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

Abstract

This invention relates to the use (or use in treating, preventing, or improving diseases or conditions involving PI3K activity) of phosphoinositol 3-kinase (PI3K) inhibitors targeting both PI3K pockets. These PI3K inhibitors can be used in combination and can simultaneously, separately, or sequentially target both PI3Kα pockets. In some embodiments of the disclosed methods, the PI3Kα inhibitor can target both PI3Kα pockets of a PI3Kα mutant resistant to treatment with another PI3Kα inhibitor targeting a different pocket of PI3Kα.

Description

Targeting allosteric and orthosteric pockets of phosphoinositide 3-kinase (PI3K) for the treatment of disease The present invention relates to phosphoinositide 3-kinase (PI3K) inhibitors and combinations thereof, which are useful for treating diseases or conditions associated with PI3K regulation. The present invention also relates to allochromenone inhibitors of phosphoinositide 3-kinase (PI3K), which are useful for treating diseases or conditions associated with PI3K regulation; and to the use of allochromenone inhibitors in combination with other allo- or orthochrome PI3K inhibitors, which are useful for treating diseases or conditions associated with PI3K regulation. The present invention also relates to PI3K inhibitors and combinations thereof, methods (or uses) of treating diseases or conditions associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, 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 the use and methods of using PI3K inhibitors in combination with one or more other cancer therapies. The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is also implicated in other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, conditions associated with diabetic complications, and inflammatory complications of the cardiovascular system, such as acute coronary syndrome. PI3K is a unique and conserved family of intracellular lipid kinases that phosphorylate 3'-OH groups on phosphoinositides or phosphoinositides. The PI3K family includes 15 kinases with different substrate specificities, phenotypes (expression patterns) and regulatory modes. Class I PI3K (p110α, p110β, p110δ and p110γ) are usually activated by tyrosine kinases or G protein-coupled receptors to produce PIP3, which binds to downstream effectors (such as effectors in the pathway of Akt / PDK1, mTOR, Tec family kinases and Rho family GTPases). Class II and class III PI3Ks are activated through PI(3)P and PI(3,4)P 2 plays a key role in the synthesis of mitochondria and intracellular migration. PI3K isoforms have been implicated in, for example, various human cancers and disorders. PI3K α (alpha) isoforms have been implicated in, for example, various human cancers. Angiogenesis has been shown to selectively require PI3K α isoforms to control endothelial cell migration. It is believed that mutations in the gene encoding PI3K α or mutations that cause upregulation of PI3K α are present in a variety of human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the gene encoding PI3K α are point mutations clustered within several hotspots in the helix and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high mutation rate of PI3K α, targeting this pathway could provide valuable therapeutic opportunities. While other PI3K isoforms, such as PI3Kδ or PI3Kγ, are predominantly expressed in hematopoietic cells, PI3Kα is constitutively expressed together with PI3Kβ. Because PI3Kα plays a major role in regulating glucose homeostasis in the body, PI3K inhibition in patients often results in adverse events, including hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin can potentially have mitogenic and / or anti-apoptotic effects on cancer cells, thereby counteracting the anti-proliferative effects of PI3K inhibitors. In cancer settings where PI3Kα is mutated, one approach to overcoming the problem of insulin and / or glucose compensatory production following systemic PI3Kα inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3Kα relative to wild-type PI3Kα. This would create an increased window for drug administration to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that control systemic metabolism, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target. PI3Kα possesses an ATP-binding pocket that can be targeted to modulate PI3Kα activity. PI3Kα must bind ATP to catalyze the transfer of a phosphate group from ATP to the 3'-OH group on phosphatidylinositol or phosphoinositide. 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. Alternatively, the PI3Kα ATP-binding pocket can be referred to as the "PI3Kα orthosteric binding pocket." Currently, PI3Kα inhibitors are nearly equally effective against wild-type and mutant PI3Kα. Because the most common PI3Kα mutations (E542K, E545K, and H1047R) are located far from the PI3Kα orthosteric binding pocket, mutant-selective inhibitors have been elusive. Therefore, inhibitors targeting secondary, peripheral binding pockets near known mutations (e.g., H1047R) could offer a path to selective PI3Kα inhibition. The present invention provides a novel class of kinase inhibitors that target a non-ATP-binding pocket of PI3Kα, referred to herein as "PI3Kα allo-pocket 1," and can interact with amino acid residues of PI3Kα, including R1047. The disclosed kinase inhibitors target PI3Kα allo-pocket 1 and can be used in combination therapies, for example, in which the disclosed PI3Kα inhibitors are used in combination with PI3Kα inhibitors that target other pockets of PI3Kα, such as the PI3Kα orthosteric pocket. The present invention also provides characterization of another non-ATP binding pocket of PI3Kα, termed "PI3Kα allosite pocket 2," and the interaction of PI3Kα inhibitors with PI3Kα allosite pocket 2. The disclosed kinase inhibitors targeting PI3Kα allosite pocket 1 can be used in combination therapy with PI3Kα inhibitors targeting PI3Kα allosite pocket 2. The present invention relates to the use of phosphoinositide 3-kinase (PI3K) inhibitors in methods of treating, preventing, or ameliorating diseases or conditions in which PI3K is implicated (or in the treatment, prevention, or amelioration of a disease or condition). These phosphoinositide 3-kinase inhibitors target both the allosteric and orthosteric pockets of PI3K. PI3K inhibitors can be used in combination and can target the phosphatidylinositol 3-kinase α (PI3Kα) allosteric pocket, referred to herein as "PI3Kα allosteric pocket 1," the PI3Kα allosteric pocket, referred to herein as "PI3Kα allosteric pocket 2," or the PI3Kα orthosteric pocket (see Figure 1). In some aspects of the disclosed methods, the PI3Kα inhibitor can target PI3Kα allostatic pocket 1, PI3Kα allostatic pocket 2, or PI3Kα orthosteric pocket of a PI3Kα mutant that is resistant to treatment with another PI3Kα inhibitor (e.g., a PI3Kα inhibitor that targets a different pocket of PI3Kα). The method may comprise administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the present invention or a combination of a PI3K inhibitor of the present invention with other PI3K inhibitors, such as other PI3K allosteric inhibitors and PI3K orthosteric inhibitors. The methods and PI3K inhibitors of the present invention can be used to treat a variety of PI3K-dependent or PI3K-associated diseases and conditions. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with the regulation of PI3Kα. The methods can comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to the PI3Kα allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor binds to the PI3Kα orthosteric pocket. In some aspects, the disclosed methods relate to methods for treating diseases or conditions associated with the regulation of PI3Kα. These methods can comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to the PI3Kα allosteric pocket 2; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor binds to the PI3Kα orthosteric pocket. In some aspects, the disclosed methods can comprise administering to a patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor binds to PI3Kα allosite pocket 2. In some aspects, the disclosed methods can comprise administering to a patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor different from the first PI3Kα selective inhibitor, wherein the second different PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1. In some aspects, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor compete for binding to PI3Kα allosite pocket 1. In the disclosed methods, a first PI3Kα selective inhibitor and a second PI3Kα selective inhibitor are administered simultaneously, separately, or sequentially. In some embodiments, the second PI3Kα selective inhibitor is administered to the patient if the patient has a disease or condition that is resistant to treatment with the first PI3Kα selective inhibitor. In some embodiments, the second PI3Kα selective inhibitor is administered to the patient after the patient's disease or condition has acquired resistance to treatment with the first PI3Kα selective inhibitor. In some aspects of the disclosed methods, the methods comprise administering a therapeutically effective amount of a first PI3Kα selective inhibitor and a therapeutically effective amount of a second PI3Kα selective inhibitor, and an additive or synergistic effect may be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Kα selective inhibitor administered in the disclosed methods may be less than the therapeutically effective amount of the first PI3Kα selective inhibitor required in a treatment method in which the second PI3Kα selective inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the second PI3Kα selective inhibitor administered in the disclosed methods may be less than the therapeutically effective amount of the second PI3Kα selective inhibitor required in a treatment method in which the first PI3Kα selective inhibitor is not administered. In some aspects of the disclosed methods, a therapeutically effective amount of a first PI3Kα selective inhibitor effectively reduces PI3Kα activity in a patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, a therapeutically effective amount of a second PI3Kα selective inhibitor effectively reduces PI3Kα activity in a patient without inducing adverse events, or while minimizing the risk of adverse events. Adverse events may include, but are not limited to, hyperglycemia, hyperinsulinemia, diarrhea, dehydration, rash, lymphopenia, increased alanine aminotransferase, fatigue, anemia, increased serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemia, alopecia, prolonged activated partial thromboplastin time, kidney disease with decreased glomerular filtration rate (GFR), acute abdominal pain, and abnormal liver function tests. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with the regulation of PI3Kα in a patient suffering from a disease or condition that is resistant to treatment with a PI3Kα selective inhibitor, which can be a PI3Kα selective antagonist or a PI3Kα selective orthosteric inhibitor. These methods can comprise administering to the patient a different PI3Kα selective inhibitor to which the disease or condition is not resistant, such as a PI3Kα selective antagonist or a PI3Kα selective orthosteric inhibitor. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with the modulation of PI3Kα in a patient who has a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor. In some aspects, the disclosed methods relate to treating a disease or condition associated with the modulation of PI3Kα in a patient who has been identified as having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor, or who has been identified as having a disease or condition that has demonstrated an incomplete response to treatment with a PI3Kα selective orthosteric inhibitor. In some aspects, the methods may comprise administering to the patient who has been identified as having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor, or who has been identified as having a disease or condition that has demonstrated an incomplete response to treatment with a PI3Kα selective orthosteric inhibitor, a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor, wherein the PI3Kα selective orthosteric inhibitor binds to PI3Kα allosite pocket 1. In some aspects, the method can comprise administering a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor to a patient identified as having a disease or disorder that is resistant to treatment with a PI3Kα-selective orthosteric inhibitor, or identified as having a disease or disorder that exhibits an incomplete response to treatment with a PI3Kα-selective orthosteric inhibitor, wherein the PI3Kα-selective orthosteric inhibitor binds to PI3Kα allotopic pocket 2. In some aspects, the disclosed methods relate to treating a disease or condition associated with the regulation of PI3Kα that is resistant to treatment with a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1. In some aspects, the methods may comprise administering to a patient suffering from the resistant disease or condition a therapeutically effective amount of a second, different PI3Kα selective inhibitor that binds to PI3Kα allosite pocket 1. In some aspects, the methods may comprise administering to a patient suffering from the resistant disease or condition a therapeutically effective amount of a second, different PI3Kα selective inhibitor that binds to PI3Kα allosite pocket 2. In some aspects, the methods may comprise administering to a patient suffering from the resistant disease or condition a therapeutically effective amount of a PI3Kα selective inhibitor that binds to PI3Kα orthosteric pocket 2. In some aspects, the disclosed methods relate to treating a disease or condition associated with the regulation of PI3Kα that is resistant to treatment with a first PI3Kα selective allosteric inhibitor, wherein the first PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 2. In some aspects, the methods may comprise administering to a patient suffering from the resistant disease or condition a therapeutically effective amount of a second, different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1. In some aspects, the methods may comprise administering to a patient suffering from the resistant disease or condition a therapeutically effective amount of a PI3Kα selective inhibitor that binds to the PI3Kα orthosteric pocket. