 alkyl), a C3 cycloalkyl optionally substituted with C1-C3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, an optionally substituted phenyl (preferably an optionally substituted phenyl substituted by a -CN), or an optionally substituted heteroaryl selected from pyrazole or oxazole.

[428] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, -SO2R11, -CONR11R11, a Ci-Ce alkyl optionally substituted with -CN, a C3 cycloalkyl optionally substituted with C1-C3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, or an optionally substituted heteroaryl selected from pyrazole or oxazole.

[429] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, each Rio is independently SO2CH3 ; or                              .

[430] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, each Rio is independently

[431] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[432] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[433] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, -N(H)(CH2CH2CO2H), -C(O)Ci-C3 alkyl, Ci-C6 alkyl, Ci-C6 haloalkyl, oxetane, isoxazole, or pyridine (preferably 3-pyridine). In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl, oxetane, or isoxazole. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, Ci-Ce alkyl, or C1-C6 haloalkyl. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rais -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably Rjis -H, -CN, or C1-C3 alkyl); most preferably Rjis -H, or methyl.

[434] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is H or halogen, preferably Ri is H.

[435] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl; preferably Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R is -H, halogen, methyl, or trifluoromethyl.

[436] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R is -H, or halogen.

[437] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), and R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[438] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), and R2 is a group of the formula: R10 10 . Preferably, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[439] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rj is -H, methyl or trifluoromethyl (preferably Ra is -H, or methyl), and R2 is a group of the formula: R. R10 10 . Preferably, each Rio is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[440] In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, C1-C6 haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[441] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula: ; or Preferably, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[442] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[443] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl, and R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[444] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula: ; or Preferably, each Rio is independently -H, -CN, halogen, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Cg alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Cg alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[445] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Cg alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Cg alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[446] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Re is -H, or halogen, and R2 is a group of the formula: wherein each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each Rn is independently -H or C1-C3 alkyl.

[447] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Re is -H, or halogen, and R2 is a group of the formula: ;                   ;                   ; or                 . Preferably, each Rio is independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[448] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Re is -H, or halogen, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[449] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R4 is H or halogen; more preferably R3 is -H, -CN, or C1-C3 alkyl, and R-i is H; most preferably R3 is -H, or methyl, and R4 is H.

[450] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably Rs is -H, -CN, or C1-C3 alkyl), and Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably Rj is -H, or methyl, and Rs is -H, halogen, methyl, or trifluoromethyl.

[451] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN, or C1-C3 alkyl), and Re is -H, or halogen; more preferably Rj is -H, or methyl, and Re is -H, or halogen.

[452] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), and Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably Rs is -H, halogen, methyl, or trifluoromethyl.

[453] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H) and Re is -H, or halogen.

[454] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and Re is -H, or halogen; preferably Rs is -H, halogen, methyl, or trifluoromethyl, and Re is H.

[455] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula: methyl, R4 is -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[456] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN, or C1-C3 alkyl), Rs is -H, halogen, C1-C6 alkyl, or Ci-Ce haloalkyl, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[457] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rj is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably Rs is -H, -CN, or C1-C3 alkyl), Rs is -H, or halogen, and R2 is a group of the formula: more preferably R3 is -H, or methyl, Re is -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NRnRn, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[458] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), Rsis -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula: more preferably R5 is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[459] In a compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, and R2 is a group of the formula: ; more preferably R4 and Re are each -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[460] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, Re is -H, or halogen, and R2 is a group of the formula: ; preferably R5 is -H, halogen, methyl, or trifluoromethyl, Re is -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[461] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably Rj is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably Ri is -H), and Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably Rj is -H, or methyl, R4 is -H, and Rs is -H, halogen, methyl, or trifluoromethyl.

[462] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R» is -H), and Rs is -H, or halogen; more preferably Rj is -H, or methyl, and R4 and Rs are each H.

[463] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, Rs is -H, or halogen; more preferably Rs is -H, or methyl, Rs is -H, halogen, methyl, or trifluoromethyl, and Rs is H.

