Targeting the allosteric and orthosteric pockets of phosphoinositide 3-kinase (PI3K) for the treatment of disease

Abstract

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

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 501,614, filed May 11, 2023, U.S. Provisional Application No. 63 / 382,980, filed November 9, 2022, and U.S. Provisional Application No. 63 / 382,029, filed November 1, 2022, all of which documents cited herein are incorporated by reference in their entirety.

[0002] (Reference to sequence listing) This application has been submitted with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided in a file titled "30449SequenceListing.xml," created on October 30, 2023, and is 2,777 bytes in size. The Sequence Listing information in ST.26 XML format is incorporated herein by reference in its entirety.

[0003] FIELD OF THE INVENTION The present invention relates to inhibitors of phosphoinositide 3-kinase (PI3K), and combinations thereof, useful in the treatment of diseases or disorders associated with PI3K regulation. The present invention also relates to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K), useful in the treatment of diseases or disorders associated with PI3K regulation, 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 regulation. The present invention also relates to inhibitors of PI3K and combinations thereof, methods of treating (or uses to treat) diseases or disorders associated with PI3K (e.g., CLOVES (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 uses of PI3K inhibitors in combination with one or more additional cancer treatments. [Background technology]

[0004] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is also involved in other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders associated with diabetic complications, and cardiovascular inflammatory complications such as acute coronary syndrome.

[0005] PI3Ks are members of a unique, conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which engages downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play important roles in the synthesis and intracellular transport of PI(3)P and PI(3,4)P2.

[0006] PI3K isoforms are involved in various human cancers and disorders. The alpha (α) isoform of PI3K is involved in various human cancers. It has been shown that angiogenesis selectively requires the α isoform of PI3K in the control of endothelial cell migration. Mutations in the gene encoding PI3Kα, or mutations leading to upregulation of PI3Kα, are thought to occur in many human cancers, including those of the lung, stomach, endometrium, ovary, bladder, breast, colon, brain, prostate, and skin. Mutations in the gene encoding PI3Kα are point mutations clustered within several hotspots in the helix and kinase domain, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high rate of PI3Kα mutations, targeting this pathway may offer beneficial therapeutic opportunities. PI3Kα, along with PI3Kβ, are constitutively expressed, whereas other PI3K isoforms such as PI3Kδ or PI3Kγ are expressed primarily in hematopoietic cells.

[0007] Due to the central role of PI3Kα in regulating glucose homeostasis in the organism, PI3K inhibition in patients often leads to adverse events, including hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin can potentially be mitogenic and / or antiapoptotic to cancer cells, thus negating the antiproliferative effects of PI3K inhibitors. In the context of cancers with mutant PI3Kα, one way to overcome the compensatory insulin and / or glucose production caused by systemic PI3Kα inhibition is to develop inhibitors with enhanced selectivity for mutant PI3Kα over wild-type PI3Kα. This increases the opportunity for drug administration that selectively inhibits the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that control systemic metabolism, thus limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

[0008] PI3Kα has an ATP-binding pocket that can be targeted to regulate PI3Kα activity. PI3Kα must bind to ATP to catalyze the transfer of a phosphate group from ATP to the 3'-OH group on phosphatidylinositol or phosphoinositides. Almost all PI3K inhibitors tested in clinical trials are antagonists that interact within the PI3Kα ATP-binding pocket and compete with ATP as orthosteric inhibitors. The PI3Kα ATP-binding pocket can alternatively be referred to as the "PI3Kα orthosteric binding pocket."

[0009] Current PI3Kα inhibitors have roughly equivalent potency for wild-type and mutant PI3Kα. Mutant-selective inhibitors have been difficult to achieve due to the fact that the most common PI3Kα mutations (E542K, E545K, and H1047R) are located far from the PI3Kα orthosteric binding pocket. Therefore, inhibitors targeting the second peripheral binding pocket near known mutations (e.g., H1047R) may provide a means for selective PI3Kα inhibition.

[0010] The present invention provides a new class of kinase inhibitors that target a non-ATP-binding pocket of PI3K α, referred to herein as "PI3K α allosteric pocket 1," and can interact with amino acid residues of PI3K α, including R1047. The disclosed kinase inhibitors target PI3K α allosteric pocket 1 and can be utilized in combination therapies, for example, in which the disclosed PI3K α inhibitors are used in combination with PI3K α inhibitors that target other pockets of PI3K α, such as the PI3K α orthosteric pocket.

[0011] The present invention also provides characterization of another non-ATP-binding pocket of PI3K α, termed "PI3K α allosteric pocket 2," and the interaction of inhibitors of PI3K α with PI3K α allosteric pocket 2. The disclosed kinase inhibitors that target PI3K α allosteric pocket 1 can be used in combination therapy with PI3K α inhibitors that target PI3K α allosteric pocket 2. Summary of the Invention

[0012] The present disclosure relates to the use of inhibitors of phosphoinositide 3-kinase (PI3K) that target the allosteric and orthosteric pockets of PI3K in methods for treating, preventing, or ameliorating diseases or disorders in which PI3K plays a role (or for use in treating, preventing, or ameliorating diseases or disorders). PI3K inhibitors may be used in combination and may target the allosteric pocket of phosphatidylinositol 3-kinase alpha (PI3Kα) PI3Kα referred to herein as "PI3Kα allosteric pocket 1," the allosteric pocket of PI3Kα referred to herein as "PI3Kα allosteric pocket 2," or the PI3Kα orthosteric pocket. (See FIG. 1 ). In some aspects of the disclosed methods, the PI3K α inhibitor may target PI3K α allosteric pocket 1, PI3K α allosteric pocket 2, or PI3K α orthosteric pocket of a PI3K α mutant that is resistant to treatment with another PI3K α inhibitor, e.g., a PI3K α inhibitor that targets a different pocket of PI3K α.

[0013] The methods may include administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the invention, or a combination of a PI3K inhibitor of the invention and another PI3K inhibitor (which may include other allosteric inhibitors of PI3K and orthosteric inhibitors of PI3K). The methods and PI3K inhibitors of the invention may be used to treat a variety of PI3K-dependent or PI3K-related diseases and disorders.

[0014] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K alpha. The methods may include administering to a patient in need thereof (i) a therapeutically effective amount of a first PI3K alpha-selective inhibitor that binds to PI3K alpha allosteric pocket 1, and (ii) a therapeutically effective amount of a second PI3K alpha-selective inhibitor that binds to the PI3K alpha orthosteric pocket.

[0015] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K alpha. The methods may include administering to a patient in need thereof (i) a therapeutically effective amount of a first PI3K alpha-selective inhibitor that binds to PI3K alpha allosteric pocket 2, and (ii) a therapeutically effective amount of a second PI3K alpha-selective inhibitor that binds to the PI3K alpha orthosteric pocket.

[0016] In some embodiments, the disclosed methods may include administering to a patient (i) a therapeutically effective amount of a first PI3Kα selective inhibitor that binds to PI3Kα allosteric pocket 1, and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor that binds to PI3Kα allosteric pocket 2.

[0017] In some embodiments, the disclosed methods may include administering to a patient (i) a therapeutically effective amount of a first PI3K α-selective inhibitor that binds to PI3K α allosteric pocket 1, and (ii) a therapeutically effective amount of a second PI3K α-selective inhibitor, different from the first PI3K α-selective inhibitor, that binds to PI3K α allosteric pocket 1. In some embodiments, the first PI3K α-selective inhibitor and the second PI3K α-selective inhibitor competitively bind to PI3K α allosteric pocket 1.

[0018] In the disclosed methods, the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor are administered simultaneously, separately, or sequentially. In some embodiments, the second PI3K alpha selective inhibitor is administered to the patient when the patient has a disease or disorder that is resistant to treatment with the first PI3K alpha selective inhibitor. In some embodiments, the second PI3K alpha selective inhibitor is administered to the patient after the patient's disease or disorder has acquired resistance to treatment with the first PI3K alpha selective inhibitor.

[0019] In some embodiments of the disclosed methods, which involve administering a therapeutically effective amount of a first PI3K alpha-selective inhibitor and a therapeutically effective amount of a second PI3K alpha-selective inhibitor, additive or synergistic effects may be observed. In some embodiments of the disclosed methods, the therapeutically effective amount of the first PI3K alpha-selective inhibitor administered in the disclosed methods may be less than the therapeutically effective amount of the first PI3K alpha-selective inhibitor required in a treatment method in which the second PI3K alpha-selective inhibitor is not administered. In some embodiments of the disclosed methods, the therapeutically effective amount of the second PI3K alpha-selective inhibitor administered in the disclosed methods may be less than the therapeutically effective amount of the second PI3K alpha-selective inhibitor required in a treatment method in which the first PI3K alpha-selective inhibitor is not administered.

[0020] In some embodiments of the disclosed methods, a therapeutically effective amount of a first PI3K alpha selective inhibitor is effective to reduce PI3K alpha activity in a patient without inducing adverse events or with a minimal risk of adverse events. In some embodiments of the disclosed methods, a therapeutically effective amount of a second PI3K alpha selective inhibitor is effective to reduce PI3K alpha activity in a patient without inducing adverse events or with a minimal 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 disorders, hair loss, prolonged activated partial thromboplastin time, kidney disease with reduced glomerular filtration rate (GFR), acute abdominal pain, and abnormal liver function tests.

[0021] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha in a patient having a disease or disorder that is resistant to treatment with a PI3K alpha-selective inhibitor, which can be a PI3K alpha-selective allosteric inhibitor or a PI3K alpha-selective orthosteric inhibitor. The method can include administering to the patient a different PI3K alpha-selective inhibitor that the disease or disorder is not tolerant of, such as a PI3K alpha-selective allosteric inhibitor or a PI3K alpha-selective orthosteric inhibitor.

[0022] In some aspects, the disclosed methods relate to treating a disease or disorder associated with the regulation of PI3K alpha in a patient having a disease or disorder that is resistant to treatment with a PI3K alpha-selective orthosteric inhibitor. In some aspects, the disclosed methods relate to treating a disease or disorder associated with the regulation of PI3K alpha in a patient identified as having a disease or disorder that is resistant to treatment with a PI3K alpha-selective orthosteric inhibitor, or a patient identified as having a disease or disorder that shows an incomplete response to treatment with a PI3K alpha-selective orthosteric inhibitor. In some aspects, the methods can include administering a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor to a patient identified as having a disease or disorder that is resistant to treatment with a PI3K alpha-selective orthosteric inhibitor, or a patient identified as having a disease or disorder that shows an incomplete response to treatment with a PI3K alpha-selective orthosteric inhibitor, wherein the PI3K alpha-selective allosteric inhibitor binds to PI3K alpha allosteric pocket 1. In some aspects, the method may include administering a therapeutically effective amount of a PI3K alpha selective allosteric inhibitor to a patient identified as having a disease or disorder that is resistant to treatment with a PI3K alpha selective orthosteric inhibitor or that has an incomplete response to treatment with a PI3K alpha selective orthosteric inhibitor, wherein the PI3K alpha selective allosteric inhibitor binds to PI3K alpha allosteric pocket 2.

[0023] In some embodiments, disclosed methods relate to treating a disease or disorder associated with modulation of PI3K α that is resistant to treatment with a first PI3K α-selective allosteric inhibitor, where the first PI3K α-selective allosteric inhibitor binds to PI3K α allosteric pocket 1. In some embodiments, the method can include administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second, different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1. In some embodiments, the method can include administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second, different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 2. In some embodiments, the method can include administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3K α-selective inhibitor that binds to the PI3K α orthosteric pocket.

[0024] In some embodiments, disclosed methods relate to treating a disease or disorder associated with modulation of PI3K α that is resistant to treatment with a first PI3K α-selective allosteric inhibitor, where the first PI3K α-selective allosteric inhibitor binds to PI3K α allosteric pocket 2. In some embodiments, the methods can include administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second, different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1. In some embodiments, the methods can include administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3K α-selective inhibitor that binds to the PI3K α orthosteric pocket.

[0025] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3K alpha-selective inhibitor, and the patient's disease or disorder has acquired resistance to treatment with the PI3K alpha-selective inhibitor. The method can include administering to the patient a different PI3K alpha-selective inhibitor to which the disease or disorder is not tolerant.

[0026] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K α in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1 or PI3K α allosteric pocket 2. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with the PI3K α-selective allosteric inhibitor, and the method may comprise administering to the patient a therapeutically effective amount of the PI3K α-selective orthosteric inhibitor. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 2. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1.

[0027] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K α in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1 or PI3K α allosteric pocket 2. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with the PI3K α-selective allosteric inhibitor, and the method may comprise administering to the patient a therapeutically effective amount of the PI3K α-selective orthosteric inhibitor. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 2. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1. In the disclosed methods, the patient's disease or disorder may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3K α-selective allosteric inhibitor that binds to PI3K α allosteric pocket 1.

[0028] In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K alpha 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 method can include administering a therapeutically effective amount of a PI3K alpha selective orthosteric inhibitor to a patient having the disease or disorder. The method can include administering a therapeutically effective amount of a PI3K alpha allosteric inhibitor to a 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), wherein the PI3K alpha allosteric inhibitor binds to PI3K alpha allosteric pocket 1. The method may include administering a therapeutically effective amount of a PI3K alpha selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 2 to 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).

[0029] In some aspects, the methods relate to treating a disease or disorder associated with modulation of PI3K alpha in a patient in need thereof, e.g., a patient having a disease or disorder comprising a M1043 mutation (e.g., M1043I / L, optionally in cis with a H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with a H1047R mutation). The methods can include determining that the patient has a disease or disorder comprising a M1043 mutation (e.g., M1043I / L, optionally in cis with a H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with a H1047R mutation), e.g., by ordering or performing a genomic analysis. If the patient is found to have 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 method may further include administering treatment to the patient, which may include administering to the patient one or more PI3K alpha selective inhibitors, which may include allosteric inhibitors as disclosed herein (e.g., allosteric inhibitors that bind to PI3K alpha allosteric pocket 1 and / or allosteric inhibitors that bind to PI3K alpha allosteric pocket 2), orthosteric inhibitors, or combinations thereof.

[0030] In some embodiments, the disclosed methods include selecting a patient for treatment with one or more PI3K alpha-selective inhibitors. In some embodiments, the patient is selected based on the 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). Optionally, the selected patient may be administered a treatment, which may include administering to the patient one or more PI3K alpha-selective inhibitors, which may include an allosteric inhibitor (e.g., an allosteric inhibitor that binds to PI3K alpha allosteric pocket 1 or an allosteric inhibitor that binds to PI3K alpha allosteric pocket 2), an orthosteric inhibitor, or a combination thereof, as disclosed herein.

[0031] In the disclosed methods, a patient in need thereof may have cancer. In some embodiments, a patient in need thereof may have breast cancer. In some embodiments, a patient in need thereof may have PIK3CA mutant, advanced, or metastatic breast cancer. In some embodiments, a 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-).

[0032] In the disclosed methods, a patient in need thereof can have cancer and can have previously been administered one or more therapeutic agents for treating the cancer, which can include a PI3K alpha selective inhibitor. In some aspects, the patient can have a cancer that exhibits de novo or acquired resistance to treatment with a therapeutic agent, which can include a PI3K alpha selective inhibitor, and the patient can be administered a different therapeutic agent, which can include a different PI3K alpha selective inhibitor.