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with PI3Kα regulation in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3Kα selective inhibitor, and the patient's disease or condition has acquired resistance to treatment with the PI3Kα selective inhibitor. The methods may include administering to the patient a different PI3Kα selective inhibitor to which the disease or condition is not resistant. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with regulation of PI3Kα in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3Kα-selective inhibitor, wherein the PI3Kα-selective inhibitor binds to PI3Kα allosite pocket 1 or PI3Kα allosite pocket 2. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with the PI3Kα-selective inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allosite pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allosite pocket 2. In the disclosed methods, the patient's disease or condition may have acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1. In the disclosed methods, the patient's disease or condition may have acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1. In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with regulation of PI3Kα in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a PI3Kα-selective inhibitor, wherein the PI3Kα-selective inhibitor binds to PI3Kα allosite pocket 1 or PI3Kα allosite pocket 2. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with the PI3Kα-selective inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allosite pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allosite pocket 2. In the disclosed methods, the patient's disease or condition may have acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1. In the disclosed methods, the patient's disease or condition may have acquired resistance to treatment with a PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 1. In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with the regulation of PI3Kα in a patient in need thereof, wherein the patient suffers from a disease or disorder comprising an M1043 mutation (e.g., M1043I / L, optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation). The methods may comprise administering to the patient suffering from the disease or disorder a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor. The methods may comprise administering to the patient suffering from the disease or disorder a therapeutically effective amount of a PI3Kα allosteric inhibitor, wherein the disease or disorder comprises 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 PI3Kα allosteric inhibitor binds to site 1 of the PI3Kα allosteric pocket. The method may comprise administering a therapeutically effective amount of a PI3Kα allotopic inhibitor that binds to PI3Kα allotopic 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). In some aspects, the method relates to a method for treating a disease or disorder associated with the regulation of PI3Kα in a patient in need thereof, such as a patient suffering from 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 comprise determining, for example, by sequencing or performing genomic analysis, that the patient suffers from 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). If the patient is found to have a disease or disorder 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 comprise administering to the patient one or more PI3Kα selective inhibitors, which may comprise an allosteric inhibitor as disclosed herein (e.g., an allosteric inhibitor that binds to PI3Kα allosite pocket 1 and / or an allosteric inhibitor that binds to PI3Kα allosite pocket 2), an orthosteric inhibitor, or a combination thereof. In some aspects, the disclosed methods include selecting a patient for treatment with one or more PI3Kα selective inhibitors. In some aspects, the patient is selected based on having a disease or condition 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 can be administered a treatment that may include administering to the patient one or more PI3Kα selective inhibitors, which may include an allosteric inhibitor as disclosed herein (e.g., an allosteric inhibitor that binds to PI3Kα allosite pocket 1 or an allosteric inhibitor that binds to PI3Kα allosite pocket 2), an orthosteric inhibitor, or a combination thereof. In the disclosed methods, a patient in need may have cancer. In some aspects, a patient in need may have breast cancer. In some aspects, a patient in need may have a PIK3CA mutant advanced or metastatic breast cancer. In some aspects, a patient in need may have a PIK3CA H1047R mutant advanced or metastatic breast cancer, i.e., estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-). In the disclosed methods, a patient in need thereof may have cancer and may have previously been administered one or more therapeutic agents for treating the cancer, which may include a PI3Kα selective inhibitor. In some aspects, the patient may have cancer that exhibits de novo or acquired resistance to treatment with a therapeutic agent that may include a PI3Kα selective inhibitor, and the patient may be administered a different therapeutic agent, which may include a different PI3Kα selective inhibitor. In the disclosed methods, the patient may not have been previously administered a therapeutic agent for treating cancer, which may include a PI3Kα selective inhibitor. In some aspects, the patient may be characterized as having not been treated with a PI3Kα selective inhibitor. Cross-reference to related patent applications This application claims priority to U.S. Provisional Application No. 63 / 501,614, filed on May 11, 2023; U.S. Provisional Application No. 63 / 382,980, filed on November 9, 2022; and U.S. Provisional Application No. 63 / 382,029, filed on November 2, 2022; the contents of each of which are incorporated herein by reference in their entirety. Sequence Listing Of Reference This application is filed with a sequence listing in ST.26 XML format. The sequence listing is provided as a file named "30449SequenceListing.xml," created on October 30, 2023, and 2,777 bytes in size. The ST.26 XML format sequence listing information is incorporated herein by reference in its entirety. The present invention provides methods for treating, preventing, or ameliorating diseases or conditions, or uses of PI3K inhibitors for treating, preventing, or ameliorating diseases or conditions, wherein the disease or condition is dependent on or associated with PI3K activity. In the disclosed methods and uses, a therapeutically effective amount of a PI3K inhibitor or combination of PI3K inhibitors, which may include allosteric and orthosteric inhibitors, is administered to a patient in need thereof. The methods and uses disclosed herein can be used to treat a variety of PI3K-dependent or PI3K-associated diseases and conditions. In some embodiments of the disclosed methods and uses, the disease or disorder is cancer, such as 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, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal 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 tumors, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, mixed neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma. The details of the present invention are described in the following accompanying description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objectives, and advantages of the present invention will be apparent from the embodiments and from the claims. Unless the context clearly indicates otherwise, in this specification and the accompanying claims, the singular also includes the plural. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications cited in this specification regarding the disclosed PI3Kα inhibitor compounds and methods for preparing and using PI3Kα inhibitor compounds are incorporated herein by reference in their entirety. definition The articles "a" and "an" refer to one or to more than one (ie, to at least one) of the grammatical object of the article. As an example, "an element" means one element or more than one element. Unless otherwise indicated, the term "and / or" means "and" or "or". The terms "administer," "administering," or "administration" refer to administering a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition, directly or indirectly to a patient. "Administering" or "administration" can be performed by a caregiver, e.g., by a medical professional or other caregiver, wherein the medical professional or other caregiver administers a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition, to the patient. "Administering" or "administration" can be performed by the patient, e.g., wherein the patient administers a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition, to themselves. The term "alkenyl" refers to a straight or branched unsaturated hydrocarbon chain 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 may be unbound or bound to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, which contains a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy. The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. 1-C 6) Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, and isohexyl. 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, isobutynyl, pentynyl, and hexynyl. The term "aromatic" means having 4 A planar ring of n + 2 electrons. As used herein, "bound system" means a system having connected p orbitals with delocalized electrons, and the system may include lone electron pairs. Unless otherwise expressly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having from one to three aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl, or naphthyl. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). In addition, when two fused rings are contained, the aryl group defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzoannulenyl. The term "carrier" encompasses vehicles, excipients, and diluents, and means a material, composition, or vehicle involved in carrying or transporting a pharmaceutical agent from one organ or body part to another in a patient, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. The term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom via a triple bond, ie, C≡N. 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, cycloheptyl, cyclooctyl, norbornyl, norborenyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl. Unless otherwise indicated, the term "disorder" means, and is used interchangeably with, the term disease, condition, or illness. As defined herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy. As defined herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl. The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine. Unless otherwise expressly defined, the term "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group having 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 groups include two or more fused rings and may further include two or more spirofused rings, such as bicyclic, tricyclic, tetracyclic, and similar rings. Unless otherwise expressly defined, "fused" means that the two rings share two ring atoms. Unless otherwise expressly defined, "spirofused" means that the two rings share one ring atom. As defined herein, heteroaryl also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl as defined herein also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P or B, preferably selected from N, O or S. Heteroaryl as defined herein also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P or B, preferably selected from N, O or S.Examples of heteroaromatic groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triamcinolyl, 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, ]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indolinyl, indolinone, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuranyl, thiophene, thiophene, tetrahydroquinolinyl, dihydrobenzothiaphene, quinolinyl, isoquinolinyl, 1,6-oxadinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]oxadinyl, thieno[2,3-b]pyridinyl, 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]thiazolyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophene, 1,5-oxadiazolyl, 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]pyrimidinyl, 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]oxadiazole, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and 3H-indolyl. Additionally, when containing two or more fused rings, a heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to saturated or partially unsaturated rings as described herein. In addition, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated spirofused rings. Any saturated or partially unsaturated ring described herein may be substituted with one or more pendant oxy groups. Exemplary ring systems of such heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, iodinealkyl, thioiodinealkyl, tetrahydroquinolinyl, dihydrobenzothiazolium, 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]pyrrolidone. yl, 8​​H-pyrido[3,2-b]pyridin 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyridinyl yl, pyrazolo[1,5-a]pyrimidin-7(4H)-one, 3,4-dihydropyrazolo[1,2-a]indol-1(2H)-one, benzo[ c][1,2]oxaborole-1(3 H)-alcohol, 6,6a,7,8-tetrahydro-9 H-pyrido[2,3- b]pyrrolo[1,2- d][1,4]㗁𠯤-9-one and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3- b]pyrrolo[1,2- d][1,4]㗁𠯤]-9'-keto. The