[464] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably R4 is -H), and Rs is -H, or halogen; more preferably Rs is -H, halogen, methyl, or trifluoromethyl, and R4 and Rs are each H.

[465] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rj is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably Rj is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R, is -H), Rs is -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Cs alkoxy, and R2 is a group of the formula: more preferably Rj is -H, or methyl, R4 is -H, Rs is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Cs haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[466] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, and R2 is a group of the formula: ; or more preferably R3 is -H, or methyl, R4 and Re are each -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[467] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably Rs is -H, -CN, or C1-C3 alkyl), R5 is -H, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl, Re is -H, or halogen, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR.11-CO2R11, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[468] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, and R2 is a group of the formula: more preferably Rs is -H, halogen, methyl, or trifluoromethyl, R4 is -H, Re is -H, or halogen, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NRnRn, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[469] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, and Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably Rj is -H, or methyl, R4 and Re are each -H, and Rs is -H, halogen, methyl, or trifluoromethyl.

[470] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably Rj is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula: more preferably R3 is -H, or methyl, R4 is -H, Rs is -H, or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[471] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R is -H.

[472] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, Ci-Ce alkyl, or C1-C6 haloalkyl; preferably R? is -CN, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R7 is -CN, methyl or trifluoromethyl.

[473] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H.

[474] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R is -H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and R is -H.

[475] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs and R are each -H.

[476] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and Rs is H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and Rs is H.

[477] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and Rs and R are each -H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R?is C1-C3 alkyl (preferably methyl), and Rs and R are each -H.

[478] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, Rs is -H, R is -H, and R2 is a group of the formula:

[479] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), Rs is -H, R is -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted Ci-Ce alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[480] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably Rj is -H, -CN, or C1-C3 alkyl), R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and Rs and R are each -H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rj is -H, or methyl, R7 is C1-C3 alkyl (preferably methyl), and Rs and R are each -H.

[481] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R4, Rs and R are each -H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, Rs and R are each -H.

[482] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is -CN, methyl or trifluoromethyl, and Rs and R are each -H. In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rs is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and Rs and R are each -H.

[483] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Rj is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), Re is -H, or halogen, Rs is -H, halogen, Ci-Ce alkyl, or Ci-Ce haloalkyl, R7 is -CN, methyl or trifluoromethyl, Rs is -H, R is -H, and R2 is a group of the formula: R10 ; more preferably R3 is -H, or methyl, R4 is -H, Re is -H, or halogen, Rs is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, Rs is -H, R is -H, and R2 is a group of the formula: independently -H, -CN, halogen, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted Ci-Ce alkyl is optionally substituted with a -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[484] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; or wherein each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[485] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: r9 ; wherein each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; more preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[486] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: HO O ; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3 Cs cycloalkyl; preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[487] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: r9 ; wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[488] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; or

[489] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[490] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: wherein each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl. Preferably each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[491] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; or wherein each R9 is independently -H, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl. Preferably each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. More preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[492] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula ; or                     ; wherein each R9 is independently -H, halogen, -CM, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; more preferably each R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[493] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula alkyl, Ci-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; more preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[494] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; wherein each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy. Preferably each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. More preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[495] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl, or C1-C3 alkoxy. Preferably R9 is -H, halogen, or C1-C3 haloalkyl. More preferably R9 is -H, or trifluoromethyl.

[496] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl, or C1-C3 alkoxy. Preferably R9 is -H, halogen, or C1-C3 haloalkyl. More preferably R9 is -H, or halogen. Even more preferably, R9 is -H, or fluoro.

[497] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl. Preferably R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[498] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; wherein R9 is -H, halogen, or C1-C3 haloalkyl. Preferably R9 is independently halogen or trifluoromethyl. More preferably R9 is chloro or trifluoromethyl.