[0033] In the disclosed methods, the patient may not have previously been administered a therapeutic agent for treating cancer, which may include a PI3K alpha-selective inhibitor, hi some embodiments, the patient may be characterized as naive to treatment with a PI3K alpha-selective inhibitor. [Brief explanation of the drawings]

[0034] [Figure 1] Schematic diagram of PI3Kα(H1047R) showing the orthosteric pocket, allosteric pocket 1, and allosteric pocket 2. [Figure 2] Dose-response curve for alpelisib in a T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 3] Dose-response curve of compound 21 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 4] Dose-response curve of compound N1 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 5] Dose-response curve of compound N2 in T47D(M1043I+H1047R) (double, cis, 6x) cell proliferation assay. [Figure 6] Dose-response curve of Compound 1 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 7] Dose-response curve of compound HP1 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 8] Dose-response curve for alpelisib in a T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 9] Dose-response curve of compound HP1 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 10] Dose-response curve of Compound 1 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 11] Dose-response curve of compound 21 in T47D(M1043I+H1047R) (double, cis, 6×) cell proliferation assay. [Figure 12]Combination index plot of compound 21 and alpelisib in T47D naive cells based on growth inhibition assay (CTG). [Figure 13] Combination index plot of compound 21 and alpelisib in T47D (M1043I+H1047R) (double, cis, 6×) cells based on growth inhibition assay (CTG). [Figure 14] Combination index plot of compound 21 and compound HP1 in T47D naive cells based on growth inhibition assay (CTG). [Figure 15] Combination index plot of compound 21 and compound HP1 in T47D (M1043I+H1047R) (double, cis, 6×) cells based on growth inhibition assay (CTG). [Figure 16] Combination index plot of compound 21 and alpelisib in MDA453 naive cells based on growth inhibition assay (CTG). [Figure 17] Combination index plot of compound 21 and alpelisib in MDA453 (compound 21-R) (double, cis, 6×) cells based on growth inhibition assay (CTG). [Figure 18] Combination index plot of compound 21 and compound HP1 in MDA453 naive cells based on growth inhibition assay (CTG). [Figure 19] Combination index plot of Compound 21 and Compound HP1 in MDA453 (Compound 21-R) cells based on growth inhibition assay (CTG). [Figure 20] Graphical representation of the interaction between PIKα_H1047R and compound 21 based on X-ray structural analysis. The interactions include direct hydrogen bonds between the carboxylic acid group of compound 21 and the side chains of R1047 and Q981, hydrogen bonds between the carboxylic acid group of compound 21, a bridging water molecule, and the side chain of Y985, and hydrogen bonds 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)). [Figure 21]Graphical representation of the interactions between PIKα_H1047R and compound 172 based on X-ray structural analysis. The interactions include direct hydrogen bonds between the carboxylic acid group of compound 172 and the side chains of R1047 and Q981, hydrogen bonds between the chromenone exocyclic ketone group of compound 172, a bridging water molecule, and the side chain of H931, hydrogen bonds between the cyano group of compound 172 and the side chain of Y1021, core π-π stacking between the chromenone core of compound 172 and the side chain of F954, and π-π T-stacking between the 4-cyano-phenyl group of compound 172 and the side chain of F909. [Figure 22] Graphical representation of the interaction between PIKα_H1047R and compound N3 based on X-ray structural analysis. The interactions include direct hydrogen bonds between the carboxylic acid group of compound N3 and the side chains of R1047 and Q981, core π-π stacking between the chromenone core of compound N3 and the side chain of F954, and π-π T-stacking between the phenyl group of compound N3 and the side chain of F954. [Figure 23] Graphical representation of the interaction between PIKα_H1047R and compound N4 based on X-ray structural analysis. The interactions include direct hydrogen bonds between the carboxylic acid group of compound N4 and the side chains of R1047 and Q981, as well as hydrogen bonds between the chromenone exocyclic ketone group of compound N4, a bridging water molecule, and the side chain of H931. [Figure 24] Graphical representation of the interactions between PIKα_H1047R and compound N5 based on X-ray structural analysis. The interactions include direct hydrogen bonds between the carboxylic acid group of compound N5 and the side chains of R1047 and Q981, direct hydrogen bonds between the isoxazole group of compound N5 and the side chain of H931, and core π-π stacking between the isoxazole core of compound N5 and the side chain of F954. [Figure 25]Graphical representation of the interaction between PIKα_M1043I_H1047R and compound HP1 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-1-one core of compound HP1 and the carbonyl backbone group of D1018, core π-π stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of compound HP1 and the side chain of F937, and π-πT stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of compound HP1 and the side chain of F1002. [Figure 26] Graphical representation of the interactions between PIKα_M1043I_H1047R and compound HP2 based on X-ray structural analysis. The interactions include a direct hydrogen bond between the nitrogen atom in the isoindolin-1-one core of compound HP2 and the carbonyl backbone group of D1018, a core π-πT-stacking between the core of the 3-trifluoromethyl,5-fluorophenyl group of compound HP2 and the side chain of F1002, and a chlorine-carbonyl interaction between the chlorine atom in the 2-chloro,5-fluorophenyl group of compound HP2 and the side chain carbonyl of E1012. [Figure 27] Graphical representation of the interactions of PIKα_H1047R, compound N6, and compound HP2 in their respective allosteric pockets based on X-ray structural analysis. [Figure 28] Effect of compound 21 (37.5 mg / kg), alpelisib (12.5 mg / kg), and fulvestrant (5 mg / animal) in T47D xenografts (H1047+ / 1, ER+, PR+, HER2-). [Figure 29] Effect of compound 21 (37.5 mg / kg), alpelisib (6.25 mg / kg), and fulvestrant (5 mg / animal) in T47D xenografts (H1047+ / 1, ER+, PR+, HER2-). [Figure 30] Naive and compound 21-resistant MDA453 cells (harboring the M1043I second site mutation) were treated with compound 21, alpelisib, or compound HP1. [Figure 31]Naive and engineered T47D cells (with 6xM1043I second site mutations) were treated with compound 21, alpelisib, or compound HP1. [Figure 32] Parental SUM185PE cells and compound 21-resistant SUM185PE cells were treated with compound 21, compound 1, alpelisib, or compound HP1. [Figure 33] MDA453 naive cells were treated with compound 21 in combination with alpelisib. [Figure 34] Synergy plot of MDA453 naive cells treated with compound 21 in combination with alpelisib. [Figure 35] MDA453 naive cells were treated with compound 21 in combination with compound HP1. [Figure 36] Synergy plot of MDA453 naive cells treated with compound 21 in combination with compound HP1. [Figure 37] MDA453 naive cells were treated with alpelisib in combination with compound HP1. [Figure 38] MDA453 naive cells were treated with alpelisib in combination with compound HP1. [Figure 39] H1047R homozygous SUM185PE cells were treated with compound 21 in combination with alpelisib. [Figure 40] Compound 21-resistant SUM185PE cells treated with a combination of compound 21 and alpelisib. [Figure 41] H1047R homozygous SUM185PE cells were treated with compound 21 in combination with compound HP1. [Figure 42] H1047R homozygous SUM185PE cells were treated with alpelisib in combination with compound HP1. [Figure 43] T47D cells treated with compound 21 in combination with alpelisib. [Figure 44] T47D cells treated with compound 21 in combination with compound HP1. [Figure 45]T47D cells treated with alpelisib in combination with compound HP1. [Figure 46] Naive T47D cells were treated with compound 21 in combination with alpelisib. [Figure 47] T47D 6 × H1043I cells treated with compound 21 in combination with alpelisib. [Figure 48] Parental SUM185PE cells and Compound 21-R SUM185PE cells treated with Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6. [Figure 49] T47D cells (5×H1047R / 1×WT) or engineered T47D cells harboring second-site mutations (5×H1047R / 6×C901F or 6×H1047R / M1043I) treated with Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6. [Figure 50] T47D cells treated with compound 21 in combination with compound HP6. [Figure 51] T47D cells treated with compound 21 in combination with compound HP6. [Figure 52] Combination index plot of compound 21 in combination with compound HP6 in T47D cells. [Figure 53] SUM185PE cells treated with compound 21 in combination with compound HP6. [Figure 54] Combination index plot of compound 21 in combination with compound HP6 in SUM185PE cells. [Figure 55] T47D cells treated with compound 21 in combination with compound HP5. [Figure 56] Combination index plot of compound 21 in combination with compound HP5 in T47D cells. [Figure 57] SUM185PE cells treated with compound 21 in combination with compound HP5. [Figure 58] Combination index plot of compound 21 in combination with compound HP5 in SUM185PE cells. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention provides methods for treating, preventing, or ameliorating a disease or disorder, or the use of a PI3K inhibitor in the treatment, prevention, or amelioration of a disease or disorder, wherein the disease or disorder is dependent on 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 an allosteric inhibitor and an orthosteric inhibitor. The methods and uses disclosed herein can be practiced in the treatment of a variety of PI3K-dependent or PI3K-related diseases and disorders.

[0036] In some embodiments of the disclosed methods and uses, the disease or disorder is cancer (e.g., 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). In some embodiments, diseases or disorders associated with PI3K include CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal cord syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, nerve sheath tumor. These include, but are not limited to, squamous cell carcinoma of the head and neck, 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, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, heterogeneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma.

[0037] Details of the present invention are described 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, exemplary methods and materials are now described. Other features, objects, and advantages of the present invention will be apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, 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 herein with respect to PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed therein are hereby incorporated by reference in their entirety.

[0038] definition The articles "a" and "an" refer to one or to 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.

[0039] The term "and / or" means either "and" or "or" unless otherwise indicated.

[0040] The terms "administer," "administering," or "administration" refer to either direct or indirect administration of a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition to a patient. "Administering" or "administration" can be performed by a caregiver, for example, by a medical professional or other caregiver, who administers a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition to a patient. "Administering" or "administration" can be performed by the patient, for example, when the patient administers a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition to themselves.

[0041] The term "alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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.

[0042] The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0043] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0044] The term "alkynyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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.

[0045] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a bonding p-orbital system with delocalized electrons, which may include lone pairs.

[0046] The term "aryl," unless otherwise defined, refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). Furthermore, when containing two fused rings, an aryl group as defined herein can have one or more saturated or partially unsaturated rings fused to 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 tetrahydrobenzoannurenyl.

[0047] 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, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a patient.

[0048] The term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e.

[0049] [ka] means.

[0050] The term "cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.

[0051] The term "disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0052] The term "haloalkoxy" refers to an alkoxy group, as defined herein, that is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0053] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0054] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0055] The term "heteroaryl," unless otherwise defined, refers to a monovalent monocyclic or 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, with the remaining ring atoms being C. Polycyclic aromatic radicals contain two or more fused rings and may further contain two or more spiro-fused rings (e.g., bicyclic, tricyclic, tetracyclic, etc.). Unless specifically defined otherwise, "fused" means two rings that share two ring atoms. Unless specifically defined otherwise, "spiro-fused" means two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl, as defined herein, also refers to 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 defined herein, also refers to 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[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-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][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1 ,5-a]pyridinyl, [1,2,4]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[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-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[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] 3-b]pyrrolyl, and 3H-indolyl. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein can have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing three or more fused rings, the saturated or partially unsaturated rings can be further fused with a saturated or partially unsaturated ring as described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein can have one or more spiro-fused saturated or partially unsaturated rings. Any saturated or partially unsaturated ring as 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-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazo 4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0056] The terms "heterocyclyl," "heterocycle," or "heterocycloalkyl" mean a monocyclic or polycyclic ring containing 3 to 24 atoms, preferably 3 to 10 atoms, including 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 ring is 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.

[0057] The term "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with a hydroxy group.

[0058] The term "in cis" when referring to two different mutations means that the two different mutations are located on the same chromosome.

[0059] 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 spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0060] The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K. Modulation can include inhibition.

[0061] The terms "patient" or "subject" may be used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human.

[0062] The term "therapeutically effective amount" when used in reference to a compound refers to an amount or dose of the compound that, upon administration to the patient in single or multiple doses, produces a desired effect in the patient being diagnosed or treated.

[0063] The effective amount can be determined by those skilled in the art by using known techniques and observing the results obtained under similar circumstances. In determining the effective amount for a patient, the attending physician will take into account several factors, including but not limited to, the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0064] The term "treating" with respect to a patient includes inhibiting, slowing, halting, or reversing the progression or severity of an existing condition or disorder. The term "treating" with respect to a patient can include prescribing a therapeutic agent or patient treatment regimen to the patient to be administered to the patient. The term "treating" with respect to a patient can include ordering a diagnostic test for the patient. Diagnostic tests can include genomic analysis to identify mutations present in PI3K alpha, e.g., mutations at C901 (e.g., C901F), M1043 (e.g., M1043I / L), and / or H1047 (e.g., H1047R), as disclosed herein, where these mutations can be in cis (i.e., on the same allele).

[0065] The term "preventing," with respect to a patient, can mean preventing a disease or disorder and / or preventing the symptoms of a disease or disorder. A patient in need thereof can include a patient at risk of developing a disease or disorder, where the disclosed methods can be performed to prevent the patient from developing the disease or disorder. A patient in need thereof can include a patient in remission, where the disclosed methods can be performed to prevent the disease or disorder from recurring in the patient.

[0066] With respect to cancer, treating can mean administering a therapeutic agent to a patient and observing a decrease in tumor growth, a decrease in tumor size, and / or an increase in average survival time for the patient after treatment.

[0067] The term "PI3K" refers to "phosphoinositide 3-kinase." The term "PI3Kα" refers to phosphoinositide 3-kinase alpha, a Class I PI3K that includes a PI3K, catalytic, alpha polypeptide (p110-α) encoded by the gene PIK3CA. The p110-α polypeptide may alternatively be referred to as "PIK3CA." The p110-α polypeptide contains 1068 amino acids and has the amino acid sequence of SEQ ID NO: 1.

[0068] [ka]

[0069] The Enzyme Commission (EC) number for the catalytic activity of PI3Kα is 2.7.1.153. The catalytic activity of PI3Kα involves phosphatidylinositol-4,5-bisphosphate 3-kinase activity, whereby a phosphate group from adenosine triphosphate (ATP) is transferred to phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). PI3Kα catalyzes the addition of a 3-phosphate group from ATP to PIP2 by binding to ATP in an ATP-binding pocket within the kinase catalytic domain in the p100α subunit of PI3Kα.

[0070] The PI3K α inhibitors disclosed herein inhibit the phosphatidylinositol-4,5-bisphosphate 3-kinase activity of PI3K α. The disclosed inhibitors can inhibit PI3K α activity by binding at or near the ATP-binding pocket of PI3K α, which may be referred to as the "PI3K α orthosteric pocket." The disclosed inhibitors can act as antagonists to prevent ATP from binding at the ATP-binding pocket, and / or the disclosed inhibitors can displace ATP from the ATP-binding pocket. The disclosed inhibitors can include orthosteric inhibitors that compete with ATP for binding at the ATP-binding site of PI3K α. The ATP-binding pocket of PI3K α has been studied and characterized by X-ray crystallography. (Gkeka et al., Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Kα, J.Phys.Chem.B 2015, 119, 1002-1016, published October 9, 2014; and Fairhurst et al., Identification and Optimization of 4,5-Dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-Dihydrothiazolo[4,5-h]quinazoline Series of Selective Phosphatidylinositol-3 Kinase Alpha Inhibitors, Bior. & Medic. Chem. Lett. 25(2015) 3575-3581, published June 26, 2015.) The ATP-binding pocket is located in the cleft between the N- and C-terminal lobes of the kinase catalytic domain of p100α. The ATP binding pocket may comprise one or more amino acid residues selected from R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933.

[0071] Orthosteric inhibitors of PI3K α may bind to PI3K α at or near the ATP-binding pocket of PI3K α and may form interactions with one or more amino acids selected from R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933. The interactions may include, but are not limited to, hydrogen bonding, either directly or via bridging water molecules, π-πT stacking, and cofacial core π-π stacking. Orthosteric inhibitors of PI3K α are known and may include, but are not limited to, alpelisib, inavolisib, and ceravelisib, which are selective PI3K α inhibitors.

[0072] The disclosed inhibitors can inhibit PI3K α by binding at or near a pocket of PI3K α that is not the ATP-binding pocket of PI3K α, which may be referred to as the "allosteric pocket." The disclosed inhibitors can function as allosteric inhibitors of PI3K α. Allosteric inhibitors of PI3Kα that can be utilized in the disclosed methods are disclosed in WO 2021 / 202964 (Petra), WO 2021 / 222556, WO 2022 / 235574, WO 2022 / 235575, WO 2022 / 251482, WO 2022 / 265993, WO 2023 / 018636, WO 2023 / 039532, WO 2023 / 056407, WO 2023 / 060262, WO 2023 / 288242, WO 2023 / 081209, WO 2023 / 0 Nos. 81757, 2023 / 081759, 2023 / 078401, 2023 / 104111, 2023 / 109870, 2023 / 159155, 2023 / 168378, 2023 / 173124, 2023 / 192416, and 2023 / 288242, the contents of which are incorporated by reference in their entireties herein with respect to PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed therein.