term "heterocyclyl", "heterocycle" or "heterocycloalkyl" means a monocyclic or polycyclic ring containing 3 to 24 atoms, preferably 3 to 10 atoms, comprising 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, dioxazolinyl, piperidinyl, oxazolinyl, thiooxazolinyl, thiooxazolinyl S-oxide, thiooxazolinyl S-dioxide, piperolyl, azapentyl, oxazolinyl, diazapentyl, tropanyl, oxazolidinone, and homotropanyl. As defined herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group. When referring to two different mutations, the term "in cis" "Cis)" means that the two different mutations are located on the same chromosome. The term "isomers" refers to compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates about the plane of polarized light and designated as right-handed or left-handed (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K. Modulation may include inhibition. The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human. The term "therapeutically effective amount" when used in connection with a compound refers to that amount or dosage of the compound which, following single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. The effective amount can be determined by one skilled in the art by using known techniques and by observations obtained under similar circumstances. In determining the effective amount for a patient, the attending physician considers a number of factors, including but not limited to: the species of the patient; their size, age, and general health; the specific disease or condition involved; the extent or severity of the disease or condition; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the formulation being administered; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances. The term "treat" with respect to a patient includes limiting, slowing, stopping, or reversing the progression or severity of an existing symptom or condition. The term "treat" with respect to a patient may include prescribing a therapeutic agent to be administered to the patient or a treatment regimen for the patient. The term "treat" with respect to a patient may include arranging diagnostic testing for the patient. Diagnostic testing may include genomic analysis that identifies mutations present in PI3Kα, such as mutations in C901 (e.g., C901F), M1043 (e.g., M1043I / L), and / or H1047 (e.g., H1047R), wherein the mutations may be in cis (i.e., on the same allele), as disclosed herein. The term "prevent" with respect to a patient can mean preventing a disease or condition and / or preventing symptoms of a disease or condition. A patient in need thereof can include a patient at risk of developing a disease or condition, in which case the disclosed methods can be performed to prevent the patient from developing the disease or condition. A patient in need thereof can include a patient in remission, in which case the disclosed methods can be performed to prevent the disease or condition from recurring in the patient. With respect to cancer, treatment 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 the average survival time of patients following treatment. The term "PI3K" means "phosphoinositide 3-kinase". The term "PI3Kα" means phosphoinositide 3-kinase α, which is a class I PI3K and includes PIK3CA encodes the PI3k catalytic alpha polypeptide (p110-α). Alternatively, the p110-α polypeptide may be referred to as "PIK3CA." The p110-α polypeptide comprises 1068 amino acids and has the amino acid sequence of SEQ ID NO: 1: p110- α (SEQ ID NO: 1) The Enzyme Commission (EC) number for the catalytic activity of PI3Kα is 2.7.1.153. PI3Kα's catalytic activity includes phosphatidylinositol-4,5-bisphosphate 3-kinase activity, in which 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 ATP in the ATP-binding pocket within the kinase catalytic domain of the p100α subunit of PI3Kα. The PI3Kα inhibitors disclosed herein inhibit the phosphatidylinositol-4,5-bisphosphate 3-kinase activity of PI3Kα. The disclosed inhibitors can inhibit PI3Kα activity by binding at or near the ATP binding pocket of PI3Kα (which may be referred to as the "PI3Kα orthosteric pocket"). The disclosed inhibitors can act as antagonists to prevent ATP from binding to 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 to the ATP binding site of PI3Kα. The ATP binding pocket of PI3Kα 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 optimisation 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, Biorg. & Medic. Chem. Lett. 25 (2015) 3575-3581, published June 26, 2015). The ATP-binding pocket is located in the cleft between the N-terminal 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 the group consisting of R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933. Orthosteric inhibitors of PI3Kα can bind to PI3Kα at or near the ATP binding pocket of PI3Kα and can form interactions with one or more amino acids selected from the group consisting of R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933. Interactions can include, but are not limited to, hydrogen bonding, pi-pi T-stacks, and coplanar core pi-pi stacks, either directly or via bridging water molecules. Orthosteric inhibitors of PI3Kα are known and can include, but are not limited to, apoxib, inavolisib, and serabelisib, which are selective inhibitors of PI3Kα. The disclosed inhibitors can inhibit PI3Kα by binding at or near a PI3Kα pocket that is not the ATP binding pocket of PI3Kα (which can be referred to as an "allosite pocket"). The disclosed inhibitors can act as allosite inhibitors of PI3Kα. Allosite inhibitors of PI3Kα that can be used in the disclosed methods are disclosed in: WO2021 / 202964 (Petra), WO2021 / 222556, WO2022 / 235574, WO2022 / 235575, WO2022 / 251482, WO2022 / 265993, WO2023 / 01863 6. WO2023 / 039532, WO2023 / 056407, WO2023 / 060262, WO2023 / 288242, WO2023 / 081209, WO2023 / 081757, WO202 3 / 081759, WO2023 / 078401, WO2023 / 104111, WO2023 / 109870, WO2023 / 159155, WO2023 / 168378, WO2023 / 173124, WO2023 / 192416 and WO2023 / 288242, the contents of which regarding the disclosed PI3Kα inhibitor compounds and methods of preparing and using PI3Kα inhibitor compounds are incorporated herein by reference in their entirety. In some aspects, the allosteric inhibitors disclosed herein can bind to PI3Kα at or near the allosteric pocket of PI3Kα (referred to herein as "PI3Kα allosteric pocket 1"). In some aspects, the allosteric inhibitor of PI3Kα can bind to PI3Kα allosteric pocket 1 and can form interactions with one or more amino acids selected from the group consisting of C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. Interactions can include, but are not limited to, hydrogen bonding, directly or through bridging water molecules, pi-pi T-stacks, and coplanar core pi-pi stacks. Specific interactions may include one or more of the following interactions: direct hydrogen bonding between the carboxylic acid group of the inhibitor and the side chains of R1047 and Q981; hydrogen bonding between the carboxylic acid group of the inhibitor, the bridging water molecule, and the side chain of Y985; hydrogen bonding between the oxadione exocyclic ketone group of the inhibitor, the bridging water molecule, and the side chain of H931; hydrogen bonding between the oxadione exocyclic ketone group of the inhibitor, the bridging water molecule, and the carbonyl backbone group of C901; hydrogen bonding between the cyano group of the inhibitor and the side chain of Y1021; core pi-pi stacking between the oxadione core of the inhibitor and the side chain of F954; pi-pi bonding between the phenyl core of the inhibitor (e.g., a core in a substituent at the C2 position of the oxadione core) and the side chain of F909. T-type stacking; direct hydrogen bonding between the C3 substituent on the oxadione core of the inhibitor and the side chain of H931; and core pi-pi stacking between the core of the inhibitor (e.g., the core in the substituent at the C3 position of the oxadione core) and the side chain of F954. PI3Kα allostatic inhibitors that bind to PI3Kα allostatic pocket site 1 are disclosed in WO2021 / 202964, WO2022 / 235574, WO2022 / 235575, WO2022 / 251482, WO2023 / 056407, WO2023 / 060262, and WO2023 / 078401, which are incorporated herein by reference in their entirety for the disclosed PI3Kα inhibitor compounds and methods of making and using the PI3Kα inhibitor compounds. In some aspects, the allosteric inhibitors disclosed herein can bind to PI3Kα at or near the allosteric pocket of PI3Kα (referred to herein as "PI3Kα allosteric pocket 2"). In some aspects, the allosteric inhibitor of PI3Kα can bind to PI3Kα allosteric pocket 2 and can form interactions with one or more amino acids selected from the group consisting of L911, F937, F1002, E1012, and D1018. Interactions can include, but are not limited to, hydrogen bonding, directly or through bridging water molecules, pi-pi T-type stacking, and coplanar core pi-pi stacking. 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 pi-pi stacking between the 3-trifluoromethyl, 5-fluorophenyl core of the inhibitor and the side chain of F937; pi-pi T-type stacking between the 3-trifluoromethyl, 5-fluorophenyl core of the inhibitor and the side chain of F1002; and chloro-carbonyl interactions between the chlorine atoms of the 2-chloro, 5-fluorophenyl groups of the compound and the side chain carbonyl group of E1012. Allosteric inhibitors of PI3Kα are disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757 and WO2023 / 081759, the contents of which regarding the disclosed PI3Kα inhibitor compounds and methods for preparing and using PI3Kα inhibitor compounds are incorporated herein by reference in their entirety. In some embodiments, the disclosed methods may utilize the PI3Kα allotopic specific inhibitors disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, which may optionally bind to PI3Kα allotopic pocket 2. In some embodiments of the methods disclosed herein, the methods may utilize the PI3Kα allotopic specific inhibitors disclosed in WO2021 / 222556, Table 1, pages 162-855 and designated as compounds I-1 to I-2704, or pharmaceutically acceptable salts thereof. In some embodiments, the methods may utilize a PI3Kα allotopic specific inhibitor selected from: or a pharmaceutically acceptable salt thereof. In some embodiments, the method may utilize a PI3Kα allotopic specific inhibitor as disclosed in WO2021 / 222556, Table 1, selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. In some aspects of the methods disclosed herein, the methods may utilize a PI3Kα allotopic specific inhibitor disclosed in WO2022 / 265993, Tables A to D, pages 175 to 259. In some embodiments, the methods may utilize a PI3Kα allotopic specific inhibitor disclosed in WO2022 / 265993 selected from: , or a pharmaceutically acceptable salt thereof. In some aspects, the PI3Kα inhibitors used in the disclosed methods can bind to PI3Kα simultaneously. In some aspects, the disclosed inhibitor combinations can bind to one or more allostatic pockets (e.g., PI3Kα allostatic pocket 1 and / or PI3Kα allostatic pocket 2), and the disclosed inhibitor combinations can bind to the PI3Kα orthosteric pocket simultaneously. In some aspects, the disclosed inhibitor combinations can bind to a first allostatic pocket (e.g., one of PI3Kα allostatic pocket 1 and PI3Kα allostatic pocket 2), and the disclosed inhibitor combinations can bind to a second allostatic pocket (e.g., the other of PI3Kα allostatic pocket 1 and PI3Kα allostatic pocket 2). In some aspects, the disclosed inhibitor combinations can bind to the first allosteric pocket (e.g., PI3Kα allosteric pocket 1), or the disclosed inhibitor combinations can bind to the second allosteric pocket (e.g., PI3Kα allosteric pocket 2), and the disclosed inhibitor combinations can bind to both PI3Kα orthosteric pockets simultaneously. In some aspects, the PI3Kα inhibitors used in the disclosed methods can competitively bind to PI3Kα. In some aspects, the disclosed inhibitor combinations competitively bind to one or more allopockets (e.g., PI3Kα allopocket 1 and / or PI3Kα allopocket 2). In some aspects, PI3Kα selective inhibitors, which may include PI3Kα selective isosteric inhibitors and PI3Kα selective orthosteric inhibitors, can inhibit the activity of PI3Kα, such as the phosphorylation activity of PI3Kα. Phosphorylation activity can be assayed by methods including those disclosed herein. In some aspects, the PI3Kα 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. 50In some aspects, the PI3Kα selective inhibitors disclosed herein have an EC 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 PI3Kα substrate such as p-AKT, p-S6, or FOXM1). 50 In some embodiments, PI3Kα selective inhibitors, which may include PI3Kα selective isosteric inhibitors and PI3Kα selective orthosteric inhibitors, can inhibit the growth of cancer cells whose growth depends on PI3Kα activity. Growth inhibition can be analyzed using methods including those disclosed herein, including using a cell titer glow reagent (CTG). In some aspects, the PI3Kα selective inhibitors disclosed herein have an EC of less than about 100 nM, 50 nM, 10 nM, or 1 nM in a growth inhibition assay. 50 . In some aspects, the disclosed subject matter relates to methods of using multiple PI3Kα inhibitors or combinations of PI3Kα inhibitors for treating diseases and conditions associated with PI3Kα regulation. As used herein, the term "multiple PI3Kα inhibitors" or "combination of PI3Kα inhibitors" should be interpreted to mean "two or more different PI3Kα inhibitors." Multiple PI3Kα inhibitors can inhibit PI3Kα by binding at or near the same PI3Kα pocket (e.g., at or near an allosteric pocket of PI3Kα), or multiple PI3Kα inhibitors can inhibit PI3Kα by binding at or near different pockets of PI3Kα (e.g., one inhibitor binds at or near an allosteric pocket of PI3Kα and another inhibitor binds at or near an orthosteric pocket of PI3Kα, or one inhibitor binds at or near an allosteric pocket of PI3Kα and another inhibitor binds at or near a different allosteric pocket of PI3Kα). The disclosed methods may include administering a PI3Kα selective inhibitor. A PI3Kα selective inhibitor may be defined as a PI3Kα inhibitor that has greater inhibitory activity against PI3Kα than against one or more of PI3Kβ, PI3Kγ, and PI3Kδ. In some aspects, the PI3Kα selective inhibitor has an IC of 0.001 for PI3Kα in a phosphorylation assay. 