[499] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: r9 ; wherein R9 is -H, halogen, -CN, Ci-Ce alkyl, Ci-Ce haloalkyl or C1-C6 alkoxy. Preferably R9 is -H, halogen, Ci-Ce alkyl or C1-C6 haloalkyl. More preferably R9 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[500] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: HCT^O ; wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl. Preferably R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[501] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; or

[502] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, Ri is a group of the formula: ; or

[503] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H, or halogen, Re is -H, or halogen, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and Ri is a group of the formula: is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably R3 is -H, methyl, or trifluoromethyl, R4 is -H, or halogen, Re is -H, or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[504] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl, R4 is -H, Re is -H, or halogen, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and Ri is a group of the formula: ; or wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Preferably R3 is -H, or methyl, R4 is -H, Re is -H, or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[505] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R? is -CN, methyl or trifluoromethyl, Rs and R are each -H, and Ri is a group of the formula: is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; more preferably R7 is methyl, Rs and R are each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[506] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R7 is -CN, methyl or trifluoromethyl, Rs and R are each -H, and Ri is a group of the formula: halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R7 is methyl, Rs and R are each -H, and each R9 is in...

Claims

1. A method for treating cancer associated with modulation ofphosphatidylinositol 3-kinase alpha (PI3Ka) that is resistant to treatment with alpelisib or inavolisib, the method comprising administering to a patient in need thereof a therapeutically effective amount of a PI3Ka selective inhibitor selected from:or a pharmaceutically acceptable salt thereof.

2. A method for treating cancer associated with modulation ofphosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation, the method comprising administering to the patient a therapeutically effective amount of a PI3Ka selective inhibitor selected from:or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the cancer is breast cancer.

4. The method of claim 1 or 2, wherein the cancer is PIK3CA-mutated,advanced or metastatic breast cancer.5.The method of claim 1 or 2, wherein the cancer is PIK3CA H1047R-2023373343  25 Mar 2026- 442 -mutant advanced or metastatic breast cancer.

6. The method of claim 1 or 2, wherein the cancer is estrogen receptorpositive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant advanced or metastatic breast cancer.

7. The method of any one of claims 1-6, wherein the patient is apostmenopausal female.

8. The method of any one of claims 1-6, wherein the patient has type IIdiabetes mellitus.

9. The method of any one of claims 1-6, wherein the treatment furthercomprises administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

10. The method of claim 9, wherein the SERD is selected from imlunestrant,fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, and camizestrant.

11. The method of claim 10, wherein the therapeutically effective amountof the SERD is a 500 mg dose administered on days 1, 15, and 29.

12. Use of a PI3Ka selective inhibitor that binds to PI3Ka allosteric pocket2 in the manufacture of a medicament for treating a cancer associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) that is resistant to treatment with alpelisib or inavolisib, wherein the PI3Ka selective inhibitor is:H H              or a pharmaceutically acceptable salt thereof.

13. Use of a PI3Ka selective inhibitor in the manufacture of a medicamentfor treating a cancer associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Ka) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation, and wherein the PI3Ka selective inhibitor is:2023373343  25 Mar 2026- 443 -H H             or a pharmaceutically acceptable salt thereof.

14. The use of claim 12 or 13, wherein the cancer is breast cancer.

15. The use of claim 12 or 13, wherein the cancer is PIK3CA-mutated,advanced or metastatic breast cancer.

16. The use of claim 12 or 13, wherein the cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

17. The use of claim 12 or 13, wherein the cancer is estrogen receptorpositive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant advanced or metastatic breast cancer.

18. The use of any one of claims 12-17, wherein the patient is apostmenopausal female.

19. The use of any one of claims 12-17, wherein the patient has type IIdiabetes mellitus.

20. The use of any one of claims 12-17, wherein the treatment furthercomprises administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

21. The use of claim 20, wherein the SERD is selected from imlunestrant,fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, and camizestrant.

22. The use of claim 21, wherein the therapeutically effective amount of theSERD is a 500 mg dose administered on days 1, 15, and 29.

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