[0073] In some embodiments, the allosteric inhibitors disclosed herein may bind to PI3K α at or near the allosteric pocket of PI3K α, referred to herein as "PI3K α allosteric pocket 1." In some embodiments, the allosteric inhibitor of PI3K α may bind to PI3K α allosteric pocket 1 and form interactions with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The interactions may include, but are not limited to, hydrogen bonding, π-πT stacking, and cofacial core π-π stacking, either directly or via bridging water molecules. The specific interaction may include one or more of the following interactions: direct hydrogen bonds between the carboxylic acid group of the inhibitor and the side chains of R1047 and Q981; hydrogen bonds between the carboxylic acid group of the inhibitor, a bridging water molecule, and the side chain of Y985; hydrogen bonds between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the side chain of H931; hydrogen bonds between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the carbonyl backbone group of C901; hydrogen bonds between the cyano group of the inhibitor and Y1021 hydrogen bonding between the side chain of H931; core π-π stacking between the chromenone core of the inhibitor and the side chain of F954; π-π T-stacking between the phenyl core group of the inhibitor (e.g., the core in the substituent at the C2 position of the chromenone core) and the side chain of F909; direct hydrogen bonding between the C3 substituent on the chromenone core of the inhibitor and the side chain of H931; and core π-π stacking between the core of the inhibitor (e.g., the core in the substituent at the C3 position of the chromenone core) and the side chain of F954. Allosteric inhibitors of PI3Kα that bind to PI3Kα allosteric pocket 1 are disclosed in WO 2021 / 202964, WO 2022 / 235574, WO 2022 / 235575, WO 2022 / 251482, WO 2023 / 056407, WO 2023 / 060262, and WO 2023 / 078401, the contents of which are incorporated by reference in their entireties herein with respect to PI3Kα inhibitor compounds and methods of making and using the PI3Kα inhibitor compounds disclosed therein.

[0074] In some embodiments, the allosteric inhibitors disclosed herein may bind to PI3K α at or near the allosteric pocket of PI3K α referred to herein as "PI3K α allosteric pocket 2." In some embodiments, the allosteric inhibitor of PI3K α may bind to PI3K α allosteric pocket 2 and form interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. The interactions may include, but are not limited to, hydrogen bonding, π-πT stacking, and cofacial core π-π stacking, either directly or via bridging water molecules. The specific interactions may include one or more of the following interactions: direct hydrogen bonding between the nitrogen atom in the isoindolin-1-one core of the inhibitor and the carbonyl backbone group of D1018; core π-π stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of F937; π-π T-stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of F1002; and chlorine-carbonyl interactions between the chlorine atom of the 2-chloro, 5-fluorophenyl group of the compound and the side chain carbonyl of E1012.

[0075] Allosteric inhibitors of PI3K alpha are disclosed in International Publication Nos. 2021 / 222556, 2022 / 265993, 2023 / 018636, 2023 / 039532, 2023 / 288242, 2023 / 081757, and 2023 / 081759, the contents of which are incorporated by reference in their entireties herein with respect to the PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed herein. In some embodiments, the disclosed methods can utilize a PI3K alpha allosteric-specific inhibitor disclosed in WO 2021 / 222556, WO 2022 / 265993, WO 2023 / 018636, WO 2023 / 039532, WO 2023 / 288242, WO 2023 / 081757, or WO 2023 / 081759, which can optionally bind to PI3K alpha allosteric pocket 2.

[0076] In some embodiments of the methods disclosed herein, the methods may utilize the PI3Kα allosteric-specific inhibitors disclosed in Table 1, pages 162-855 of WO 2021 / 222556, and designated compounds I-1 to I-2704, or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, the method comprises administering to a subject a PI3K alpha allosteric-specific inhibitor selected from:

[0078] [Table 1-1]

[0079] [Table 1-2]

[0080] [Table 1-3]

[0081] [Table 1-4]

[0082] [Table 1-5]

[0083] [Table 1-6]

[0084] [Table 1-7]

[0085] [Table 1-8]

[0086] [Table 1-9]

[0087] [Table 1-10]

[0088] [Table 1-11]

[0089] [Table 1-12]

[0090] [Table 1-13]

[0091] [Table 1-14]

[0092] [Table 1-15] Or a pharmaceutically acceptable salt thereof may be used.

[0093] In some embodiments, the method comprises a PI3K alpha allosteric-specific inhibitor selected from the following, as disclosed in Table 1 of WO 2021 / 222556:

[0094] [ka] Or a pharmaceutically acceptable salt thereof may be used.

[0095] In some aspects of the methods disclosed herein, the methods may utilize a PI3K alpha allosteric-specific inhibitor disclosed in Tables A-D, pages 175-259 of WO 2022 / 265993. In some embodiments, the methods utilize a PI3K alpha allosteric-specific inhibitor disclosed in WO 2022 / 265993 selected from:

[0096] [ka] Or a pharmaceutically acceptable salt thereof may be used.

[0097] In some embodiments, the PI3K alpha inhibitors utilized in the disclosed methods can simultaneously bind to PI3K alpha. In some embodiments, the disclosed inhibitor combinations can bind to one or more allosteric pockets (e.g., PI3K alpha allosteric pocket 1 and / or PI3K alpha allosteric pocket 2), and the disclosed inhibitor combinations can simultaneously bind to the PI3K alpha orthosteric pockets. In some embodiments, the disclosed inhibitor combinations can bind to a first allosteric pocket (e.g., one of PI3K alpha allosteric pocket 1 and PI3K alpha allosteric pocket 1), and the disclosed inhibitor combinations can simultaneously bind to a second allosteric pocket (e.g., the other of PI3K alpha allosteric pocket 1 and PI3K alpha allosteric pocket 2). In some embodiments, the disclosed inhibitor combinations can bind to a first allosteric pocket (e.g., PI3Kα allosteric pocket 1), the disclosed inhibitor combinations can bind to a second or allosteric pocket (e.g., PI3Kα allosteric pocket 2), and the disclosed inhibitor combinations can simultaneously bind to the PI3Kα orthosteric pocket.

[0098] In some embodiments, the PI3K alpha inhibitors utilized in the disclosed methods can competitively bind to PI3K alpha. In some embodiments, the disclosed inhibitor combinations competitively bind to one or more allosteric pockets (e.g., PI3K alpha allosteric pocket 1 and / or PI3K alpha allosteric pocket 2).

[0099] In some embodiments, PI3K α-selective inhibitors, which may include PI3K α-selective allosteric inhibitors and PI3K α-selective orthosteric inhibitors, may inhibit the activity of PI3K α, such as the phosphorylation activity of PI3K α. The phosphorylation activity may be assayed by methods including those disclosed herein. In some embodiments, the PI3K α-selective inhibitors disclosed herein have an IC of less than about 100 nM, 50 nM, 10 nM, or 1 nM in an in vitro phosphorylation assay. 50 In some aspects, the PI3K alpha selective inhibitors disclosed herein have an EC50 of less than about 100 nM, 50 nM, 10 nM, or 1 nM in an in vitro cellular phosphorylation assay (e.g., a phosphorylation assay that measures phosphorylation of a substrate of PI3K alpha, such as p-AKT, p-S6, or FOXM1). 50 In some embodiments, PI3K alpha selective inhibitors, which may include PI3K alpha selective allosteric inhibitors and PI3K alpha selective orthosteric inhibitors, may inhibit the growth of cancer cells whose proliferation depends on PI3K alpha activity. Growth inhibition may be assayed using methods, including those disclosed herein, that involve the use of cell titer glow (CTG). In some aspects, the PI3K alpha selective inhibitors disclosed herein have an EC50 of less than about 100 nM, 50 nM, 10 nM, or 1 nM in a growth inhibition assay. 50 It has.

[0100] In some aspects, the disclosed subject matter relates to methods of using multiple PI3K alpha inhibitors or combinations of PI3K alpha inhibitors to treat diseases and disorders associated with PI3K alpha modulation. As used herein, the terms "multiple PI3K alpha inhibitors" or "combination of PI3K alpha inhibitors" should be interpreted to mean "two or more different PI3K alpha inhibitors." Multiple PI3Kα inhibitors may inhibit PI3Kα by binding to the same pocket of PI3Kα (e.g., at or near the allosteric pocket of PI3Kα), or multiple PI3Kα inhibitors may inhibit PI3Kα by binding to different pockets of PI3Kα (e.g., when one inhibitor binds to or near the allosteric pocket of PI3Kα and the other inhibitor binds to or near the orthosteric pocket of PI3Kα, or when one inhibitor binds to or near the allosteric pocket of PI3Kα and the other inhibitor binds to a different allosteric pocket of PI3Kα).

[0101] The disclosed methods can include administering a PI3K alpha selective inhibitor. A PI3K alpha selective inhibitor can be defined as an inhibitor of PI3K alpha that has greater inhibitory activity against PI3K alpha than against one or more of PI3K beta, PI3K gamma, and PI3K delta. In some embodiments, a PI3K alpha selective inhibitor has an IC of 100 or less against one or more of PI3K beta, PI3K gamma, and PI3K delta in a phosphorylation assay. 50 Value or EC 50 IC values ​​for PI3Kα in phosphorylation assays were lower than those of 50 Value or EC 50 IC values ​​for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. 50 Suitable phosphorylation assays for determining the IC value may include, but are not limited to, in vitro biochemical or cell-based phosphorylation assays. In some embodiments, a PI3K alpha selective inhibitor has an IC value for PI3K alpha of less than about 100 nM, 50 nM, 10 nM, or 1 nM in a phosphorylation assay.50 Value or EC 50 In some embodiments, a PI3K alpha selective inhibitor has an IC value against one or more of PI3K beta, PI3K gamma, and PI3K delta in a phosphorylation assay of greater than about 100 nM, 200 nM, 500 nM, or 1000 nM. 50 Value or EC 50 In some embodiments, the PI3K alpha selective inhibitor has an IC value against one or more of PI3K beta, PI3K gamma, and PI3K delta in a phosphorylation assay. 50 Value or EC 50 IC for PI3Kα in a phosphorylation assay at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold less than the IC 50 Value or EC 50 It has a value.

[0102] The disclosed PI3K α selective inhibitors may exhibit selectivity for mutant forms of PI3K α compared to wild-type forms of PI3K α. In some embodiments, the disclosed PI3K α selective inhibitors may exhibit selectivity for H1047R mutant PI3K α compared to wild-type PI3K α. In some embodiments, the PI3K α selective inhibitors exhibit an IC of 1.2 or less relative to wild-type PI3K α in a phosphorylation assay. 50 Value or EC 50 IC values ​​for H1047R mutant PI3Kα in phosphorylation assays were lower than those of the corresponding values, respectively. 50 Value or EC 50 In some embodiments, the PI3K alpha selective inhibitor has an IC value against H1047R mutant PI3K alpha in a phosphorylation assay that is less than about 100 nM, 50 nM, 10 nM, or 1 nM. 50 Value or EC 50 In some embodiments, the PI3K alpha selective inhibitor has an IC value relative to wild-type PI3K alpha in a phosphorylation assay that is greater than about 100 nM, 200 nM, 500 nM, or 1000 nM. 50 Value or EC 50In some embodiments, the PI3K alpha selective inhibitor has an IC value relative to wild-type PI3K alpha in a phosphorylation assay. 50 Value or EC 50 an IC for H1047R mutant PI3Kα in a phosphorylation assay that is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold less than the IC 50 Value or EC 50 IC values ​​for H1047R mutant PI3Kα compared to wild-type PI3Kα 50 Value or EC 50 Suitable phosphorylation assays for determining the value may include, but are not limited to, in vitro biochemical or cell-based phosphorylation assays.

[0103] The methods disclosed herein may recite a "first PI3K alpha selective inhibitor" and a "second PI3K alpha selective inhibitor." This should not be construed as requiring that the first PI3K alpha selective inhibitor be administered before (e.g., temporally) the second PI3K alpha selective inhibitor in the disclosed methods. In the disclosed methods, the first and second PI3K alpha selective inhibitors can 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., when the first PI3K alpha selective inhibitor is administered before the second PI3K alpha selective inhibitor, or when the second PI3K alpha selective inhibitor is administered before the first PI3K alpha selective inhibitor).

[0104] In the disclosed methods, the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor can be administered by the same actor. In some embodiments, a caregiver (e.g., the patient's physician or a caregiver other than the patient's physician) administers both the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor to the patient. In some embodiments, the patient administers both the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor to themselves. In the disclosed methods, the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor can be administered by different actors. In some embodiments, one caregiver administers one of the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor, and a different caregiver administers the other of the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor. In some embodiments, a caregiver administers one of the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor to a patient, and the patient administers the other of the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor to themselves.

[0105] In some embodiments of the disclosed methods, a therapeutically effective amount of a PI3K alpha selective inhibitor is effective to reduce PI3K alpha activity in a patient without inducing adverse events or while minimizing the risk of adverse events, which 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 in a fasting state (e.g., after not eating for at least 8 hours), or greater than about 155, 160, 165, 170, 175, or 180 mg / dL 1-2 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 disorders, hair loss, prolonged activated partial thromboplastin time, renal disease with reduced glomerular filtration rate (GFR), acute abdominal pain, and abnormal liver function tests.

[0106] In some embodiments of the disclosed methods, a therapeutically effective amount of a PI3K alpha selective inhibitor is administered to a patient in need thereof, where the PI3K alpha selective inhibitor functions as an allosteric inhibitor. In some embodiments, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to the patient is an oral dose of 100-1200 mg (e.g., administered twice daily). In some embodiments, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is an oral dose of 9-75 mg / kg (e.g., 37.5 mg / kg oral dose BID).

[0107] The PI3Kα selective allosteric inhibitors, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents and their respective pharmaceutically acceptable salts disclosed herein are generally effective over a wide dosage range. It is understood that the amount of compound actually administered will be determined by a physician taking into account relevant circumstances, including the condition being treated, the selected route of administration, the actual compound(s) being administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0108] In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 200 mg to 2400 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 400 mg to 2000 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 600 mg to 1200 mg.

[0109] In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 200 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 300 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 400 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 500 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 600 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 700 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 800 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 900 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1000 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1100 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1200 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1300 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1400 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1500 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1600 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1700 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1800 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1900 mg.In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2000 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2100 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2200 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2300 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2400 mg.

[0110] In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 200 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 300 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 400 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 500 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 600 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 700 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 800 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 900 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1000 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1100 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1200 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1300 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1400 mg in a 28 day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1500 mg in a 28 day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1600 mg in a 28 day cycle.In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1700 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1800 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 1900 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2000 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2100 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2200 mg in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2300 mg in a 28 day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a total daily dose of 2400 mg in a 28 day cycle.

[0111] In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 100 mg to 1200 mg twice daily. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 200 mg to 1000 mg twice daily. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 300 mg to 600 mg twice daily.

[0112] In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 100 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 150 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 200 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 250 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 300 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 350 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 400 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 450 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 500 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 550 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 600 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 650 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 700 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 750 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 800 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 850 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 900 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 950 mg twice daily.In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1150 mg twice daily. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1200 mg twice daily.

[0113] In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 100 mg to 1200 mg. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 200 mg to 1000 mg. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 100 mg. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 200 mg. In one embodiment, the PI3K α selective allosteric inhibitor or pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 150 mg. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 200 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 250 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 300 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 350 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 400 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 450 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 500 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 550 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 600 mg twice daily in a 28-day cycle.In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 650 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 700 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 750 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 800 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 850 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 900 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 950 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1150 mg twice daily in a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1200 mg twice daily in a 28-day cycle.

[0114] In a preferred embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 200 mg twice daily in a 28-day cycle. In another preferred embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 400 mg twice daily in a 28-day cycle. In another preferred embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 600 mg twice daily in a 28-day cycle. In another preferred embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 800 mg twice daily in a 28-day cycle. In another preferred embodiment, the PI3K alpha selective allosteric inhibitor or pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily in a 28-day cycle.