50 Value or EC 50 The value may be less than the IC value of one or more of PI3Kβ, PI3Kγ and PI3Kδ in the phosphorylation assay. 50 Value or EC 50 Used to determine the IC values ​​of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ 50 Suitable phosphorylation assays for PI3Kα values ​​may include, but are not limited to, in vitro biochemical phosphorylation assays or cell-based phosphorylation assays. In some aspects, a PI3Kα selective inhibitor has an IC value of less than about 100 nM, 50 nM, 10 nM, or 1 nM for PI3Kα in a phosphorylation assay. 50 Value or EC 50 In some aspects, the PI3Kα selective inhibitor has an IC greater than about 100 nM, 200 nM, 500 nM, or 1000 nM for one or more of PI3Kβ, PI3Kγ, and PI3Kδ in a phosphorylation assay. 50 Value or EC 50 In some aspects, a PI3Kα selective inhibitor has an IC of 50 Value or EC 50 The values ​​are respectively greater than the IC values ​​of one or more of PI3Kβ, PI3Kγ and PI3Kδ in the phosphorylation assay. 50 Value or EC 50 The value is at least 5×, 10×, 20×, 30×, 40×, 50×, 100×, 500×, or 1000× less. The disclosed PI3Kα selective inhibitors can exhibit selectivity for mutant forms of PI3Kα relative to the wild-type form of PI3Kα. In some aspects, the disclosed PI3Kα selective inhibitors can exhibit selectivity for the H1047R mutant PI3Kα relative to the wild-type PI3Kα. In some aspects, the PI3Kα selective inhibitors have an IC of 0.001 for the H1047R mutant PI3Kα in a phosphorylation assay. 50 Value or EC 50 The values ​​were less than the IC of wild-type PI3Kα in phosphorylation assay. 50 Value or EC 50In some aspects, the PI3Kα selective inhibitor has an IC value of less than about 100 nM, 50 nM, 10 nM, or 1 nM against H1047R mutant PI3Kα in a phosphorylation assay. 50 Value or EC 50 In some aspects, the PI3Kα selective inhibitor has an IC greater than about 100 nM, 200 nM, 500 nM, or 1000 nM against wild-type PI3Kα in a phosphorylation assay. 50 Value or EC 50 In some aspects, the PI3Kα selective inhibitor has an IC of 0.001 for H1047R mutant PI3Kα in a phosphorylation assay. 50 Value or EC 50 The IC value of wild-type PI3Kα in phosphorylation assay was 50 Value or EC 50 The value is at least 5×, 10×, 20×, 30×, 40×, 50×, 100×, 500× or 1000× smaller. Used to determine the IC value of H1047R mutant PI3Kα relative to wild-type PI3Kα 50 Value or EC 50 Suitable phosphorylation assays for the expression of phosphorylation proteins may include, but are not limited to, in vitro biochemical phosphorylation assays or cell-based phosphorylation assays. The methods disclosed herein may recite a "first PI3Kα selective inhibitor" and a "second PI3Kα selective inhibitor." This should not be construed as requiring that the first PI3Kα selective inhibitor be administered before (e.g., sequentially) the second PI3Kα selective inhibitor in the disclosed methods. In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor 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, or more than 1, 2, 3, or 4 weeks, or more than 1, 2, 3, or 4 months), or sequentially (e.g., wherein the first PI3Kα selective inhibitor is administered before the second PI3Kα selective inhibitor, or wherein the second PI3Kα selective inhibitor is administered before the first PI3Kα selective inhibitor). In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor can be administered by the same person. In some aspects, a caregiver (e.g., the patient's physician or a non-physician caregiver of the patient) administers both the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor to the patient. In some aspects, the patient administers both the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor to themselves. In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor can be administered by separate persons. In some aspects, a caregiver administers one of the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor, and a different caregiver administers the other of the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor. In some aspects, a caregiver administers one of the first and second PI3K alpha selective inhibitors to the patient, and the patient administers the other of the first and second PI3K alpha selective inhibitors to themselves. In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα selective inhibitor can effectively reduce PI3Kα activity in a patient without inducing adverse events, or while minimizing the risk of adverse events. Adverse events may include, but are not limited to, hyperglycemia, which can be defined as a fasting blood glucose level greater than about 100, 105, 110, 115, 120, or 125 mg / dL (e.g., after at least 8 hours without food), or a blood glucose level greater than about 155, 160, 165, 170, 175, or 180 mg / dL one to two hours after a meal. Adverse events may include, but are not limited to, hyperinsulinemia, diarrhea, dehydration, rash, lymphopenia, increased alanine aminotransferase, fatigue, anemia, increased serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemia, alopecia, prolonged activated partial thromboplastin time, kidney disease with decreased glomerular filtration rate (GFR), acute abdominal pain, and abnormal liver function tests. In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα selective inhibitor is administered to a patient in need thereof, and the PI3Kα selective inhibitor acts as an allosteric inhibitor. In some aspects, the therapeutically effective amount of the PI3Kα selective allosteric inhibitor administered to the patient is 100 to 1200 mg orally (e.g., twice daily). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9 to 75 mg / kg orally (e.g., 37.5 mg / kg orally BID). The PI3Kα selective site inhibitors disclosed herein, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents and their respective pharmaceutically acceptable salts are generally effective over a wide dosage range. It should be understood that the actual amount of compound administered will be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 200 mg to 2400 mg. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 400 mg to 2000 mg. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 600 mg to 1200 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 200 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 300 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 400 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 500 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 600 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 700 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 800 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 900 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1000 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1100 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1200 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1300 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1400 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1500 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1600 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1700 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1800 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1900 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2000 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2100 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2200 mg.In one embodiment, the PI3Kα site-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2300 mg. In one embodiment, the PI3Kα site-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2400 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 200 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 300 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 400 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 500 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 600 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 700 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 800 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 900 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1000 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1100 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1200 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1300 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1400 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1500 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1600 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1700 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1800 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1900 mg over a 28-day cycle. In one embodiment, the PI3Kα site-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2000 mg over a 28-day cycle.In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2100 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2200 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2300 mg over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2400 mg over a 28-day cycle. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg to 1200 mg twice a day. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg to 1000 mg twice a day. In one embodiment, the PI3Kα selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg to 600 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 150 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 250 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 350 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 400 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 450 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 500 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 550 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 600 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 650 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 700 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 750 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 800 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 850 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 900 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 950 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily.In one embodiment, the PI3Kα site-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1150 mg twice a day. In one embodiment, the PI3Kα site-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice a day. In one embodiment, the PI3Kα sex-selective inhibitor or a 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 PI3Kα sex-selective inhibitor or a 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 PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 100 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 200 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 150 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily in a 28-day cycle at a dose of 200 mg. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 250 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 350 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 400 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 450 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 500 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 550 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 600 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 650 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 700 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 750 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 800 mg twice daily over a 28-day cycle.In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 850 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 900 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 950 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily over a 28-day cycle. In one embodiment, the PI3Kα selective site inhibitor or a pharmaceutical salt thereof is administered at a dose of 1150 mg twice a day in a 28-day cycle. In one embodiment, the PI3Kα selective site inhibitor or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice a day in a 28-day cycle. In a preferred embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily at a dose of 200 mg over a 28-day cycle. In another preferred embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily at a dose of 400 mg over a 28-day cycle. In another preferred embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily at a dose of 600 mg over a 28-day cycle. In another preferred embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily at a dose of 800 mg over a 28-day cycle. In another preferred embodiment, the PI3Kα sex-selective inhibitor or a pharmaceutical salt thereof is administered twice daily at a dose of 1000 mg over a 28-day cycle. In some aspects, the therapeutically effective amount of the PI3Kα selective inhibitor administered to the patient is 9, 15, 20, 25, 30, 35, 37.5, 40, 45, 50, 55, 60, 65, 70, or 75 mg / kg oral dose (e.g., QD or BID), or a dose within a range defined by any of these values. In some aspects, the therapeutically effective amount of the PI3Kα selective inhibitor administered to the patient is 9 to 75 mg / kg oral dose (e.g., 37.5 mg / kg QD or BID). In some aspects, the therapeutically effective amount of the PI3Kα selective inhibitor administered to the patient is less than