[0115] In some embodiments, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to a patient is an oral dose of 9, 15, 20, 25, 30, 35, 37.5, 40, 45, 50, 55, 60, 65, 70, or 75 mg / kg (e.g., QD or BID), or a dose within a range bounded by any of these values. In some embodiments, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to a patient is an oral dose of 9-75 mg / kg (e.g., 37.5 mg / kg QD or BID). In some embodiments, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to the patient is an oral dose (e.g., QD or BID) of 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.

[0116] In some embodiments of the disclosed methods, a therapeutically effective amount of a PI3K alpha selective inhibitor is administered to a patient in need thereof, where the PI3K alpha selective inhibitor functions as an orthosteric inhibitor. In some embodiments, the therapeutically effective amount of the PI3K alpha selective orthosteric inhibitor administered to the patient is an oral dose of 300 mg QD (i.e., administered once daily) or an oral dose of less than about 300 mg QD, e.g., less than about 250, 200, 150, 100, or 50 mg QD. In some embodiments, the therapeutically effective amount of a PI3K alpha selective orthosteric inhibitor administered to a patient is 50 mg / kg oral dose QD (i.e., administered once daily), or an oral dose of less than about 50 mg / kg QD, e.g., less than about 30, 12.5, 6.25, or 3.125 mg / kg QD, for example, when the PI3K alpha selective orthosteric inhibitor is administered simultaneously, separately, or sequentially with a PI3K alpha selective allosteric inhibitor (e.g., a PI3K alpha selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 1 or PI3K alpha allosteric pocket 2).

[0117] The disclosed methods can involve treating a patient having a disease or disorder that is resistant to treatment with a PI3K alpha-selective inhibitor. Resistance can include "acquired resistance," where the patient has a disease or disorder that has developed resistance to treatment with a PI3K alpha-selective inhibitor after previously being treated with the inhibitor. Resistance can include "de novo resistance," where the patient has a disease or disorder that is resistant to treatment with a PI3K alpha-selective inhibitor and the patient has not previously been treated with a PI3K alpha-selective inhibitor.

[0118] The disclosed methods may involve patients with a disease or disorder that has acquired resistance to a PI3Kα selective inhibitor. Acquired resistance can include, but is not limited to, a decrease in EC of growth inhibition, as measured by, for example, a cell viability assay. 50 shift; assayed for example by Western blot and quantification of phosphorylated bands, or IC in phosphorylation assays 50Acquired resistance can be characterized in vitro by methods including changes in phosphorylation inhibition, assayed by determining the PI3Kα value; and stability of cell colonies in selection-free conditions. Acquired resistance can be characterized in vivo or clinically by observing recurrence in a patient after the patient has been treated with a PI3Kα-selective inhibitor and the patient has previously shown remission. For a patient with cancer, acquired resistance can be clinically characterized by observing recurrence after a previous remission was observed in the patient when the patient was treated with a PI3Kα-selective inhibitor. For a patient with cancer, acquired resistance can be clinically characterized by observing an increase in cancer growth after a previous decrease in cancer growth was observed after treatment with a PI3Kα-selective inhibitor. For a patient with cancer, acquired resistance can be clinically characterized by observing a recurrence of cancer in a part of the patient's body different from where the cancer was first observed before treatment with a PI3Kα-selective inhibitor.

[0119] In the disclosed methods, the patient may be administered a therapeutically effective amount of one or more PI3Kα-selective inhibitors, which may include a combination of allosteric and / or orthosteric inhibitors. In some embodiments, the disclosed methods further comprise administering to the patient a therapeutically effective amount of another therapeutic agent. In some embodiments of the disclosed methods, the patient is further administered a therapeutically effective amount of a selective estrogen receptor degrader (SERD). Suitable SERDs may include, but are not limited to, imrunestrant, fulvestrant, diledestrant, amsenestrant, lintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502. In some embodiments of the disclosed methods, the therapeutically effective amount of the SERD is a 500 mg dose, which may be administered on days 1, 15, and 29 of the treatment regimen.

[0120] In the disclosed methods, a patient in need thereof may have cancer. In some embodiments, a patient in need thereof may have breast cancer. In some embodiments, a patient in need thereof may have PIK3CA mutant, advanced, or metastatic breast cancer. PIK3CA mutant cancers may include, but are not limited to, cancers with one or more mutations selected from E542K, E545K, E453Q / K, E726K, C901F, M1043I / L, and H1047R, optionally wherein one or more mutations are in cis (i.e., on the same allele). In some embodiments, a patient in need thereof may have PIK3CACA H1047R mutant advanced or metastatic breast cancer that is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-).

[0121] In some aspects of the disclosed methods, the patient in need thereof is a postmenopausal woman.

[0122] In some aspects of the disclosed methods, the patient has type II diabetes.

[0123] Use of a combination of allosteric and orthosteric inhibitors of IA phosphoinositide 3-kinase (PI3K) to treat diseases and disorders associated with PI3K regulation In some aspects, the disclosed methods relate to methods for treating diseases or disorders associated with modulation of PI3K alpha. The methods may include administering to a patient in need thereof (i) a therapeutically effective amount of a first PI3K alpha-selective inhibitor that binds to PI3K alpha allosteric pocket 1 and, optionally, can 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 PI3K alpha-selective inhibitor that binds to the PI3K alpha orthosteric pocket. The disclosed methods may include administering the first PI3K alpha-selective inhibitor, which is a PI3K alpha-selective allosteric inhibitor, and the second PI3K alpha-selective inhibitor, which is a PI3K alpha-selective orthosteric inhibitor. In the disclosed methods, the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor can be administered simultaneously, separately, or sequentially.

[0124] In some embodiments of the disclosed methods, the first PI3K alpha selective inhibitor is an allosteric inhibitor of Formula I:

[0125] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0126] [ka] R2 is a group of the formula:

[0127] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0128] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0129] [ka] or a pharmaceutically acceptable salt thereof.

[0130] The second PI3K alpha selective inhibitor utilized in the disclosed methods can bind to the PI3K alpha orthosteric pocket and function as an orthosteric inhibitor. In some embodiments, the orthosteric inhibitor is alpelisib or a pharmaceutically acceptable salt thereof. In some embodiments, the orthosteric inhibitor is inavolisib or a pharmaceutically acceptable salt thereof. In some embodiments, the orthosteric inhibitor is ceravelisib or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments of the disclosed methods, a therapeutically effective amount of a first PI3K alpha selective inhibitor is administered to a patient in need thereof, where the first PI3K alpha selective inhibitor functions as an allosteric inhibitor. In some embodiments, the therapeutically effective amount of the allosteric inhibitor administered to the patient is an oral dose of 100-1200 mg BID (i.e., administered twice daily). In some embodiments, the therapeutically effective amount of the allosteric inhibitor administered to the patient is an oral dose of 9-75 mg / kg BID (e.g., 37.5 mg / kg or less than about 37 mg / kg).

[0132] In some embodiments of the disclosed methods, a therapeutically effective amount of a second PI3K alpha-selective inhibitor is administered to a patient in need thereof, where the PI3K alpha-selective inhibitor functions as an orthosteric inhibitor. In some embodiments, the therapeutically effective amount of the orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once daily) or an oral dose of less than about 300 mg QD.

[0133] In some aspects of the disclosed methods, a synergistic effect may be observed after administering a therapeutically effective amount of an allosteric inhibitor and a therapeutically effective amount of an orthosteric inhibitor. In some aspects of the disclosed methods, the therapeutically effective amount of the allosteric inhibitor administered to a patient may be less than the therapeutically effective amount of the allosteric inhibitor required in a treatment method in which an orthosteric inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the orthosteric inhibitor administered to a patient may be less than the therapeutically effective amount of the orthosteric inhibitor required in a treatment method in which an allosteric inhibitor is not administered.

[0134] In some aspects of the disclosed methods, a therapeutically effective amount of the allosteric inhibitor is effective to reduce PI3K alpha activity in a patient without inducing adverse events or with a minimal risk of adverse events. In some aspects of the disclosed methods, a therapeutically effective amount of the orthosteric inhibitor is effective to reduce PI3K alpha activity in a patient without inducing adverse events or with a minimal risk of adverse events.

[0135] In some embodiments of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously, separately, or sequentially. In some embodiments of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously or substantially simultaneously. In some embodiments of the disclosed methods, the dose of the orthosteric inhibitor administered to the patient is less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, and optionally, the orthosteric inhibitor is alpelisib.

[0136] In the disclosed methods, the first PI3K alpha-selective inhibitor and the second PI3K alpha-selective inhibitor can be administered sequentially. In some embodiments, the method comprises administering the second PI3K alpha-selective inhibitor after the disease or disorder has developed resistance to the first PI3K alpha-selective inhibitor. In some embodiments, the second PI3K alpha-selective inhibitor is first administered after the disease or disorder has developed resistance to the first PI3K alpha-selective inhibitor. In some embodiments, the second PI3K alpha-selective inhibitor is not administered until after the disease or disorder has developed resistance to the first PI3K alpha-selective inhibitor. In some embodiments, the resistance is characterized by the occurrence of an M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). A patient who exhibits resistance may have a disease or disorder comprising an H1047R mutation and an M1043I / L mutation and / or a C901F mutation (optionally, the M1043I / L mutation and the C901F mutation are in cis on the same allele as the H1047R mutation).

[0137] Use of a combination of a first and a second allosteric inhibitor of phosphoinositide 3-kinase (PI3K), wherein the first and second allosteric inhibitors bind to different allosteric pockets, to treat diseases and disorders associated with the regulation of PI3K. In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha in a patient in need thereof. The method may include administering to the patient: (i) a therapeutically effective amount of a first PI3K alpha-selective inhibitor that binds to PI3K alpha allosteric pocket 1 and, optionally, may interact 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 PI3K alpha-selective inhibitor that binds to a different allosteric pocket of PI3K alpha, such as PI3K alpha allosteric pocket 2, where the second PI3K alpha-selective inhibitor may optionally interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. The disclosed methods may include administering a PI3K α selective allosteric inhibitor (i.e., a first allosteric inhibitor) and a different PI3K α 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., PI3K α allosteric pocket 1 and PI3K α allosteric pocket 2, respectively), and the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially.

[0138] In the disclosed methods, the first PI3K alpha selective inhibitor is an allosteric inhibitor of Formula I:

[0139] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0140] [ka] R2 is a group of the formula:

[0141] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0142] In some embodiments of the disclosed methods, the first PI3K alpha selective inhibitor is an allosteric inhibitor of the following formula:

[0143] [ka] or a pharmaceutically acceptable salt thereof.

[0144] In some aspects of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor disclosed in WO 2021 / 222556, WO 2022 / 265993, WO 2023 / 018636, WO 2023 / 039532, WO 2023 / 288242, WO 2023 / 081757, or WO 2023 / 081759, the contents of which are incorporated by reference in their entireties herein with respect to the PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed therein.

[0145] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor of Formula IV:

[0146] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R 1 -L 1 -R 1A and R 2 -L 2 -R 2A and R E each independently represents H or -L E -REA and R Q -L Q -R QA and R X -L X -R XA and R Y -L Y -R YA and R Z -L Z -R ZA or 2 R's E together with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1 together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZC is replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Z each of which is independently a covalent bond or C 1~4A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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-; R 1A is r 1 R 1C R replaced by A or R B and R 2A is r 2 R 2C R replaced by A or R B and R EA is r 3 R EC R replaced by A or R B and R QA is r 4 R QC R replaced by A or R B and R XA is r 5 R XC R replaced by A or R B and R YA is r 6 R YC R replaced by A or R B and R ZA is r 7 R ZC R replaced by Aor R B and R L is r 8 R LC R replaced by A or R B and R A each independently represents 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, R B Each of the following is independently 1~6 an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZCeach independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with a substituent selected from 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; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r 2 , r 3 , r4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0147] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor of Formula XXVIII:

[0148] [ka] or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor of the following formula:

[0150] [ka] or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the second PI3K alpha selective inhibitor is: R 1 but

[0152] [ka] is of the formula:

[0153] In some embodiments, the second PI3K alpha selective inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0154] In some embodiments, the second PI3K alpha selective inhibitor is R 1Ceach independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0155] In some embodiments, the second PI3K alpha selective inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A or of the formula -C(H)(CH3)OH.

[0156] In some embodiments, the second PI3K alpha selective inhibitor is R 2A but C in one or more positions 1~3 and those of the formula that are phenyl optionally substituted with aliphatic (eg, methyl), haloalkyl (eg, trifluoromethyl or difluoromethyl), or halogen.

[0157] In some embodiments, the second PI3K alpha selective inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0158] In some embodiments, the second PI3K alpha selective inhibitor is R 2C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0159] In some embodiments, the second PI3K alpha selective inhibitor is R YAis a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is 6 R YC is of the formula:

[0160] In some embodiments, the second PI3K alpha selective inhibitor is R YA but,

[0161] [ka] It is of the formula:

[0162] In some embodiments, the second PI3K alpha selective inhibitor is R YC each independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0163] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor has a formula selected from:

[0164] [ka] or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is disclosed in WO 2022 / 265993;

[0166] [ka] a formula selected from or a pharmaceutically acceptable salt thereof.

[0167] In the disclosed methods, a therapeutically effective amount of a first PI3K alpha selective inhibitor is administered to a patient in need thereof, where the first PI3K alpha selective inhibitor functions as an allosteric inhibitor (i.e., a first allosteric inhibitor). In some embodiments, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is an oral dose of 100-1200 mg BID (i.e., administered twice daily). In some embodiments, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is an oral dose of 9-75 mg / kg BID (e.g., 37.5 mg / kg).

[0168] In some embodiments of the disclosed methods, which include 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 embodiments of the disclosed methods, the therapeutically effective amount of the first allosteric inhibitor administered to a patient may be less than the therapeutically effective amount of the first allosteric inhibitor required in methods in which the second allosteric inhibitor is not administered. In some embodiments of the disclosed methods, the therapeutically effective amount of the second allosteric inhibitor administered to a patient may be less than the therapeutically effective amount of the second allosteric inhibitor required in methods in which the first allosteric inhibitor is not administered.

[0169] In some embodiments of the disclosed methods, the therapeutically effective amount of the first allosteric inhibitor is effective to reduce PI3K alpha activity in the patient without inducing adverse events or with a minimal risk of adverse events. In some embodiments of the disclosed methods, the therapeutically effective amount of the second allosteric inhibitor is effective to reduce PI3K alpha activity in the patient without inducing adverse events or with a minimal risk of adverse events.

[0170] In the disclosed methods, the first and second allosteric inhibitors can be administered sequentially. In some embodiments, the methods include administering the second allosteric inhibitor after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the second allosteric inhibitor is administered first after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the second allosteric inhibitor is not administered until after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the resistance is characterized by the occurrence of an M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). In some embodiments, the patient has a disease or disorder comprising an H1047R mutation and an M1043I / L mutation and / or a C901F mutation (optionally, the M1043I / L mutation and the C901F mutation are in cis on the same allele as the H1047R mutation).

[0171] Use of a combination of a first and a second allosteric inhibitor of phosphoinositide 3-kinase (PI3K), wherein the first and second allosteric inhibitors bind to the same allosteric pocket, to treat diseases and disorders associated with the regulation of PI3K The disclosed methods may relate to methods for treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof. The method may include administering to the patient (i) a therapeutically effective amount of a first PI3Kα-selective inhibitor that binds to PI3Kα allosteric pocket 1 and is capable of interacting 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 PI3Kα-selective inhibitor that binds to PI3Kα allosteric pocket 1 and is capable of interacting with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The disclosed methods can include administering a PI3K alpha selective allosteric inhibitor (e.g., a first allosteric inhibitor) and a different PI3K alpha selective allosteric inhibitor (e.g., a second allosteric inhibitor), where the PI3K alpha selective allosteric inhibitor binds to PI3K alpha allosteric pocket 1. In the disclosed methods, the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially.

[0172] In some embodiments of the disclosed methods, the first PI3K alpha selective inhibitor is an allosteric inhibitor of Formula I:

[0173] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0174] [ka] R2 is a group of the formula:

[0175] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0176] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor of Formula I:

[0177] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0178] [ka] R2 is a group of the formula:

[0179] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0180] In some embodiments of the disclosed methods, the first allosteric inhibitor of Formula I and the second allosteric inhibitor of Formula I are different.

[0181] In some embodiments of the disclosed methods, the first allosteric inhibitor is of the formula:

[0182] [ka] or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is of the formula:

[0184] [ka] or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is an allosteric inhibitor of the following formula:

[0186] [ka] or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments of the disclosed methods, the second allosteric inhibitor is of a formula selected from:

[0188] [ka] or a pharmaceutically acceptable salt thereof.

[0189] In the disclosed methods, a therapeutically effective amount of a first PI3K α-selective inhibitor is administered to a patient in need thereof, where the first PI3K α-selective inhibitor functions as an allosteric inhibitor. In some embodiments, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is an oral dose of 100-1200 mg BID (i.e., administered twice daily). In some embodiments, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is an oral dose of 9-75 mg / kg BID (e.g., 37.5 mg / kg).

[0190] In the disclosed methods, the first and second allosteric inhibitors can be administered sequentially. In some embodiments, the methods include administering the second allosteric inhibitor after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the second allosteric inhibitor is administered first after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the second allosteric inhibitor is not administered until after a disease or disorder has caused resistance to the first allosteric inhibitor. In some embodiments, the resistance is characterized by the occurrence of an M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). In some aspects, the patient may have a disease or disorder comprising an H1047R mutation and an M1043I / L mutation and / or a C901F mutation (optionally, the M1043I / L mutation, the C901F mutation are in cis on the same allele as the H1047R mutation).

[0191] ID(i). Use of allosteric inhibitors to treat diseases or disorders resistant to treatment with orthosteric inhibitors In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha that is resistant to treatment with a PI3K alpha-selective orthosteric inhibitor. The method may include administering to a patient having the disease or disorder a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 1 and, optionally, can form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0192] In some aspects of the disclosed methods, the patient has a disease or disorder that has developed resistance to treatment with an orthosteric inhibitor after the patient was previously treated with an orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder that exhibits de novo resistance to treatment with an orthosteric inhibitor, and the patient has not previously been treated with an orthosteric inhibitor.

[0193] 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 ceravelisib or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula I:

[0195] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0196] [ka] R2 is a group of the formula:

[0197] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0198] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0199] [ka] or a pharmaceutically acceptable salt thereof.

[0200] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0201] [ka] or a pharmaceutically acceptable salt thereof.

[0202] In some aspects of the disclosed methods, the allosteric inhibitor is of a formula selected from:

[0203] [ka] or a pharmaceutically acceptable salt thereof.

[0204] The disclosed methods can include administering a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor. In some embodiments, the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0205] ID(ii). Use of other allosteric inhibitors to treat diseases or disorders resistant to orthosteric inhibitors In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha that is resistant to treatment with a PI3K alpha-selective orthosteric inhibitor. The method may include administering to a patient having the disease or disorder a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 2 and, optionally, may form one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0206] In some aspects of the disclosed methods, the patient develops a disease or disorder that is resistant to treatment with an orthosteric inhibitor after the patient was previously treated with an orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder that exhibits de novo resistance to treatment with an orthosteric inhibitor, and the patient has not been previously treated with an orthosteric inhibitor.

[0207] 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 ceravelisib or a pharmaceutically acceptable salt thereof.

[0208] In some aspects of the disclosed methods, the PI3K alpha selective allosteric inhibitor is an allosteric inhibitor disclosed in WO 2021 / 222556, WO 2022 / 265993, WO 2023 / 018636, WO 2023 / 039532, WO 2023 / 288242, WO 2023 / 081757, or WO 2023 / 081759, the contents of which are incorporated by reference in their entireties herein with respect to the PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed therein.

[0209] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula IV:

[0210] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E)C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R 1 -L 1 -R 1A and R 2 -L 2 -R 2A and R E each independently represents H or -L E -R EA and R Q -L Q -R QA and R X -L X -R XA and R Y -L Y -R YA and R Z -L Z -R ZA or 2 R's E together with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZC is replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Z each of which is independently a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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-; R 1A is r 1 R 1C R replaced by A or R B and R 2A is r 2 R 2C R replaced by A or R B and R EA is r3 R EC R replaced by A or R B and R QA is r 4 R QC R replaced by A or R B and R XA is r 5 R XC R replaced by A or R B and R YA is r 6 R YC R replaced by A or R B and R ZA is r 7 R ZC R replaced by A or R B and R L is r 8 R LC R replaced by A or R B and R A each independently represents 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, R B Each of the following is independently 1~6an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZC each independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3optionally substituted at one or more positions with a substituent selected from 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; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0211] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula XXVIII:

[0212] [ka] or a pharmaceutically acceptable salt thereof.

[0213] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0214] [ka] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the allosteric inhibitor is R 1 but

[0216] [ka] It is of the formula:

[0217] In some embodiments, the allosteric inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0218] In some embodiments, the allosteric inhibitor is R 1C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0219] In some embodiments, the allosteric inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A or of the formula -C(H)(CH3)OH.

[0220] In some embodiments, the allosteric inhibitor is R2A but C in one or more positions 1~3 and those of the formula that are phenyl optionally substituted with aliphatic (eg, methyl), haloalkyl (eg, trifluoromethyl or difluoromethyl), or halogen.

[0221] In some embodiments, the allosteric inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0222] In some embodiments, the allosteric inhibitor is R 2C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0223] In some embodiments, the second PI3K alpha selective inhibitor is R YA is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is 6 R YC is of the formula:

[0224] In some embodiments, the allosteric inhibitor is R YA but

[0225] [ka] It is of the formula:

[0226] In some embodiments, the second PI3K alpha selective inhibitor is R YCeach independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0227] In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from the following:

[0228] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor has a formula selected from:

[0229] [ka] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is disclosed in WO 2022 / 265993 and has a formula selected from the following:

[0231] [ka] or a pharmaceutically acceptable salt thereof.

[0232] The disclosed methods can include administering a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor. In some embodiments, the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0233] ID(iii) Use of an allosteric inhibitor to treat a disease or disorder resistant to another allosteric inhibitor In some aspects, disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K alpha that is resistant to treatment with a first PI3K alpha-selective allosteric inhibitor, where the first PI3K alpha-selective allosteric inhibitor can bind to PI3K alpha 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. The method can include administering to a patient having the disease or disorder a therapeutically effective amount of a second, different PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 1 and, optionally, can form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0234] In some aspects of the disclosed methods, the patient has a disease or disorder that has developed resistance to treatment with the first allosteric inhibitor after the patient was previously treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder that exhibits de novo resistance to treatment with the first allosteric inhibitor, and the patient has not previously been treated with the first allosteric inhibitor.

[0235] In some embodiments of the disclosed methods, the patient is administered a first allosteric inhibitor of formula I:

[0236] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0237] [ka] R2 is a group of the formula:

[0238] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0239] In some aspects of the disclosed methods, the disease or disorder is treated with an allosteric inhibitor of the following formula:

[0240] [ka] or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments of the disclosed methods, a patient resistant to treatment with a first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor of Formula I:

[0242] [ka] or a pharmaceutically acceptable salt thereof, wherein R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0243] [ka] R2 is a group of the formula:

[0244] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0245] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient is of the formula:

[0246] [ka] or a pharmaceutically acceptable salt thereof.

[0247] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient is of a formula selected from:

[0248] [ka] or a pharmaceutically acceptable salt thereof.

[0249] The disclosed methods can include administering a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with a different PI3K alpha-selective allosteric inhibitor. In some embodiments, the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0250] ID(iv) Use of an allosteric inhibitor to treat a disease or disorder in which resistance to another allosteric inhibitor has been acquired In some aspects, disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K alpha that is resistant to treatment with a first PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 1 and may optionally interact with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The method may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a second, different PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha allosteric pocket 2 and may optionally interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0251] In some aspects of the disclosed methods, the patient has a disease or disorder that has developed resistance to treatment with the first allosteric inhibitor after the patient was previously treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder that exhibits de novo resistance to treatment with the first allosteric inhibitor, and the patient has not previously been treated with the first allosteric inhibitor.

[0252] In some embodiments of the disclosed methods, the patient is administered a first allosteric inhibitor of formula I:

[0253] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0254] [ka] R2 is a group of the formula:

[0255] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0256] In some aspects of the disclosed methods, the disease or disorder is treated with an allosteric inhibitor of the following formula:

[0257] [ka] or a pharmaceutically acceptable salt thereof.

[0258] In some aspects of the disclosed methods, a patient resistant to treatment with a first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor, such as those disclosed in WO 2021 / 222556, WO 2022 / 265993, WO 2023 / 018636, WO 2023 / 039532, WO 2023 / 288242, WO 2023 / 081757, or WO 2023 / 081759, the contents of which are incorporated by reference herein in their entireties with respect to the PI3K alpha inhibitor compounds and methods of making and using the PI3K alpha inhibitor compounds disclosed therein. In some aspects of the disclosed methods, the second allosteric inhibitor is of Formula IV:

[0259] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R 1 -L 1 -R 1A and R 2 -L 2 -R 2A and R E each independently represents H or -L E -R EA and R Q -L Q -R QA and R X -L X -R XA and R Y -L Y -R YA and R Z -L Z -R ZA or 2 R's E together with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1 together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZC is replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Z each of which is independently a covalent bond or C 1~4A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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-; R 1A is r 1 R 1C R replaced by A or R B and R 2A is r 2 R 2C R replaced by A or R B and R EA is r 3 R EC R replaced by A or R B and R QA is r 4 R QC R replaced by A or R B and R XA is r 5 R XC R replaced by A or R B and R YA is r 6 R YC R replaced by A or R B and R ZA is r 7 R ZC R replaced by Aor R B and R L is r 8 R LC R replaced by A or R B and R A each independently represents 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, R B Each of the following is independently 1~6 an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZCeach independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with a substituent selected from 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; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r 2 , r 3 , r4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0260] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula XXVIII:

[0261] [ka] or a pharmaceutically acceptable salt thereof.

[0262] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0263] [ka] or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the allosteric inhibitor is R 1 but

[0265] [ka] It is of the formula:

[0266] In some embodiments, the allosteric inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0267] In some embodiments, the allosteric inhibitor is R 1C each independently represents a C optionally substituted with halogen or 1 to 3 halogens1~3 It is of the formula: aliphatic.

[0268] In some embodiments, the allosteric inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A or of the formula -C(H)(CH3)OH.

[0269] In some embodiments, the allosteric inhibitor is R 2A but C in one or more positions 1~3 and those of the formula that are phenyl optionally substituted with aliphatic (eg, methyl), haloalkyl (eg, trifluoromethyl or difluoromethyl), or halogen.

[0270] In some embodiments, the allosteric inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0271] In some embodiments, the allosteric inhibitor is R 2C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0272] In some embodiments, the second PI3K alpha selective inhibitor is R YAis a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is 6 R YC is of the formula:

[0273] In some embodiments, the allosteric inhibitor is R YA but,

[0274] [ka] It is of the formula:

[0275] In some embodiments, the second PI3K alpha selective inhibitor is R YC each independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0276] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from:

[0277] [ka] or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is disclosed in WO 2022 / 265993 and has a formula selected from:

[0279] [ka] or a pharmaceutically acceptable salt thereof.

[0280] The disclosed methods can include administering a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with another PI3K alpha-selective allosteric inhibitor. In some embodiments, the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0281] IEM1043I / L+H1047R Orthosteric inhibitors for treating cancer In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha 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), optionally after the patient has been previously treated with a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor. In the disclosed methods, the PI3K alpha-selective allosteric inhibitor can bind to PI3K alpha 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. In the disclosed methods, the patient may have a cancer that exhibits acquired resistance to treatment with a PI3K alpha-selective allosteric inhibitor, or the patient may have a cancer that exhibits de novo resistance to treatment with a PI3K alpha-selective allosteric inhibitor, and in the disclosed methods, the patient may be administered a therapeutically effective amount of a PI3K alpha-selective orthosteric inhibitor.

[0282] In some embodiments of the disclosed methods, the patient is administered a PI3K alpha selective allosteric inhibitor of Formula I:

[0283] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0284] [ka] R2 is a group of the formula:

[0285] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R11 , -NR 11 R 11 , -NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0286] In some embodiments of the disclosed methods, the patient is administered a therapeutically effective amount of a PI3K alpha selective allosteric inhibitor of the following formula:

[0287] [ka] or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments of the disclosed methods, the therapeutically effective amount of the PI3K α-selective allosteric inhibitor administered to the patient was an oral dose of 100 to 1200 mg administered twice daily. In some embodiments of the disclosed methods, the therapeutically effective amount of the first PI3K α-selective inhibitor administered to the patient was an oral dose of 9 to 75 mg / kg administered twice daily (e.g., a 37.5 mg / kg oral dose administered twice daily). In the disclosed methods, the patient may have acquired resistance to treatment with a PI3K α-selective allosteric inhibitor administered at the indicated doses.

[0289] In the disclosed methods, a therapeutically effective amount of a PI3K alpha selective orthosteric inhibitor is administered to a patient in need thereof. In some embodiments, the therapeutically effective amount of the PI3K alpha selective orthosteric inhibitor administered to the patient is an oral dose of 300 mg QD (i.e., administered once daily) or less than about 300 mg QD, for example, less than about 250, 200, 150, 100, or 50 mg QD.

[0290] In some aspects, the disclosed methods include administering to a patient a therapeutically effective amount of a PI3K alpha selective orthosteric inhibitor, and the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, the administered PI3K alpha selective orthosteric inhibitor is selected from alpelisib, inavolisib, ceravelisib, or a pharmaceutically acceptable salt thereof.

[0291] IF(i).M1043I / L+H1047R allosteric inhibitors for treating cancer In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha 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 method comprises administering to the patient a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor that can bind to PI3K alpha allosteric pocket 2 and, optionally, form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0292] In some embodiments, the PI3K alpha selective allosteric inhibitor administered to the patient is of Formula IV:

[0293] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R 1 -L 1 -R 1A and R 2 -L 2 -R 2A and RE each independently represents H or -L E -R EA and R Q -L Q -R QA and R X -L X -R XA and R Y -L Y -R YA and R Z -L Z -R ZA or 2 R's E together with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1 together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZC is replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Zeach of which is independently a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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-; R 1A is r 1 R 1C R replaced by A or R B and R 2A is r 2 R 2C R replaced by A or R B and R EA is r 3 R EC R replaced by A or R B and R QA is r 4 R QC R replaced by A or R B and R XA is r 5 R XC R replaced by A or R B and R YA is r 6 R YC R replaced by A or R B and R ZA is r 7 RZC R replaced by A or R B and R L is r 8 R LC R replaced by A or R B and R A each independently represents 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, R B Each of the following is independently 1~6 an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , RQ1C , and R YZC each independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with a substituent selected from 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; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0294] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula XXVIII:

[0295] [ka] or a pharmaceutically acceptable salt thereof.

[0296] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0297] [ka] or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the allosteric inhibitor is R 1 but

[0299] [ka] It is of the formula:

[0300] In some embodiments, the allosteric inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0301] In some embodiments, the allosteric inhibitor is R 1Ceach independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0302] In some embodiments, the allosteric inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A or of the formula -C(H)(CH3)OH.

[0303] In some embodiments, the allosteric inhibitor is R 2A but C in one or more positions 1~3 and those of the formula that are phenyl optionally substituted with aliphatic (eg, methyl), haloalkyl (eg, trifluoromethyl or difluoromethyl), or halogen.

[0304] In some embodiments, the allosteric inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0305] In some embodiments, the allosteric inhibitor is R 2C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0306] In some embodiments, the second PI3K alpha selective inhibitor is R YAis a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is 6 R YC is of the formula:

[0307] In some embodiments, the allosteric inhibitor is R YA but,

[0308] [ka] It is of the formula:

[0309] In some embodiments, the second PI3K alpha selective inhibitor is R YC each independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0310] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of a formula selected from:

[0311] [ka] or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is disclosed in WO 2022 / 265993 and has a formula selected from:

[0313] [ka] or a pharmaceutically acceptable salt thereof.