about 75, 70, 65, 60, 55, 50, 45, 40, 37.5, 35, 30, 25, 20, 15, 9, 8, 7, 6, or 5 mg / kg oral dose (e.g., QD or BID). In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα selective inhibitor is administered to a patient in need thereof, and the PI3Kα selective inhibitor acts as an orthosteric inhibitor. In some aspects, the therapeutically effective amount of the PI3Kα selective orthosteric inhibitor administered to the patient is 300 mg orally QD (i.e., once a day) or less than about 300 mg orally QD, such as less than about 250, 200, 150, 100, or 50 mg QD. In some aspects, a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor administered to a patient is 50 mg / kg oral dose QD (i.e., administered once a day) or less than about 50 mg / kg oral dose QD, such as less than about 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, for example, when the PI3Kα selective orthosteric inhibitor is administered together, simultaneously, separately, or sequentially with a PI3Kα selective allosteric inhibitor (e.g., a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosite pocket 1 or PI3Kα allosite pocket 2). The disclosed methods may be directed to treating a patient suffering from a disease or condition that is resistant to treatment with a PI3Kα selective inhibitor. Resistance may include "acquired resistance," where the patient has a disease or condition that has developed resistance to treatment with a PI3Kα selective inhibitor after prior treatment with the PI3Kα selective inhibitor. Resistance may also include "de novo resistance," where the patient has a disease or condition that is resistant to treatment with a PI3Kα selective inhibitor and has not previously been treated with a PI3Kα selective inhibitor. The disclosed methods may be directed to patients with a disease or condition that is resistant to a PI3Kα selective inhibitor. Acquired resistance can be characterized in vitro by methods including, but not limited to, growth inhibition of ECs. 50changes in phosphorylation inhibition, such as by Western blot and quantification of phosphorylation bands, or by determining IC in a phosphorylation assay. 50 Values ​​analyzed; and stability of the cell population under non-selective conditions. Acquired resistance can be characterized in vivo or clinically by observing relapse in a patient after the patient has been treated with a PI3Kα selective inhibitor and the patient previously exhibited remission. For a patient with cancer, acquired resistance can be clinically characterized by observing relapse after the patient has been observed to have been in remission when the patient was previously treated with a PI3Kα selective inhibitor. For a patient with cancer, acquired resistance can be clinically characterized by observing increased cancer growth after a decrease in cancer growth has been observed after previous treatment with a PI3Kα selective inhibitor. For a patient with cancer, acquired resistance can be clinically characterized by observing recurrence of cancer in a part of the patient's body that is different from the part of the patient's body where the cancer was first observed before treatment with the PI3Kα selective inhibitor. In the disclosed methods, a therapeutically effective amount of one or more PI3Kα selective inhibitors may be administered to the patient, which may include a combination of allosteric inhibitors and / or orthosteric inhibitors. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of another therapeutic agent. In some aspects of the disclosed methods, a therapeutically effective amount of a selective estrogen receptor degrader (SERD) is further administered to the patient. Suitable SERDs may include, but are not limited to, imlunestrant, fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502. In some aspects of the disclosed methods, the therapeutically effective amount of the SERD is a dose of 500 mg, which may be administered on day 1, day 15, and day 29 or in the treatment regimen. In the disclosed methods, patients in need may suffer from cancer. In some aspects, patients in need may suffer from breast cancer. In some aspects, patients in need may suffer from PIK3CA mutant advanced or metastatic breast cancer. PIK3CA mutant cancers may include cancers with one or more mutations selected from (but not limited to) E542K, E545K, E453Q / K, E726K, C901F, M1043I / L and H1047R, optionally one or more of which are cis (i.e., on the same allele). In some aspects, patients in need may suffer from PIK3CACA H1047R mutant advanced or metastatic breast cancer, i.e., estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-). In some aspects of the disclosed methods, the patient in need thereof is a postmenopausal female. In some aspects of the disclosed methods, the patient has type 2 diabetes. I . A . Used for Treatment and PI3K Inositol phosphates that regulate related diseases and conditions 3 - Kinase ( PI3K ) Use of a combination of allosteric and orthosteric inhibitors In some aspects, the disclosed methods relate to methods for treating diseases or conditions associated with the regulation of PI3Kα. The methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to the PI3Kα allosteric pocket 1 and, optionally, interacts 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, wherein the second PI3Kα selective inhibitor binds to the PI3Kα orthosteric pocket. The disclosed methods may comprise administering a first PI3Kα selective inhibitor that is a PI3Kα selective allosteric inhibitor and a second PI3Kα selective inhibitor that is a PI3Kα selective orthosteric inhibitor. In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor can be administered simultaneously, separately, or sequentially. In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ;or ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. The second PI3Kα selective inhibitor used in the disclosed methods binds to the PI3Kα orthosteric pocket and can act as an orthosteric inhibitor. In some aspects, the orthosteric inhibitor is apoxib or a pharmaceutically acceptable salt thereof. In some aspects, the orthosteric inhibitor is invoxib or a pharmaceutically acceptable salt thereof. In some aspects, the orthosteric inhibitor is celecoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a therapeutically effective amount of a first PI3Kα selective inhibitor is administered to a patient in need thereof, and the first PI3Kα selective inhibitor acts as an allosteric inhibitor. In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is 100 to 1200 mg orally twice daily (i.e., twice daily). In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is 9 to 75 mg / kg orally twice daily (e.g., 37.5 mg / kg or less than about 37 mg / kg). In some aspects of the disclosed methods, a therapeutically effective amount of a second PI3Kα selective inhibitor is administered to a patient in need thereof, and the PI3Kα selective inhibitor acts as an orthosteric inhibitor. In some aspects, the therapeutically effective amount of the orthosteric inhibitor administered to the patient is 300 mg orally QD (i.e., once a day) or less than about 300 mg orally QD. In some aspects of the disclosed methods, a synergistic effect can be observed following administration of 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 can be less than the therapeutically effective amount of the allosteric inhibitor required in a treatment method in which the orthosteric inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the orthosteric inhibitor administered to a patient can be less than the therapeutically effective amount of the orthosteric inhibitor required in a treatment method in which the allosteric inhibitor is not administered. In some aspects of the disclosed methods, a therapeutically effective amount of an allosteric inhibitor is effective to reduce PI3Kα activity in a patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, a therapeutically effective amount of an orthosteric inhibitor is effective to reduce PI3Kα activity in a patient without inducing adverse events, or while minimizing the risk of adverse events. In some aspects of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously, separately, or sequentially. In some aspects of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously or substantially simultaneously. In some aspects of the disclosed methods, the dose of the orthosteric inhibitor administered to the patient is less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, optionally wherein the orthosteric inhibitor is apecoxib. In the disclosed methods, a first PI3Kα selective inhibitor and a second PI3Kα selective inhibitor can be administered sequentially. In some aspects, the method comprises administering the second PI3Kα selective inhibitor after the disease or condition has developed resistance to the first PI3Kα selective inhibitor. In some aspects, the second PI3Kα selective inhibitor is initially administered after the disease or condition has developed resistance to the first PI3Kα selective inhibitor. In some aspects, the second PI3Kα selective inhibitor is not administered until after the disease or condition has developed resistance to the first PI3Kα selective inhibitor. In some aspects, resistance is characterized by the presence of an M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). Patients exhibiting resistance may have a disease or disorder comprising an M1043I / L mutation and / or a C901F mutation and an H1047R mutation (optionally wherein the M1043I / L mutation and the C901F mutation are in cis with the H1047R mutation on the same allele). I . B . Used for Treatment and PI3K Inositol phosphates that regulate related diseases and conditions 3 - Kinase ( PI3K ) Use of a combination of a first allostatic inhibitor and a second allostatic inhibitor , The first allosteric inhibitor and the second allosteric inhibitor bind to different allosteric sites bag point In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with modulation of PI3Kα in a patient in need thereof. The methods can comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1 and optionally interacts 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, wherein the second PI3Kα selective inhibitor binds to a different allosite pocket of PI3Kα, such as PI3Kα allosite pocket 2, and optionally interacts with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. The disclosed methods can comprise administering a PI3Kα-selective allosteric inhibitor (i.e., a first allosteric inhibitor) and a different PI3Kα-selective allosteric inhibitor (i.e., a second allosteric inhibitor), wherein the first allosteric inhibitor and the second allosteric inhibitor bind to different allosteric pockets (e.g., PI3Kα allosteric pocket 1 and PI3Kα allosteric pocket 2, respectively), and the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially. In the disclosed methods, the first PI3Kα selective inhibitor can be an allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ;or ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor having the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757 or WO2023 / 081759, the contents of which are incorporated herein by reference in their entirety regarding the disclosed PI3Kα inhibitor compounds and methods of preparing and using PI3Kα inhibitor compounds. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor having Formula IV: IV 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R ETwo examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC n instances of R Q and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -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 For R 1C r 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R A or R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubanyl; 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (where C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen substituents), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1-6 Aliphatic group (where C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor having Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor having the formula: or a pharmaceutically acceptable salt thereof. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 1 for . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2Aor -C(H)(CH 3)OH. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 Instances replaced. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA for 、 、 、 、 、 、 、 、 or . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: , or a pharmaceutically acceptable salt thereof. In the disclosed methods, a therapeutically effective amount of a first PI3Kα selective inhibitor is administered to a patient in need thereof, and the first PI3Kα selective inhibitor acts as an allosteric inhibitor (i.e., a first allosteric inhibitor). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 100 to 1200 mg orally dosed BID (i.e., administered twice daily). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9 to 75 mg / kg orally dosed BID (e.g., 37.5 mg / kg). In some aspects of the disclosed methods comprising administering a therapeutically effective amount of a first allo-inhibitor and a therapeutically effective amount of a second allo-inhibitor, a synergistic effect may be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first allo-inhibitor administered to a patient may be less than the therapeutically effective amount of the first allo-inhibitor required in a method in which the second allo-inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the second allo-inhibitor administered to a patient may be less than the therapeutically effective amount of the second allo-inhibitor required in a method in which the first allo-inhibitor is not administered. In some aspects of the disclosed methods, a therapeutically effective amount of a first allosteric inhibitor is effective to reduce PI3Kα activity in a patient without inducing an adverse event, or while minimizing the risk of an adverse event. In some aspects of the disclosed methods, a therapeutically effective amount of a second allosteric inhibitor is effective to reduce PI3Kα activity in a patient without inducing an adverse event, or while minimizing the risk of an adverse event. In the disclosed methods, the first allo-inhibitor and the second allo-inhibitor can be administered sequentially. In some aspects, the method comprises administering the second allo-inhibitor after the disease or disorder has developed resistance to the first allo-inhibitor. In some aspects, the second allo-inhibitor is initially administered after the disease or disorder has developed resistance to the first allo-inhibitor. In some aspects, the second allo-inhibitor is not administered until the disease or disorder has developed resistance to the first allo-inhibitor. In some aspects, resistance is characterized by the presence of an M1043 mutation (e.g., M1043I or M1043L) and / or a C901 mutation (e.g., C901F). In some aspects, the patient suffers from a disease or disorder comprising an M1043I / L mutation and / or a C901F mutation and an H1047R mutation (optionally wherein the M1043I / L mutation and the C901F mutation are in cis with the H1047R mutation on the same allele). I . C . Used for Treatment and PI3K Inositol phosphates that regulate related diseases and conditions 3 - Kinase ( PI3K ) Use of a combination of a first allostatic inhibitor and a second allostatic inhibitor , wherein the first allosteric inhibitor and the second allosteric inhibitor bind to the same allosteric bag point The disclosed methods may relate to methods for treating a disease or condition associated with regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof. The methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1 and can 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 PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor binds to PI3Kα allosite pocket 1 and can interact with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The disclosed methods can comprise administering a PI3Kα-selective allosteric inhibitor (e.g., a first allosteric inhibitor) and a different PI3Kα-selective allosteric inhibitor (e.g., a second allosteric inhibitor), wherein the PI3Kα-selective allosteric inhibitor binds to the PI3Kα allosteric pocket 1. In the disclosed methods, the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially. In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the first allosteric inhibitor having Formula I is different from the second allosteric inhibitor having Formula I. In some aspects of the disclosed methods, the first allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor does not have the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor having the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second allosteric inhibitor has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. In the disclosed methods, a therapeutically effective amount of a first PI3Kα selective inhibitor is administered to a patient in need thereof, and the first PI3Kα selective inhibitor acts as an allosteric inhibitor. In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 100 to 1200 mg orally twice daily (i.e., twice daily). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9 to 75 mg / kg orally twice daily (e.g., 37.5 mg / kg). In the disclosed methods, the first allo-inhibitor and the second allo-inhibitor can be administered sequentially. In some aspects, the method includes administering the second allo-inhibitor after the disease or condition has developed resistance to the first allo-inhibitor. In some aspects, the second allo-inhibitor is initially administered after the disease or condition has developed resistance to the first allo-inhibitor. In some aspects, the second allo-inhibitor is not administered until the disease or condition has developed resistance to the first allo-inhibitor. In some aspects, resistance is characterized by the presence 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 condition comprising an M1043I / L mutation and / or a C901F mutation and an H1047R mutation (optionally wherein the M1043I / L mutation and the C901F mutation are in cis with the H1047R mutation on the same allele). I . D ( i ). Used for Use of allosteric inhibitors to treat diseases or conditions resistant to treatment with orthosteric inhibitors In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with the regulation of PI3Kα that is resistant to treatment with a PI3Kα-selective orthosteric inhibitor. The methods may comprise administering to a patient suffering from the disease or condition a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor, wherein the PI3Kα-selective orthosteric inhibitor binds to PI3Kα allotopic pocket 1 and optionally interacts 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 disease or condition that has developed resistance to treatment with an orthosteric inhibitor after the patient was previously treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has developed de novo resistance to treatment with an orthosteric inhibitor, wherein the patient has not been previously treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with apoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with invoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with celecoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the allosteric inhibitor does not have the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. The disclosed methods may include administering to a patient a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor, wherein the patient has a disease or condition resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). I . D ( ii ). Use of other allosteric inhibitors for treating diseases or conditions resistant to orthosteric inhibitors In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with the regulation of PI3Kα that is resistant to treatment with a PI3Kα-selective orthosteric inhibitor. The methods may comprise administering to a patient suffering from the disease or condition a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor that binds to PI3Kα allotopic pocket 2 and, optionally, forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant to treatment with an orthosteric inhibitor following previous treatment of the patient with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has developed de novo resistance to treatment with an orthosteric inhibitor, wherein the patient has not been previously treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with apoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with invoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with celecoxib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor is an allosteric inhibitor disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757 or WO2023 / 081759, the contents of which are incorporated herein by reference in their entirety regarding the disclosed PI3Kα inhibitor compounds and methods for preparing and using PI3Kα inhibitor compounds. In some aspects of the disclosed methods, the allosteric inhibitor has Formula IV: IV 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R E Two examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC Replace n instances of R Q and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -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 For R 1C r 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R A or R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubic alkyl; adamantyl; a 5-membered to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-membered to 7-membered saturated or partially unsaturated monocyclic heteroaryl ring; Cyclic carbon ring; 5- to 12-membered saturated or partially unsaturated bicyclic carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects, the allosteric inhibitor has the formula, wherein R 1 for . In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the allosteric inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2A or -C(H)(CH 3)OH. In some aspects, the allosteric inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 In some aspects, the allosteric inhibitor has the formula, wherein R YA for 、 、 、 、 、 、 、 、 or . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YCEach example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from: In some aspects of the disclosed methods, the second PI3Kα selective inhibitor has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: , or a pharmaceutically acceptable salt thereof. The disclosed methods may include administering to a patient a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor, wherein the patient has a disease or condition resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). I . D ( iii ) Use of an allosteric inhibitor for treating a disease or condition resistant to another allosteric inhibitor In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with the regulation of PI3Kα that is resistant to treatment with a first PI3Kα-selective inhibitor, wherein the first PI3Kα-selective inhibitor binds to PI3Kα allosite pocket 1 and optionally interacts with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The methods may comprise administering to a patient suffering from the disease or disorder a therapeutically effective amount of a second, different, PI3Kα-selective inhibitor, wherein the second, different, PI3Kα-selective inhibitor binds to PI3Kα allosite pocket 1 and optionally interacts 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 disease or condition that has developed resistance to treatment with the first allostatic inhibitor after the patient was previously treated with the first allostatic inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has developed de novo resistance to treatment with the first allostatic inhibitor, wherein the patient was not previously treated with the first allostatic inhibitor. In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with an allosteric inhibitor having the formula: , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a therapeutically effective amount of a second allosteric inhibitor having Formula I is administered to a patient resistant to treatment with a first allosteric inhibitor: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, an allosteric inhibitor is administered to a patient having the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. The disclosed methods may include administering a therapeutically effective amount of a PI3Kα-selective inhibitor to a patient suffering from a disease or condition that is resistant to treatment with a different PI3Kα-selective inhibitor. In some aspects, the disclosed methods further comprise administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient. I . D ( iv ) Use of an allosteric inhibitor for treating a disease or condition with acquired resistance to another allosteric inhibitor In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with the regulation of PI3Kα that is resistant to treatment with a first PI3Kα-selective inhibitor, wherein the first PI3Kα-selective inhibitor binds to PI3Kα allotopic pocket 1 and optionally interacts with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The methods may comprise administering to a patient suffering from the disease or disorder a therapeutically effective amount of a second, different, PI3Kα-selective inhibitor that binds to PI3Kα allotopic pocket 2 and optionally interacts with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. In some aspects of the disclosed methods, the patient has a disease or condition that has developed resistance to treatment with the first allostatic inhibitor after the patient was previously treated with the first allostatic inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has developed de novo resistance to treatment with the first allostatic inhibitor, wherein the patient was not previously treated with the first allostatic inhibitor. In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with an allosteric inhibitor having the formula: , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a second allosteric inhibitor as disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, which are incorporated herein by reference in their entirety for the disclosed PI3Kα inhibitor compounds and methods of making and using PI3Kα inhibitor compounds, is administered to a patient resistant to treatment with a first allosteric inhibitor. In some aspects of the disclosed methods, the second allosteric inhibitor has Formula IV: IV 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R ETwo examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC Replace n instances of R Q and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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-divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3-6 Cycloalkyl, C 3-6Heterocycloalkyl, -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 For R 1C r 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R Aor R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubanyl; 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 carbocycle; a 5- to 12-membered saturated or partially unsaturated bicyclic carbocycle; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects, the allosteric inhibitor has the formula, wherein R 1 for . In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 1CEach instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the allosteric inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2A or -C(H)(CH 3)OH. In some aspects, the allosteric inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 Instances replaced. In some aspects, the allosteric inhibitor has the formula, wherein R YA for 、 、 、 、 、 、 、 、 or . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from: 、 、 and , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: , or a pharmaceutically acceptable salt thereof. The disclosed methods may include administering a therapeutically effective amount of a PI3Kα site-selective inhibitor to a patient suffering from a disease or condition that is resistant to treatment with another PI3Kα site-selective inhibitor. In some aspects, the disclosed methods further comprise administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient. I . E . For treatment M1043I / L + H1047R Orthosteric inhibitors of cancer In some aspects, the disclosed methods relate to treating a disease or disorder associated with the regulation of PI3Kα 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) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation) after the patient has been previously treated with a therapeutically effective amount of a PI3Kα-selective allosteric inhibitor. In the disclosed methods, the PI3Kα-selective allosteric inhibitor can bind to PI3Kα allosteric pocket 1 and can 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 PI3Kα selective orthosteric inhibitor, or the patient may have a cancer that exhibits de novo resistance to treatment with a PI3Kα selective orthosteric inhibitor; and in the disclosed methods, the patient may be administered a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor. In some aspects of the disclosed methods, the patient was previously treated with a PI3Kα site-selective inhibitor having Formula I: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ;or ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the patient was previously treated with a therapeutically effective amount of a PI3Kα site-selective inhibitor having the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα site-selective inhibitor is administered to a patient in an oral dose of 100 to 1200 mg twice daily. In some aspects of the disclosed methods, a therapeutically effective amount of a first PI3Kα site-selective inhibitor is administered to a patient in an oral dose of 9 to 75 mg / kg twice daily (e.g., 37.5 mg / kg twice daily). In the disclosed methods, the patient may have acquired resistance to treatment with the PI3Kα site-selective inhibitor administered at a given dose. In the disclosed methods, a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor is administered to a patient in need thereof. In some aspects, the therapeutically effective amount of the PI3Kα selective orthosteric inhibitor administered to the patient is 300 mg orally QD (i.e., administered once a day) or less than about 300 mg orally QD, such as less than about 250, 200, 150, 100, or 50 mg orally QD. In some aspects, the disclosed methods comprise administering to a patient a therapeutically effective amount of a selective orthosteric inhibitor of PI3Kα, and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, the administered PI3Kα selective orthosteric inhibitor is selected from apoxib, invoxib, celecoxib, or a pharmaceutically acceptable salt thereof. I . F ( i ). For treatment M1043I / L + H1047R Allosteric inhibitors of cancer In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with the regulation of PI3Kα in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L, optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation). The methods comprise administering to the patient a therapeutically effective amount of a PI3Kα-selective allodomain inhibitor that binds to PI3Kα allodomain pocket 2 and optionally interacts with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. In some aspects, the PI3Kα site-selective inhibitor administered to the patient has Formula IV: IV 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R E Two examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC n instances of R Q and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -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 For R 1C r 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R A or R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubanyl; 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects, the allosteric inhibitor has the formula, wherein R 1 for . In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the allosteric inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2A or -C(H)(CH 3)OH. In some aspects, the allosteric inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 Instances replaced. In some aspects, the allosteric inhibitor has the formula, wherein R YA for 、 、 、 、 、 、 、 、 or . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. In some aspects of the disclosed methods, a PI3Kα site-selective inhibitor is administered to the patient having a formula selected from the group consisting of: 、 、 and , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the patient has a cancer that has acquired 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) after the patient was previously treated with a therapeutically effective amount of a first PI3Kα selective site-specific inhibitor that binds to PI3Kα pocket 1 and can form interactions 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 PI3Kα selective site-selective inhibitor that binds to PI3Kα pocket 1 and can interact 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 that has acquired the M1043I / L mutation (optionally in cis with the H1047R mutation) after the patient was previously treated with a therapeutically effective amount of a first PI3Kα selective site inhibitor having Formula I. I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ;or ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα site-selective inhibitor of Formula I administered to a patient is 100 to 1200 mg orally, administered twice daily. In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα site-selective inhibitor of Formula I administered to a patient is 9 to 75 mg / kg orally, administered twice daily (e.g., 37.5 mg / kg orally, administered twice daily). In the disclosed methods, the patient may have a cancer that has acquired resistance after administration of a specified dose of the PI3Kα site-selective inhibitor to the patient. In some aspects of the disclosed methods, the patient was previously treated with a therapeutically effective amount of a PI3Kα selective inhibitor having the formula: or a pharmaceutically acceptable salt thereof. 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, the patient in need thereof may have advanced or metastatic breast cancer that is estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-). In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Kα site-selective inhibitor, and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). I . F ( ii ). For treatment M1043I / L + H1047R Other allogeneic inhibitors of cancer In some aspects, the disclosed methods relate to methods for treating a disease or disorder associated with the regulation of PI3Kα in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L, optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation). The methods comprise administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor that binds to PI3Kα pocket 1 and can interact 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, a PI3Kα site-selective inhibitor having Formula I is administered to the patient: I or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; ; ; ; ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the PI3Kα site-selective inhibitor administered to the patient does not have the formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a PI3Kα selective site inhibitor having Formula I is administered to a patient having the following formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a PI3Kα site-selective inhibitor having Formula I is administered to the patient and is selected from: , or a pharmaceutically acceptable salt thereof. In the disclosed methods, the patient may have a cancer comprising mutations M1043I / L (optionally in cis with the H1047R mutation) and / or a 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, the patient in need thereof may have advanced or metastatic breast cancer that is estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-). In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Kα site-selective inhibitor, and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). I . G . Suffering from M1043X + H1047R Cancer or C901X + H1047R Diagnosis and treatment of cancer patients In some aspects, the method relates to a method for treating a disease or disorder associated with the regulation of PI3Kα in a patient in need thereof, such as a patient having a cancer comprising an M1043 mutation (e.g., M1043I / L, optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation). The method can comprise determining that 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), for example, by arranging or performing a genomic analysis that identifies mutations (e.g., M1043I / L, optionally in cis with an H1047R mutation) in the patient's cancer. Suitable genomic analysis may include one or more steps, such as: arranging a genomic analysis to identify M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis); performing PCR amplification on alleles comprising M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis); sequencing alleles comprising M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis); probing alleles comprising M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis); identifying or detecting alleles comprising M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis); and determining that the patient has a cancer comprising M1043 mutations, C901 mutations, and / or H1047R mutations (optionally in cis). After the patient has been determined to 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), the method may further comprise administering to the patient a treatment, which may comprise administering to the patient one or more PI3Kα selective inhibitors. In some aspects of the disclosed methods, if the patient has a cancer comprising an M1043 mutation (e.g., 1043I / L, optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with an H1047R mutation), the method may comprise administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor. In some aspects, the PI3Kα selective inhibitor does not have the formula: or a pharmaceutically acceptable salt thereof. 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 the H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with the H1047R mutation), the method may comprise administering to the patient a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor. In some aspects, the PI3Kα selective orthosteric inhibitor is selected from apoxib, invoxib, celecoxib, or a pharmaceutically acceptable salt thereof. 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 PI3Kα selective inhibitor, wherein the PI3Kα selective inhibitor binds to PI3Kα allotopic pocket 2 and can interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. In some aspects, the PI3Kα selective allotopic inhibitor is a compound disclosed in WO2021 / 222556 (e.g., any one of compounds I-1 to I-2704 in Table 1, pages 162 to 855). In some aspects, the PI3Kα site-selective inhibitor is a compound disclosed in WO2022 / 265993, Tables A to D, pages 175 to 259. In some aspects of the disclosed methods, a PI3Kα-selective inhibitor having Formula IV is administered to the patient: 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R E Two examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC n instances of R Q and R 1Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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-divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -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 For R 1Cr 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R A or R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubanyl; 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the allosteric inhibitor has the formula: or a pharmaceutically acceptable salt thereof. In some aspects, the allosteric inhibitor has the formula, wherein R 1 for . In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the allosteric inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2A or -C(H)(CH 3)OH. In some aspects, the allosteric inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1 to 3 halogens 1 - 3 aliphatic groups. In some aspects, the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 Instances replaced. In some aspects, the allosteric inhibitor has the formula, wherein R YA for . In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. In some aspects of the disclosed methods, a PI3Kα site-selective inhibitor is administered to the patient having a formula selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from: , or a pharmaceutically acceptable salt thereof. 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 PI3Kα selective inhibitor that binds to PI3Kα allosite pocket 1 and can interact 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, a PI3Kα site-selective inhibitor having Formula I is administered to the patient: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In some aspects of the disclosed methods, the PI3Kα selective site inhibitor having Formula I has the following formula: or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, a PI3Kα site-selective inhibitor having Formula I is administered to the patient and is selected from: , or a pharmaceutically acceptable salt thereof. 