[0314] In some aspects of the disclosed methods, the patient has cancer that has acquired 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) after the patient was previously treated with a therapeutically effective amount of a first PI3K alpha selective allosteric inhibitor that can bind to PI3K alpha pocket 1 and 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 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 has not previously been treated with a therapeutically effective amount of a first PI3K alpha selective allosteric inhibitor that can bind to PI3K alpha pocket 1 and form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0315] In some embodiments of the disclosed methods, the patient is administered a therapeutically effective amount of a first PI3K alpha selective allosteric inhibitor of Formula I:

[0316] [ka] or a pharmaceutically acceptable salt thereof, the patient has a cancer that has acquired a M1043I / L mutation (optionally in cis with the H1047R mutation), wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0317] [ka] R2 is a group of the formula:

[0318] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0319] In some embodiments of the disclosed methods, the therapeutically effective amount of the PI3K α-selective allosteric inhibitor of Formula I administered to the patient was an oral dose of 100-1200 mg administered twice daily. In some embodiments of the disclosed methods, the therapeutically effective amount of the PI3K α-selective allosteric inhibitor of Formula I administered to the patient was an oral dose of 9-75 mg / kg administered twice daily (e.g., an oral dose of 37.5 mg / kg administered twice daily). In the disclosed methods, the patient may have a cancer that has acquired resistance after the patient was administered the PI3K α-selective allosteric inhibitor at the indicated dose.

[0320] In some embodiments of the disclosed methods, the patient is administered a therapeutically effective amount of a PI3K alpha selective inhibitor of the following formula:

[0321] [ka] or a pharmaceutically acceptable salt thereof.

[0322] 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 may further have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, a 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-).

[0323] In some embodiments, the disclosed methods include administering to the patient a therapeutically effective amount of a PI3K alpha selective allosteric inhibitor, and the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0324] IF(ii).M1043I / L+H1047R and other allosteric inhibitors for treating cancer In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K alpha 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 method comprises administering to the patient a therapeutically effective amount of a PI3K alpha-selective allosteric inhibitor that binds to PI3K alpha pocket 1 and can interact with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0325] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of Formula I:

[0326] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0327] [ka] R2 is a group of the formula:

[0328] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0329] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of the following formula:

[0330] [ka] or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor of Formula I administered to the patient is of the following formula:

[0332] [ka] or a pharmaceutically acceptable salt thereof.

[0333] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor of Formula I administered to the patient is selected from:

[0334] [ka] or a pharmaceutically acceptable salt thereof.

[0335] In the disclosed methods, the patient may have a cancer comprising the mutation M1043I / L (e.g., optionally in cis with the H1047R mutation) and / or the C901 mutation (e.g., C901F, optionally in cis with the H1047R mutation), and the patient may further have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, a 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-).

[0336] In some embodiments, the disclosed methods include administering to the patient a therapeutically effective amount of a PI3K alpha selective allosteric inhibitor, and the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0337] Diagnosis and treatment of patients with IGM1043X+H1047R or C901X+H1047R cancer In some aspects, the methods relate to treating a disease or disorder associated with modulation of PI3K alpha in a patient in need of such treatment, e.g., a patient with a cancer comprising a M1043 mutation (e.g., M1043I / L, optionally in cis with a H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with a H1047R mutation). The methods can include determining that the patient has a cancer comprising a M1043 mutation (e.g., M1043I / L, optionally in cis with a H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with a H1047R mutation), for example, by ordering or performing a genomic analysis that identifies the mutations (e.g., M1043I / L and / or C901F and / or H1047R, optionally in cis) in the patient's cancer. Suitable genomic analysis may include one or more steps, such as ordering a genomic analysis to identify the M1043, C901, and / or H1047R mutations (optionally in cis), performing PCR amplification of alleles containing the M1043, C901, and / or H1047R mutations (optionally in cis), sequencing the alleles containing the M1043, C901, and / or H1047R mutations (optionally in cis). probing for alleles comprising the (optionally in cis) M1043, C901, and / or H1047R mutations, identifying or detecting alleles comprising the (optionally in cis) M1043, C901, and / or H1047R mutations, and determining that the patient has a cancer comprising the (optionally in cis) M1043, C901, and / or H1047R mutations. After determining that the patient has a cancer comprising an 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), the method may further comprise administering to the patient a treatment, which may include administering to the patient one or more PI3K alpha selective inhibitors.

[0338] In some aspects of the disclosed methods, when 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 method can comprise administering to the patient a therapeutically effective amount of a PI3K alpha selective inhibitor. In some aspects, the PI3K alpha selective inhibitor is of the following formula:

[0339] [ka] or a pharmaceutically acceptable salt thereof.

[0340] 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 method can comprise administering to the patient a therapeutically effective amount of a PI3K alpha-selective orthosteric inhibitor. In some aspects, the PI3K alpha-selective orthosteric inhibitor is selected from alpelisib, inavolisib, selavelisib, or a pharmaceutically acceptable salt thereof.

[0341] In some aspects of the disclosed methods, where the patient has a cancer comprising an M1043 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 method can include administering to the patient a therapeutically effective amount of a PI3K alpha selective inhibitor, wherein the PI3K alpha selective inhibitor can bind to PI3K alpha allosteric pocket 2 and interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. In some aspects, the PI3K alpha selective allosteric inhibitor is a compound disclosed in WO 2021 / 222556 (e.g., any of compounds I-1 to I-2704 in Table 1, pages 162-855). In some embodiments, the PI3K alpha selective allosteric inhibitor is a compound disclosed in Tables AD, pages 175-259 of WO 2022 / 265993.

[0342] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of formula IV:

[0343] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R1 -L 1 -R 1A and R 2 -L 2 -R 2A and R E each independently represents H or -L E -R EA and R Q -L Q -R QA and R X -L X -R XA and R Y -L Y -R YA and R Z -L Z -R ZA or 2 R's E together with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1 together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZCis replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Z each of which is independently a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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-; R 1A is r 1 R 1C R replaced by A or R B and R 2A is r 2 R 2C R replaced by A or R B and R EA is r 3 R EC R replaced by A or R B and R QA is r 4 R QC R replaced by A or R B and R XA is r 5 R XC R replaced by A or R B and R YA is r6 R YC R replaced by A or R B and R ZA is r 7 R ZC R replaced by A or R B and R L is r 8 R LC R replaced by A or R B and R A each independently represents 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, R B Each of the following is independently 1~6 an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C, R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZC each independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with a substituent selected from 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; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0344] In some embodiments of the disclosed methods, the allosteric inhibitor is of formula XXVIII:

[0345] [ka] or a pharmaceutically acceptable salt thereof.

[0346] In some aspects of the disclosed methods, the allosteric inhibitor is of the formula:

[0347] [ka] or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the allosteric inhibitor is R 1 but

[0349] [ka] It is of the formula:

[0350] In some embodiments, the allosteric inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0351] In some embodiments, the allosteric inhibitor is R 1C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0352] In some embodiments, the allosteric inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A or of the formula -C(H)(CH3)OH.

[0353] In some embodiments, the allosteric inhibitor is R 2A but C in one or more positions 1~3 and those of the formula that are phenyl optionally substituted with aliphatic (eg, methyl), haloalkyl (eg, trifluoromethyl or difluoromethyl), or halogen.

[0354] In some embodiments, the allosteric inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 aliphatic, wherein each C 1~6 The aliphatic is optionally substituted with one or more halogen atoms.

[0355] In some embodiments, the allosteric inhibitor is R 2C each independently represents a C optionally substituted with halogen or 1 to 3 halogens 1~3 It is of the formula: aliphatic.

[0356] In some embodiments, the second PI3K alpha selective inhibitor is R YA is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is 6 R YC is of the formula:

[0357] In some embodiments, the allosteric inhibitor is R YA but,

[0358] [ka] It is of the formula:

[0359] In some embodiments, the second PI3K alpha selective inhibitor is R YC each independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0360] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of a formula selected from:

[0361] [ka] or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments of the disclosed methods, the second PI3K alpha selective inhibitor is disclosed in WO 2022 / 265993 and has a formula selected from:

[0363] [ka] or a pharmaceutically acceptable salt thereof.

[0364] 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 method may comprise administering to the patient a therapeutically effective amount of a PI3K alpha selective inhibitor that can bind to PI3K alpha allosteric pocket 1 and form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0365] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor administered to the patient is of Formula I:

[0366] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0367] [ka] R2 is a group of the formula:

[0368] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0369] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor of Formula I is of the following formula:

[0370] [ka] or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments of the disclosed methods, the PI3K alpha selective allosteric inhibitor of Formula I administered to the patient is selected from:

[0372] [ka] or a pharmaceutically acceptable salt thereof.

[0373] 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 may further have a cancer comprising one or more mutations selected from E542K, E545K, E453Q / K, and E726K. In some aspects, a 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-).

[0374] Compounds for Use in Therapy In some aspects, the disclosed subject matter relates to a first phosphatidylinositol 3-kinase alpha (PI3K alpha)-specific inhibitor for use in the treatment of a disease or disorder associated with modulation of PI3K alpha, in simultaneous, separate, or sequential combination with a second PI3K alpha-specific inhibitor. The disclosed compounds for use in treatment can be further illustrated by the following embodiments.

[0375] Embodiment 1. A PI3K alpha specific inhibitor compound of the following formula:

[0376] [ka] or a pharmaceutically acceptable salt thereof, wherein: R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0377] [ka] R2 is a group of the formula:

[0378] [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl; A PI3K alpha-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3K alpha), in simultaneous, separate or sequential combination with a second PI3K alpha-specific inhibitor that is a PI3K alpha-specific orthosteric inhibitor.

[0379] Embodiment 2. The compound for use according to embodiment 1, wherein the second PI3K alpha-specific inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.

[0380] Embodiment 3. The compound for use according to embodiment 1, wherein the second PI3K alpha-specific inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.

[0381] Embodiment 4. The compound for use according to any of embodiments 1-3, wherein the dose of the second PI3K alpha-specific inhibitor is an oral dose of less than about 300 mg administered daily.

[0382] Embodiment 5. The compound for use according to any of embodiments 1 to 4, wherein the first PI3K alpha specific inhibitor and the second PI3K alpha specific inhibitor are administered simultaneously.

[0383] Embodiment 6 The compound for use according to embodiment 5, wherein the dose of the second PI3K alpha-specific inhibitor is an oral dose of less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg administered daily.

[0384] Embodiment 7. A PI3K alpha specific inhibitor compound of Formula I:

[0385] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in embodiment 1, for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα), in simultaneous, separate or sequential combination with a second PI3Kα-specific inhibitor that binds to PI3Kα allosteric pocket 2.

[0386] Embodiment 8. The compound for use according to embodiment 7, wherein the second PI3K alpha specific inhibitor forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0387] Embodiment 9. The second PI3K alpha specific inhibitor is of the formula:

[0388] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E )2-, -C(R E )2C(R E )2-, -C(S)-, -S(O)2-, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )- or -C(R E )2C(O)-, Q is CH, C(R Q ), or N, X is CH, C(R X ), or N, Y is CH, C(R Y ), or N, Z is CH, C(R Z ), or N, R 1 But -L 1 -R 1A and R 2 But -L 2 -R 2A and Each R E are independently H or -L E -R EA and R Q -L Q -R QA and R X But -L X -R XA and R Y But -L Y -R YA and R Z But -L Z -R ZA or 2 R's Etogether with their intervening atoms form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each ring containing n R EEC is replaced by R Q and R 1 together with their intervening atoms 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, each ring containing p R Q1C is replaced by R Y and R Z together with their intervening atoms form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is YZC is replaced by L 1 , L 2 , L E , L Q , L X , L Y , and L Z each of which is independently a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3~6 Cycloalkylene, C 3~6 replaced by 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 But, r 1 R 1C R replaced by A or R B and R 2A But, r 2 R 2C R replaced by A or R B and R EA But, r 3 R EC R replaced by A or R B and R QA But, r 4 R QC R replaced by A or R B and R XA But, r 5 R XC R replaced by A or R B and R YA But, r 6 R YC R replaced by A or R B and R ZA But, r 7 R ZC R replaced by A or R B and R L But, r 8 R LC R replaced by A or R B and R Aeach independently represents 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, R B Each of these independently represents C 1~6 an aliphatic chain, phenyl, naphthyl, carboxyl, adamantyl, a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1C , R 2C , R EC , R QC , R XC , R YC , R ZC , R LC , R EEC , R Q1C , and R YZCeach independently is 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 C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen, or C 1~6 Aliphatic (where C 1~6 The aliphatic group is C 1~3 Alkyl, C 1~3 optionally substituted at one or more positions with substituents selected from haloalkyl, and halogen; phenyl; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n, p, q, r 1 , r 2 , r 3 , r4 , r 5 , r 6 , r 7 , and r 8 is independently 0, 1, 2, 3, 4, or 5.

[0389] Embodiment 10. The second PI3K alpha selective inhibitor is of the formula:

[0390] [ka] or a pharmaceutically acceptable salt thereof.

[0391] Embodiment 11. The second PI3K alpha selective inhibitor is of the formula:

[0392] [ka] or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 12. The second PI3K alpha selective inhibitor is: R 1 but

[0394] [ka] 12. The compound for use according to any of embodiments 7 to 11, wherein the compound is of the formula:

[0395] Embodiment 13. The second PI3K alpha selective inhibitor is R 1C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 is of the formula: 1~6 The compound for use according to any of embodiments 7 to 12, wherein the aliphatic is optionally substituted with one or more halogen atoms.

[0396] Embodiment 14. The second PI3K alpha selective inhibitor is R 2 But -N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O)2CH2-R 2A , -CH2S(O)2-R 2A 14. The compound for use according to any of embodiments 7 to 13, wherein the compound is of the formula:

[0397] Embodiment 15. The second PI3K alpha selective inhibitor is R 2A but C in one or more positions 1~3 The compound for use according to any of embodiments 7-14, wherein the compound is of the formula: phenyl optionally substituted with aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.

[0398] Embodiment 16. The second PI3K alpha selective inhibitor is R 2C each independently represents a halogen, —CN, —O—(C 1~6 Aliphatic), or C 1~6 is of the formula: 1~6 The compound for use according to any of embodiments 7-15, wherein the aliphatic is optionally substituted with one or more halogen atoms.

[0399] Embodiment 17. The second PI3K alpha selective inhibitor is R YA is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is of the formula r 6 R YC 17. The compound for use according to any of embodiments 7 to 16, substituted by:

[0400] Embodiment 18. The second PI3K alpha selective inhibitor is R YA but,

[0401] [ka] 18. The compound for use according to any of embodiments 7 to 17, wherein the compound is of the formula:

[0402] Embodiment 19. The second PI3K alpha selective inhibitor is R YC each independently represents oxo, halogen, —CN, —OH, —O—(C 1~3 Aliphatic), or C 1~3 Aliphatic, each C 1~3 The compound for use according to any of embodiments 7-18, wherein aliphatic is of the formula optionally substituted with one or more halogen atoms.

[0403] Embodiment 20. The second PI3K alpha selective inhibitor has a formula selected from:

[0404] [ka] or a pharmaceutically acceptable salt thereof, or the second PI3K alpha selective inhibitor has a formula selected from:

[0405] [ka] or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 21. A PI3K alpha specific inhibitor compound of Formula I:

[0407] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1, and the PI3K alpha-specific inhibitor compound or a pharmaceutically acceptable salt thereof is for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3K alpha), in simultaneous, separate, or sequential combination with a second PI3K alpha-specific inhibitor of formula I or a pharmaceutically acceptable salt thereof, wherein the first PI3K alpha-specific inhibitor and the second PI3K alpha-specific inhibitor are different compounds.

[0408] Embodiment 22. The compound for use according to embodiment 21, wherein the second PI3K alpha specific inhibitor is not of the formula

[0409] [ka]

[0410] Embodiment 23. The second PI3K alpha specific inhibitor is of the formula:

[0411] [ka] 23. The compound for use according to embodiment 21 or 22, which is:

[0412] Embodiment 24. The second PI3K alpha specific inhibitor is of a formula selected from:

[0413] [ka] or a pharmaceutically acceptable salt thereof.

[0414] Embodiment 25. The compound for use according to any of embodiments 1 to 24, wherein the therapeutically effective amount of the first PI3K alpha-specific inhibitor is effective to reduce PI3K alpha activity in the patient without inducing hyperglycemia in the patient.

[0415] Embodiment 26. The compound for use according to any of embodiments 1 to 25, wherein the therapeutically effective amount of the second PI3K alpha specific inhibitor is effective to reduce PI3K alpha activity in the patient without inducing hyperglycemia in the patient.

[0416] Embodiment 27. A PI3K alpha specific inhibitor compound of Formula I:

[0417] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in embodiment 1, for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient who is resistant to treatment with alpelisib or inavolisib.

[0418] Embodiment 28. A phosphatidylinositol 3-kinase alpha (PI3K alpha) specific inhibitor that binds to the allosteric pocket of PI3K alpha and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018, for use in treating a disease or disorder associated with the modulation of PI3K alpha in a patient who is resistant to treatment with alpelisib or inavolisib.

[0419] Embodiment 29. The inhibitor is a compound of the following formula:

[0420] [ka] or a pharmaceutically acceptable salt thereof, wherein R1, R2, E, Q, X, Y, Z are as defined in embodiment 9; or a PI3K alpha specific inhibitor for use according to embodiment 28, wherein the inhibitor is a compound of the formula selected from:

[0421] [ka] 29. The PI3K alpha specific inhibitor for use according to embodiment 28, which is:

[0422] Embodiment 30. A phosphatidylinositol 3-kinase alpha (PI3Kα) specific inhibitor that is a PI3Kα specific orthosteric inhibitor for use in the treatment of a disease or disorder associated with the regulation of PI3Kα, wherein the patient is receiving a compound of Formula I,

[0423] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in embodiment 96, and the patient has cancer that has acquired the M1043I / L mutation in cis with the H1047R mutation, and / or the C901F mutation in cis with the H1047R mutation.

[0424] Embodiment 31. A PI3K alpha-specific inhibitor that binds to PI3K alpha 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 treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3K alpha) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with the H1047R mutation, and / or a C901F mutation in cis with the H1047R mutation.

[0425] Embodiment 32. A PI3K alpha specific inhibitor compound of Formula I:

[0426] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in embodiment 1, for use in treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) 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, or a pharmaceutically acceptable salt thereof.

[0427] Embodiment 33. A PI3K alpha specific inhibitor compound of Formula I:

[0428] [ka] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in embodiment 1, for use in treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, comprising: assaying a blood sample from the patient; determining whether the patient has a cancer comprising a H1047R mutation and M1043I / L in cis, and / or a C901F mutation in cis with the H1047R mutation; and if a H1047R mutation and M1043I / L in cis, and / or a C901F mutation in cis with the H1047R mutation are present, administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0429] Embodiment 34. A phosphatidylinositol 3-kinase alpha (PI3K alpha)-specific inhibitor selected from alpelisib and inavolisib for use in treating a disease or disorder associated with modulation of PI3K alpha in a patient in need of treatment, comprising assaying a sample from the patient and determining whether the patient has cancer comprising M1043I / L in cis with the H1047R mutation, and / or C901F in cis with the H1047R mutation, and if M1043I / L in cis with the H1047R mutation and / or C901F in cis with the H1047R mutation are present, administering to the patient a therapeutically effective amount of alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof.

[0430] Embodiment 35. A phosphatidylinositol 3-kinase alpha (PI3K alpha)-specific inhibitor that binds to PI3K alpha 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 treating a disease or disorder associated with modulation of PI3K alpha in a patient in need of treatment, comprising assaying a blood sample from the patient and determining whether the patient has a cancer comprising M1043I / L in cis with the H1047R mutation, and / or C901F in cis with the H1047R mutation, and if M1043I / L in cis with the H1047R mutation and / or C901F in cis with the H1047R mutation are present, administering to the patient a therapeutically effective amount of a PI3K alpha-specific inhibitor, or a pharmaceutically acceptable salt thereof.

[0431] Embodiment 36. The compound of Formula I is of the formula:

[0432] [ka] or a pharmaceutically acceptable salt thereof.

[0433] Embodiment 37. The compound for use according to any one of embodiments 1 to 27, 30, 32, and 33, wherein the therapeutically effective amount of the compound of formula I administered to the patient is an oral dose of 100 to 1200 mg administered twice daily.

[0434] Embodiment 38. The compound for use according to any one of embodiments 1 to 27, 30, 32, and 33, wherein the therapeutically effective amount of the first PI3K alpha-specific inhibitor administered to the patient is an oral dose of 9 to 75 mg / kg administered twice daily.

[0435] Embodiment 39. A compound for use according to any one of embodiments 1 to 38, wherein the disease or disorder is cancer.

[0436] Embodiment 40. The compound for use according to any of embodiments 1 to 39, wherein the disease or disorder is breast cancer.

[0437] Embodiment 41. A compound for use according to any of embodiments 1 to 40, wherein the disease or disorder is PIK3CA-mutated, advanced, or metastatic breast cancer.

[0438] Embodiment 42. A compound for use according to any of embodiments 1 to 41, wherein the disease or disorder is PIK3CACA H1047R mutant advanced or metastatic breast cancer.

[0439] Embodiment 43. The 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-).

[0440] Embodiment 44. A compound for use according to any of embodiments 1 to 43, wherein the patient is a postmenopausal woman.

[0441] Embodiment 45. A compound for use according to any of embodiments 1 to 44, wherein the patient has type II diabetes.

[0442] Embodiment 46. The compound for use according to any of embodiments 1 to 45, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0443] Embodiment 47. A compound for use according to embodiment 46, wherein the SERD is selected from imrunestrant, fulvestrant, diledestrant, amsenestrant, lindestrant, elacestrant, kamizestrant, LSZ102, Zn-c5, and D-0502.

[0444] Embodiment 48. The compound for use according to embodiment 46 or 47, wherein the therapeutically effective amount of SERD is a 500 mg dose administered on days 1, 15, and 29.

[0445] Embodiment 49. The compound for use according to any one of embodiments 1 to 48, wherein the second PI3K alpha-specific inhibitor is administered after the disease or disorder has developed resistance to the first PI3K alpha-specific inhibitor.

[0446] Exemplary Compounds The following are exemplary compounds that can be used in some embodiments of the disclosed subject matter.

[0447] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0448] [ka] wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in the Summary of the Invention for formula (I).

[0449] In a further embodiment, the compound of formula (I) where R8 is H has the formula (II):

[0450] [ka] wherein R, R1, R2, R3, R4, R5, R6, and R7 are as defined in the Summary of the Invention for formula (I).

[0451] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0452] [ka] R2 is a group of the formula:

[0453] [ka] R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 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, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole. wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy, respectively; and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0454] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0455] [ka] R2 is a group of the formula:

[0456] [ka] R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0457] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is —H or C1-C3 alkyl; R1 is a group of the formula:

[0458] [ka] R2 is a group of the formula:

[0459] [ka] R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl; each of R4, R5, and R6 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is, respectively, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Each R 11 is independently —H or C1-C3 alkyl.

[0460] In the compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0461] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or 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 -CN, -OH, oxetanyl, or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN.

[0462] In the compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R2 is a group of the formula:

[0463] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0464] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula

[0465] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0466] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula

[0467] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0468] In still further compounds of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , -CONR 11 R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, heterocycle, or heteroaryl is, respectively, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0469] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -CN or -CONR 11 R 11 C1-C6 alkyl optionally substituted with (preferably, each R 11 is C1-C3 alkyl), C3 cycloalkyl optionally substituted with C1-C3 alkyl or —CN, an optionally substituted heterocycle selected from pyrrolidine, optionally substituted phenyl (preferably optionally substituted phenyl substituted by —CN), or an optionally substituted heteroaryl selected from pyrazole or oxazole.

[0470] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , -CONR 11 R 11 , C1-C6 alkyl optionally substituted with -CN, C3 cycloalkyl optionally substituted with C1-C3 alkyl or -CN, pyrrolidine, or optionally substituted heteroaryl selected from pyrazole or oxazole.

[0471] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R 10 is, independently,

[0472] [ka] is.

[0473] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, each R 10 is, independently,

[0474] [ka] is.

[0475] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula

[0476] [ka]

[0477] [ka]

[0478] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula

[0479] [ka]

[0480] In still further compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, oxetane, isoxazole, or pyridine (preferably 3-pyridine). In still further compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 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 still further compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane, or isoxazole. In still further compounds of formula (I) or (II), or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In still further compounds 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 most preferably, R3 is -H or methyl.

[0481] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 4 is H or halogen; preferably, R 4 is H.

[0482] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; preferably, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R5 is -H, halogen, methyl, or trifluoromethyl.

[0483] In still further compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is -H or halogen.

[0484] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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:

[0485] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0486] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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

[0487] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0488] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, methyl, or trifluoromethyl (preferably, R3 is -H or methyl), and R2 is a group of the formula

[0489] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0490] In the compounds 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:

[0491] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0492] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H) and R2 is a group of the formula

[0493] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0494] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H) and R2 is a group of the formula

[0495] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0496] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and R2 is a group of the formula:

[0497] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0498] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl and R2 is a group of the formula:

[0499] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0500] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, methyl, or trifluoromethyl and R2 is a group of the formula:

[0501] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0502] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is -H or halogen and R2 is a group of the formula:

[0503] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0504] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is -H or halogen and R2 is a group of the formula:

[0505] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0506] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is -H or halogen and R2 is a group of the formula:

[0507] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0508] In still further compounds 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 R4 is H, most preferably R3 is -H or methyl and R4 is H.

[0509] In still further compounds 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 R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably, R3 is -H or methyl and R5 is -H, halogen, methyl, or trifluoromethyl.

[0510] In still further compounds 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 R6 is -H or halogen; more preferably, R3 is -H or methyl and R6 is -H or halogen.

[0511] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is H), and R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, preferably, R5 is -H, halogen, methyl, or trifluoromethyl.

[0512] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H) and R6 is -H or halogen.

[0513] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl and R6 is -H or halogen, preferably R5 is -H, halogen, methyl or trifluoromethyl and R6 is H.

[0514] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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:

[0515] [ka] Preferably, R3 is -H or methyl, R4 is -H, and R2 is a group of the formula

[0516] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0517] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R5 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and R2 is a group of the formula:

[0518] [ka] More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula

[0519] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0520] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably, R3 is -H, -CN, or C1-C3 alkyl), R6 is -H or halogen, and R2 is a group of the formula:

[0521] [ka] More preferably, R3 is -H or methyl, R6 is -H and R2 is a group of the formula

[0522] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0523] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H), R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula:

[0524] [ka] More preferably, R5 is -H, halogen, methyl, or trifluoromethyl and R2 is a group of the formula

[0525] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0526] In the compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably, R4 is -H), R6 is -H or halogen, and R2 is a group of the formula:

[0527] [ka] More preferably, R4 and R6 are each -H and R2 is a group of the formula

[0528] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0529] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, and R2 is a group of the formula:

[0530] [ka] Preferably, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and R2 is a group of the formula

[0531] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0532] In still further compounds 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 R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R3 is -H or methyl, R4 is -H, and R5 is -H, halogen, methyl, or trifluoromethyl.

[0533] In still further compounds 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 R6 is -H or halogen, more preferably, R3 is -H or methyl, and R4 and R6 are each H.

[0534] In still further compounds 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), R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R6 is -H or halogen; more preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is H.

[0535] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably, R4 is -H), and R6 is -H or halogen, more preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each H.

[0536] In still further compounds 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), R5 is -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, and R2 is a group of the formula:

[0537] [ka] More preferably, R3 is -H or methyl, R4 is -H, R5 is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula

[0538] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0539] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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), R6 is -H or halogen, and R2 is a group of the formula:

[0540] [ka] More preferably, R3 is -H or methyl, R4 and R6 are each -H, and R2 is a group of the formula

[0541] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0542] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is -H, -CN, or C1-C3 alkyl), R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R6 is -H or halogen, and R2 is a group of the formula:

[0543] [ka] More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and R2 is a group of the formula

[0544] [ka] Preferably, each R 10are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0545] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably, R4 is -H), R6 is -H or halogen, and R2 is a group of the formula:

[0546] [ka] More preferably, R5 is -H, halogen, methyl, or trifluoromethyl, R4 is -H, R6 is -H or halogen, and R2 is a group of the formula

[0547] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0548] In still further compounds 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), R6 is -H or halogen, and R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R3 is -H or methyl, R4 and R6 are each -H, and R5 is -H, halogen, methyl, or trifluoromethyl.

[0549] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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), R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is a basis of the formula:

[0550] [ka] More preferably, R3 is -H or methyl, R4 is -H, R6 is -H or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and R2 is a group of the formula

[0551] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0552] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R is —H.

[0553] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, more preferably R7 is -CN, methyl, or trifluoromethyl.

[0554] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R8 is -H.

[0555] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl and R is -H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl) and R is -H.

[0556] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R and R are each —H.

[0557] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is —CN, C1-C3 alkyl or C1-C3 haloalkyl and R8 is H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl) and R8 is H.

[0558] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R8 and R are each -H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0559] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, R8 is -H, R is -H and R2 is a group of the formula

[0560] [ka]

[0561] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), R8 is -H, R is -H and R2 is a group of the formula

[0562] [ka] Preferably, each R 10are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0563] In still further compounds 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), R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R8 and R are each -H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H or methyl, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0564] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R4, R8 and R are each -H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, R8 and R are each -H.

[0565] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is -CN, methyl or trifluoromethyl, and R8 and R are each -H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R8 and R are each -H.

[0566] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt 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), R6 is -H or halogen, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R7 is -CN, methyl, or trifluoromethyl, R8 is -H, R is -H, and R2 is a group of the formula:

[0567] [ka] More preferably, R3 is -H or methyl, R4 is -H, R6 is -H or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, R8 is -H, R is -H, and R2 is a group of the formula

[0568] [ka] Preferably, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0569] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0570] [ka] 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.

[0571] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0572] [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-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.

[0573] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0574] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0575] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0576] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0577] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0578] [ka]

[0579] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0580] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0581] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0582] [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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.

[0583] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0584] [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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.

[0585] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0586] [ka] wherein each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 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.

[0587] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0588] [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-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.

[0589] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0590] [ka] 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.

[0591] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0592] [ka] In the formula, 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.

[0593] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0594] [ka] 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.

[0595] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0596] [ka] 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 are independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0597] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0598] [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl. Preferably, R9 is independently halogen or trifluoromethyl. More preferably, R9 is chloro or trifluoromethyl.

[0599] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0600] [ka] In the formula, R9 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Preferably, R9 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. More preferably, R9 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0601] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0602] [ka] In the formula, 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.

[0603] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0604] [ka]

[0605] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0606] [ka]

[0607] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R1 is a group of the formula:

[0608] [ka] wherein 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. Preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0609] In further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4 is -H; R6 is -H or halogen; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R1 is:

[0610] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. Preferably, R3 is -H or methyl, R4 is -H, R6 is -H or halogen, and R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0611] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula:

[0612] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; more preferably, R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0613] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula:

[0614] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0615] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0616] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; more preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0617] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4, R8, and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0618] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably, R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0619] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0620] [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably, R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0621] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4, R8, and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0622] [ka] In the formula, R9 is -H, halogen, or C1-C3 haloalkyl, and preferably, R3 is -H or methyl, R4, R6, R8, and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H or trifluoromethyl.

[0623] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4, R8, and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0624] [ka] In the formula, R9 is -H, halogen, or C1-C3 haloalkyl, preferably, R3 is -H or methyl, R4, R6, R8, and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H or halogen, more preferably, R9 is -H or fluoro.

[0625] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0626] [ka] In the formula, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0627] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4, R8, and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0628] [ka] In the formula, R9 is -H, halogen, or C1-C3 haloalkyl, and preferably, R3 is -H or methyl, R4, R6, R8, and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is independently halogen or trifluoromethyl.

[0629] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, or C1-C3 alkyl; R4, R8, and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0630] [ka] In the formula, R9 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and preferably, R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0631] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula:

[0632] [ka] In the formula, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0633] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0634] [ka] wherein each R9 is independently —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula:

[0635] [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; and each R 11 is independently —H or C1-C3 alkyl.

[0636] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0637] [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; and R2 is a group of the formula:

[0638] [ka] Preferably, each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Most preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, each R 10are independently -H, -C...

Claims

1. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, said method comprising administering to said patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor of the following formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 2】 R ２ is the base of the formula: 【Transformation 3】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ a first PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof, which is alkyl; (ii) administering a therapeutically effective amount of a second PI3Kα-selective inhibitor, wherein the second PI3Kα-selective inhibitor is a PI3Kα-selective orthosteric inhibitor selected from alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof; The method, wherein said therapeutically effective amount of said first PI3Kα selective inhibitor and said therapeutically effective amount of said second PI3Kα selective inhibitor are administered simultaneously, separately or sequentially.

2. 2. The method of claim 1, wherein the second PI3Kα selective inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.

3. 3. The method of claim 1 or 2, wherein the second PI3Kα selective inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.

4. 4. The method of any one of claims 1 to 3, wherein the dose of the second PI3Kα selective inhibitor is an oral dose of less than about 300 mg administered daily.

5. 5. The method of claim 4, wherein the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor are administered substantially simultaneously.

6. 6. The method of any one of claims 1 to 5, wherein the dose of the second PI3Kα selective inhibitor is an oral dose of less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg administered daily.

7. 7. The method of claim 6, wherein the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor are administered substantially simultaneously.

8. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, said method comprising administering to said patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor that binds to PI3Kα allosteric pocket 1 and is of the formula: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Transformation 5】 R ２ is the base of the formula: 【Transformation 6】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ a first PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof, which is alkyl; (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, 【Transformation 7】 and a second PI3Kα selective inhibitor selected from the group consisting of: The method, wherein the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor are administered simultaneously, separately, or sequentially.

9. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, said method comprising administering to said patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor of the following formula: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 9】 R ２ is the base of the formula: 【Chemistry 10】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ a first PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof, which is alkyl; (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor of the following formula: 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 12】 R ２ is the base of the formula: 【Chemistry 13】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ and a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor is alkyl, with the proviso that the second PI3Kα selective inhibitor is not a compound of the formula: 【Chemistry 14】 The method, wherein said first PI3Kα selective inhibitor and said second PI3Kα selective inhibitor are different and are administered simultaneously, separately or sequentially.

10. The second PI3Kα selective inhibitor has the formula: 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

11. the second PI3Kα selective inhibitor is of a formula selected from: 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

12. The first PI3Kα selective inhibitor has the formula: 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

13. 13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount of a first PI3Kα-specific inhibitor is effective to reduce PI3Kα activity in the patient without inducing hyperglycemia in the patient.

14. 14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of a second PI3Kα-specific inhibitor is effective to reduce PI3Kα activity in the patient without inducing hyperglycemia in the patient.

15. The first PI3Kα selective inhibitor has the formula: [Chemistry 18] or a pharmaceutically acceptable salt thereof.

16. 16. The method of claim 15, wherein the therapeutically effective amount of the first PI3Kα selective inhibitor administered to the patient is an oral dose of 100 to 1200 mg administered twice daily.

17. 16. The method of claim 15, wherein the therapeutically effective amount of the first PI3Kα-specific inhibitor administered to the patient is an oral dose of 9-75 mg / kg administered twice daily.

18. 18. The method of any one of claims 1 to 17, wherein the method comprises administering the second PI3Kα-specific inhibitor after the disease or disorder has developed resistance to the first PI3Kα-specific inhibitor.

19. 19. The method of claim 18, wherein the resistance is characterized by the occurrence of an M1043I / L mutation or a C901F mutation.

20. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) that is resistant to treatment with alpelisib, comprising administering to a patient in need thereof a therapeutically effective amount of a PI3Kα selective inhibitor of the following formula: 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 20】 R ２ is the base of the formula: 【Chemistry 21】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ alkyl, with the proviso that the PI3Kα selective inhibitor administered in the method is not a compound of the formula: 【Chemistry 22】 A method comprising administering a PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof.

21. The PI3Kα selective inhibitor is of the formula: 【Chemistry 23】 or a pharmaceutically acceptable salt thereof.

22. the second PI3Kα selective inhibitor is of a formula selected from: 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

23. 1. A method for treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) that is resistant to treatment with alpelisib, comprising administering to a patient in need thereof: 【Chemistry 25】 and pharmaceutically acceptable salts thereof.

24. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a first PI3Kα selective inhibitor of the following formula: 【Chemistry 26】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 27】 R ２ is the base of the formula: 【Chemistry 28】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ -C ３ have been previously treated with a first PI3Kα selective inhibitor, wherein the first PI3Kα inhibitor is an alkyl, or a pharmaceutically acceptable salt thereof; The patient has cancer that has acquired an M1043I / L mutation in cis with an H1047R mutation, and / or an C901F mutation in cis with an H1047R mutation, and the method comprises administering to the patient a therapeutically effective amount of a second PI3Kα selective inhibitor selected from alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof.

25. The first PI3Kα selective inhibitor has the formula: 【Chemistry 29】 or a pharmaceutically acceptable salt thereof.

26. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, wherein said 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, said method comprising administering to said patient: 【Transformation 30】 and pharmaceutically acceptable salts thereof.

27. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, wherein said 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, said method comprising administering to said patient a therapeutically effective amount of a PI3Kα selective inhibitor of the following formula: 【Chemistry 31】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 32】 R ２ is the base of the formula: 【Transformation 33】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ ~C ３ alkyl, with the proviso that the PI3Kα selective inhibitor administered in the method is not a compound of the formula: 【Transformation 34】 A method comprising administering a PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof.

28. The PI3Kα selective inhibitor is of the formula: 【Chemistry 35】 or a pharmaceutically acceptable salt thereof.

29. The PI3Kα selective inhibitor is selected from the following formula: 【Transformation 36】 or a pharmaceutically acceptable salt thereof.

30. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, comprising determining that 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 administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor selected from alpelisib and inavolisib.

31. 1. A method for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, the method comprising: determining that 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 administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor, wherein the PI3Kα selective inhibitor is: 【Chemistry 37】 and pharmaceutically acceptable salts thereof,

32. a therapeutically effective amount of a PI3Kα-specific inhibitor compound of the following formula: 【Transformation 38】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ as defined in claim 1, wherein the method comprises assaying a sample from a patient, and the patient is selected if M1043I / L in cis with the H1047R mutation and / or C901F in cis with the H1047R mutation are present in the sample.

33. 1. A method for selecting a patient having a disease or disorder associated with the modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) for treatment with a therapeutically effective amount of a PI3Kα-specific inhibitor selected from alpelisib and inavolisib, the method comprising assaying a sample from the patient, wherein the patient is selected if an M1043I / L mutation in cis with an H1047R mutation, and / or a C901F mutation in cis with an H1047R mutation, is present in the sample.

34. below: 【Chemistry 39】 1. A method for selecting a patient having a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) for treatment with a therapeutically effective amount of a PI3Kα-specific inhibitor that binds to PI3Kα allosteric pocket 2 selected from: The patient is selected if the patient has M1043I / L in cis with the H1047R mutation and / or C901F in cis with the H1047R mutation present in the sample.

35. The method of any one of claims 1 to 34, wherein the disease or disorder is cancer.

36. The method of any one of claims 1 to 34, wherein the disease or disorder is breast cancer.

37. 35. The method of any one of claims 1 to 34, wherein the disease or disorder is PIK3CA mutant, advanced, or metastatic breast cancer.

38. 35. The method of any one of claims 1 to 34, wherein the disease or disorder is PIK3CA H1047R mutant advanced or metastatic breast cancer.

39. 39. The method of claim 38, wherein the PIK3CA H1047R mutant advanced or metastatic breast cancer is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-).

40. 40. The method of any one of claims 1 to 39, wherein the patient is a postmenopausal woman.

41. 40. The method of any one of claims 1 to 39, wherein the patient has type II diabetes.

42. 40. The method of any one of claims 1 to 39, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

43. 43. The method of claim 42, wherein the SERD is selected from imrunestrant, fulvestrant, diledestrant, amsenestrant, lintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502.

44. 44. The method of claim 42 or 43, wherein the therapeutically effective amount of the SERD is a 500 mg dose administered on days 1, 15, and 29.

45. A PI3Kα-specific inhibitor compound of the formula: 【Chemistry 40】 or a pharmaceutically acceptable salt thereof, wherein: R is —H or C １ ~C ３ is alkyl, R １ is the base of the formula: 【Chemistry 41】 R ２ is the base of the formula: 【Chemistry 42】 R ３ -H, halogen, -CN, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ５ 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 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R ４ , R ５ , and R ６ each independently represents —H, a halogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ７ But, -CN, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, R ８ is -H or C １ ~C ６ is alkyl, Each R ９ are independently —H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ５ is cycloalkyl, Each R １０ are independently —H, —CN, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, —SO ２ R １１ , -CONR １１ R １１ , -NR １１ R １１ , -NR １１ -CO ２ R １１ , optionally substituted C １ ~C ６ Alkyl, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ５ an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, wherein said optionally substituted C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is —CN, —OH, oxetanyl, or C １ ~C ３ Optionally substituted with alkoxy, said optionally substituted C ３ ~C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, —SO ２ R １１ , -NR １１ R １１ , —OH, or —CN; Each R １１ are independently —H or C １ -C ３ is alkyl, A PI3Kα-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the modulation of phosphatidylinositol 3-kinase alpha (PI3Kα), in simultaneous, separate, or sequential combination with a second PI3Kα-specific inhibitor, wherein the second PI3Kα-specific inhibitor is a PI3Kα-specific orthosteric inhibitor selected from alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof.

46. 46. ​​The compound for use according to claim 45, wherein the second PI3Kα-specific inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.

47. 46. ​​The compound for use according to claim 45, wherein the second PI3Kα-specific inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.

48. 48. The compound for use according to any one of claims 45 to 47, wherein the dose of said second PI3Kα-specific inhibitor is an oral dose of less than about 300 mg administered daily.

49. 49. The compound for use according to any one of claims 45 to 48, wherein the first PI3Kα-specific inhibitor and the second PI3Kα-specific inhibitor are administered substantially simultaneously.

50. 50. The compound for use according to any one of claims 45 to 49, wherein the first PI3Kα-specific inhibitor and the second PI3Kα-specific inhibitor are administered simultaneously, and the dose of the second PI3Kα-specific inhibitor is an oral dose of less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg administered daily.

51. A PI3Kα-specific inhibitor compound of formula I, 【Chemistry 43】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ is as defined in claim 45, 【Chemistry 44】 and a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα).

52. A PI3Kα-specific inhibitor compound of formula I, 【Chemistry 45】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ 46. ​​A PI3Kα-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, as defined in claim 45, for use in the treatment of a disease or disorder associated with the modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in simultaneous, separate or sequential combination with a second PI3Kα-specific inhibitor of formula I or a pharmaceutically acceptable salt thereof, wherein the first PI3Kα-specific inhibitor and the second PI3Kα-specific inhibitor are different.

53. 53. The compound for use of claim 52, wherein said second PI3Kα specific inhibitor is not of the formula 【Chemistry 46】

54. The second PI3Kα-specific inhibitor has the formula: 【Chemistry 47】 54. The compound for use according to claim 52 or 53, which is:

55. wherein the second PI3Kα specific inhibitor is of a formula selected from: 【Chemistry 48】 55. The compound for use according to any one of claims 52 to 54, which is:

56. 56. The compound for use according to any one of claims 52 to 55, wherein the therapeutically effective amount of said first PI3Kα-specific inhibitor is effective to reduce PI3Kα activity in said patient without inducing hyperglycemia in said patient.

57. 57. The compound for use according to any one of claims 52 to 56, wherein the therapeutically effective amount of said second PI3Kα-specific inhibitor is effective to reduce PI3Kα activity in said patient without inducing hyperglycemia in said patient.

58. A PI3Kα-specific inhibitor compound of formula I, 【Chemistry 49】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ 46. ​​A PI3Kα-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient who is resistant to treatment with alpelisib or inavolisib, wherein:

59. below [Transformation 50] and pharmaceutically acceptable salts thereof, wherein the PI3Kα-specific inhibitor binds to PI3Kα allosteric pocket 2, and is for use in treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient with cancer that is resistant to treatment with alpelisib or inavolisib.

60. 1. A PI3Kα-specific inhibitor which is a PI3Kα-specific orthosteric inhibitor selected from alpelisib or inavolisib for use in the treatment of a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα), wherein the patient is receiving a compound of formula I, 【Chemistry 51】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ as defined in claim 45, wherein the patient has a cancer that has acquired the M1043I / L mutation in cis with the H1047R mutation, and / or the C901F mutation in cis with the H1047R mutation.

61. below 【Chemistry 52】 and pharmaceutically acceptable salts thereof, for use in treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα), 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.

62. A PI3Kα-specific inhibitor compound of formula I, 【Chemistry 53】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ 46. ​​A PI3Kα-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, as defined in claim 45, for use in treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) 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.

63. A PI3Kα-specific inhibitor compound of formula I, 【Chemistry 54】 or a pharmaceutically acceptable salt thereof, wherein R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ 46. ​​A PI3Kα-specific inhibitor compound, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, comprising: assaying a blood sample from the patient; determining whether the patient has a cancer comprising a H1047R mutation and M1043I / L in cis, and / or a H1047R mutation and C901F in cis; and if the patient has a cancer comprising a H1047R mutation and M1043I / L in cis, and / or a H1047R mutation and C901F in cis, administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

64. 1. A method for treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need of treatment, comprising: assaying a sample from the patient; determining whether the patient has a cancer comprising an H1047R mutation and M1043I / L in cis, and / or an H1047R mutation and C901F mutation; and if the patient has a cancer comprising an H1047R mutation and M1043I / L in cis, and / or an H1047R mutation and C901F mutation, administering to the patient a therapeutically effective amount of alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof.

65. below 【Transformation 55】 and a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα), the method comprising: assaying a blood sample from the patient; determining whether the patient has a cancer comprising an H1047R mutation and M1043I / L in cis, and / or an H1047R mutation and C901F mutation; and administering to the patient a therapeutically effective amount of the PI3Kα-specific inhibitor, or a pharmaceutically acceptable salt thereof, if the patient has a cancer comprising an H1047R mutation and M1043I / L in cis, and / or an H1047R mutation and C901F mutation.

66. The compound of formula I is of the formula: 【Transformation 56】 64. The compound for use according to any one of claims 45 to 58, 60, 62, and 63, which is:

67. 64. The compound for use of any one of claims 45-58, 60, 62, and 63, wherein said therapeutically effective amount of said compound of formula I administered to said patient is an oral dose of 100-1200 mg administered twice daily.

68. 64. The compound for use of any one of claims 45-58, 60, 62, and 63, wherein said therapeutically effective amount of said compound of formula I administered to said patient is an oral dose of 9-75 mg / kg administered twice daily.

69. 69. The compound for use according to any one of claims 45 to 68, wherein the disease or disorder is cancer.

70. 70. The compound for use according to any one of claims 45 to 69, wherein the disease or disorder is breast cancer.

71. 71. The compound for use according to any one of claims 45 to 70, wherein the disease or disorder is PIK3CA mutated, advanced, or metastatic breast cancer.

72. 72. The compound for use according to any one of claims 45 to 71, wherein the disease or disorder is PIK3CACA H1047R mutant advanced or metastatic breast cancer.

73. 73. The compound for use according to claim 72, wherein the PIK3CACA H1047R mutant advanced or metastatic breast cancer is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-).

74. 74. The compound for use according to any one of claims 45 to 73, wherein the patient is a postmenopausal woman.

75. 75. The compound for use according to any one of claims 45 to 74, wherein the patient has type II diabetes.

76. 76. The compound for use according to any one of claims 45 to 75, further comprising administering to said patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

77. 77. The compound for use according to claim 76, wherein the SERD is selected from imrunestrant, fulvestrant, diledestrant, amsenestrant, lintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502.

78. 78. The compound for use of claim 76 or 77, wherein the therapeutically effective amount of the SERD is a 500 mg dose administered on days 1, 15, and 29.

79. 79. The compound for use according to any one of claims 45 to 78, wherein the second PI3Kα-specific inhibitor is administered after the disease or disorder has developed resistance to the first PI3Kα-specific inhibitor.

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