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, the patient in need thereof may have advanced or metastatic breast cancer that is estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-). Compounds used in therapy In some aspects, the disclosed subject matter relates to a first PI3Kα-specific inhibitor that is used in combination with a second PI3Kα-specific inhibitor, either simultaneously, separately, or sequentially, for treating a disease or condition associated with the regulation of phosphatidylinositol 3-kinase α (PI3Kα). The disclosed compounds for use in treatment are further illustrated by the following examples. Example 1. A PI3Kα specific inhibitor compound having the following formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; -N(H)(C 1-C 3 alkyl); -N(C 1-C 3 alkyl) 2;-N(H)(CH 2CH 2CO 2H); -C(O)C 1-C 3 alkyl; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 1-C 6-hydroxyalkyl; C 3-C 5-cycloalkyl; an optionally substituted heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with one to three substituents each independently selected from halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-C(O)OC 1-C 3-alkyl; -CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; -OH; 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-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane, C 1-C 3-alkoxy or -CONR 11 R 11 Replaced; as the case may be, replaced C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl; which is used in combination simultaneously, separately or sequentially with a second PI3Kα specific inhibitor that is a PI3Kα specific orthosteric inhibitor for treating a disease or disorder associated with the regulation of phosphatidyl inositol 3-kinase alpha (PI3Kα). Example 2. The compound used in Example 1, wherein the second PI3Kα specific inhibitor is apecoxib or a pharmaceutically acceptable salt thereof. Example 3. The compound used in Example 1, wherein the second PI3Kα specific inhibitor is involucrib or a pharmaceutically acceptable salt thereof. Embodiment 4. The compound for use in any one of embodiments 1 to 3, wherein the dosage of the second PI3Kα specific inhibitor is a dosage of less than about 300 mg per day administered orally. Embodiment 5. The compound for use according to any one of embodiments 1 to 4, wherein the first PI3Kα specific inhibitor and the second PI3Kα specific inhibitor are administered simultaneously. Example 6. The compound for use in Example 5, wherein the dosage of the second PI3Kα specific inhibitor is less than about 50, 30, 12.5, 6.25 or 3.125 mg / kg administered orally per day. Example 7. A PI3Kα specific inhibitor compound having Formula I: or a pharmaceutically acceptable salt thereof, wherein R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R8 is as defined in Example 1; for use in combination simultaneously, separately or sequentially with a second PI3Kα specific inhibitor that binds to PI3Kα allosite pocket 2 for treating a disease or disorder associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα). Example 8. The compound for use in Example 7, wherein the second PI3Kα-specific inhibitor forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. Example 9. The compound for use in Example 7 or 8, wherein the second PI3Kα specific inhibitor has the following formula: 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 ; R 2 -L 2 -R 2A ; R E Each instance of is independently H or -L E -R EA ; R Q -L Q -R QA ; R X -L X -R XA ; R Y -L Y -R YA ; R Z -L Z -R ZA ; or R E Two examples of the present invention, taken together with their intervening atoms, form a 3- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is R EEC n instances of R Q and R 1 Together with its intervening atoms, it forms a 4- to 8-membered saturated or partially unsaturated monocyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C p instances of R Y and R Z Together with its intervening atoms, it forms a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is R YZC q instances of 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-divalent saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently substituted by: -CH(R L )-、-C(R L ) 2-、C 3 - 6-cycloalkylene, C 3 - 6-heterocycloalkyl, -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 For R 1C r 1 R A or R B ; R 2A For R 2C r 2 R A or R B ; R EA For R EC r 3 R A or R B ; R QA For R QC r 4 R A or R B ; R XA For R XC r 5 R A or R B ; R YA For R YC r 6 R A or R B ; R ZA For R ZC r 7 R A or R B ; R L For R LC r 8 R A or R B ; R A Each example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR or -B(OR) 2; R B Each instance of C is independently 1 - 6-membered aliphatic chain; phenyl; naphthyl; cubanyl; 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 example is independently a pendant oxygen group, deuterium, halogen, -CN, -NO 2. -OR, -SF5, -SR, -NR 2. -S(O) 2R, -S(O) 2NR 2. -S(O) 2F, -S(O)R, -S(O)NR 2. -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR 2. -N(R)S(O) 2NR 2. -N(R)S(O) 2R, -P(O)R 2. -P(O)(R)OR, -B(OR) 2, or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen or an optionally substituted group selected from the following: C 1 - 6 aliphatic groups (where C 1 - 6 aliphatic groups are optionally selected from C 1 - 3 alkyl, C 1 - substituted with 3 haloalkyl and halogen), phenyl, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen together with their intervening atoms form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each of which is independently 0, 1, 2, 3, 4 or 5. Embodiment 10. The compound for use in any one of embodiments 7 to 9, wherein the second PI3Kα selective inhibitor has the following formula: or a pharmaceutically acceptable salt thereof. Embodiment 11. The compound for use in any one of embodiments 7 to 10, wherein the second PI3Kα selective inhibitor has the following formula: or a pharmaceutically acceptable salt thereof. Example 12. The compound for use in any one of Examples 7 to 11, wherein the second PI3Kα selective inhibitor has the formula, wherein R 1 for . Example 13. The compound for use in any one of Examples 7 to 12, wherein the second PI3Kα selective inhibitor has the formula, wherein R 1C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. Example 14. The compound for use in any one of Examples 7 to 13, wherein the second PI3Kα selective inhibitor has the formula, wherein R 2 -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) 2CH 2-R 2A 、-CH 2S(O) 2-R 2A or -C(H)(CH 3)OH. Example 15. The compound for use in any one of Examples 7 to 14, wherein the second PI3Kα selective inhibitor has the formula, wherein R 2A At one or more locations, as appropriate, C 1 - 3. an aliphatic group (eg, methyl), a haloalkyl group (eg, trifluoromethyl or difluoromethyl), or a phenyl group substituted with halogen. Example 16. The compound for use in any one of Examples 7 to 15, wherein the second PI3Kα selective inhibitor has the formula, wherein R 2C Each example is independently halogen, -CN, -O-(C 1 - 6 aliphatic groups) or C 1 - 6 aliphatic groups; wherein each C 1 - 6. The aliphatic group is optionally substituted with one or more halogen atoms. Example 17. The compound for use in any one of Examples 7 to 16, wherein the second PI3Kα selective inhibitor has the formula, wherein 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 R YC r 6 Instances replaced. Example 18. The compound for use in any one of Examples 7 to 17, wherein the second PI3Kα selective inhibitor has the formula, wherein R YA for . Embodiment 19. The compound for use in any one of embodiments 7 to 18, wherein the second PI3Kα selective inhibitor has the formula wherein R YC Each example is independently a pendant oxy group, a halogen, -CN, -OH, -O-(C 1 - 3 aliphatic groups) or C 1 - 3 aliphatic groups, each of which C 1 - 3 The aliphatic group is optionally substituted by one or more halogen atoms. Example 20. The compound for use in Example 19, wherein the second PI3Kα selective inhibitor has a formula selected from the group consisting of: , or a pharmaceutically acceptable salt thereof, or a second PI3Kα selective inhibitor having a formula selected from the group consisting of: , or a pharmaceutically acceptable salt thereof Example 21. A PI3Kα specific inhibitor compound having Formula I: 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 technical solution 1; it is used in combination with a second PI3Kα specific inhibitor of Formula I or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for the treatment of diseases or disorders related to the regulation of phosphatidylinositol 3-kinase α (PI3Kα), wherein the first PI3Kα specific inhibitor and the second PI3Kα specific inhibitor are different compounds. Example 22. The compound for use in Example 21, wherein the second PI3Kα specific inhibitor does not have the following formula: . Example 23. The compound for use in Example 21 or 22, wherein the second PI3Kα specific inhibitor has the following formula: or a pharmaceutically acceptable salt thereof. Embodiment 24. The compound for use in any one of embodiments 21 to 23, wherein the second PI3Kα specific inhibitor has a formula selected from the following: , or a pharmaceutically acceptable salt thereof. Embodiment 25. The compound for use in any one of embodiments 1 to 24, wherein the therapeutically effective amount of the first PI3Kα specific inhibitor is effective in reducing PI3Kα activity in the patient without inducing hyperglycemia in the patient. Embodiment 26. The compound for use in any one of embodiments 1 to 25, wherein the therapeutically effective amount of the second PI3Kα specific inhibitor is effective in reducing PI3Kα activity in the patient without inducing hyperglycemia in the patient. Example 27. A PI3Kα specific inhibitor compound having Formula I: or a pharmaceutically acceptable salt thereof, wherein R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R8 is as defined in Example 1; for use in treating a disease or disorder associated with regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient who is resistant to treatment with apoxib or invoxib. Example 28. A PI3Kα-specific inhibitor that binds to an allosteric pocket of PI3Kα 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 regulation of phosphatidyl inositol 3-kinase alpha (PI3Kα) in a patient who is resistant to treatment with apoxib or invoxib. Example 29. The PI3Kα specific inhibitor used in Example 28, wherein the inhibitor is a compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein R 1. R 2. E, Q, X, Y, and Z are as defined in Example 9, or are PI3Kα-specific inhibitors as used in Example 28, wherein the inhibitor is a compound selected from the following formula: , or a pharmaceutically acceptable salt thereof. Example 30. A PI3Kα specific inhibitor as a PI3Kα specific orthosteric inhibitor for use in treating a disease or condition associated with the regulation of phosphatidylinositol 3-kinase α (PI3Kα), wherein the patient has previously been treated with a compound of formula I. or a pharmaceutically acceptable salt thereof, wherein R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R8 is as defined in Example 96, and the patient has a cancer that has acquired an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047R mutation. Example 31. A PI3Kα-specific inhibitor that binds to PI3Kα allosite pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018, for treating a disease or disorder associated with regulation of phosphatidyl inositol 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. Example 32. A PI3Kα specific inhibitor compound having Formula I: or a pharmaceutically acceptable salt thereof, wherein R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R8 is as defined in Example 1 for use in treating a disease or disorder related to 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. Example 33. A PI3Kα specific inhibitor compound having Formula I: or a pharmaceutically acceptable salt thereof, wherein R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R8 is as defined in Example 1 for use in treating a disease or disorder related to the regulation of phosphatidyl inositol 3-kinase alpha (PI3Kα) in a patient in need thereof, the treatment comprising analyzing a blood sample from the patient, determining whether 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 if an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation is present, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Example 34. A PI3Kα-specific inhibitor selected from apoxib and invoxib for use in treating a disease or disorder associated with regulation of phosphatidyl inositol 3-kinase alpha (PI3Kα) in a patient in need thereof, the treatment comprising analyzing a sample from the patient, determining whether the patient has a cancer comprising an M1043I / L mutation in cis with an H1047 mutation and / or a C901F mutation in cis with an H1047R mutation, and if an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047 mutation is present, administering to the patient a therapeutically effective amount of apoxib, invoxib, or a pharmaceutically acceptable salt thereof. Example 35. A PI3Kα-specific inhibitor that binds to PI3Kα allosite 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 regulation of phosphatidyl inositol 3-kinase alpha (PI3Kα) in a patient in need thereof, the treatment comprising analyzing a blood sample from the patient, determining whether 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 H1047 mutation, and if the M1043I / L mutation in cis with the H1047R mutation and / or the C901F mutation in cis with the H1047 mutation is present, administering to the patient a therapeutically effective amount of the PI3Kα-specific inhibitor or a pharmaceutically acceptable salt thereof. Embodiment 36. The compound for use in any one of embodiments 1 to 27, 30, 32 and 33, wherein the compound of formula I has the following formula: or a pharmaceutically acceptable salt thereof. Embodiment 37. The compound for use according to any one of embodiments 1 to 27, 30, 32 and 33, wherein a therapeutically effective amount of the compound of formula I administered to the patient is 100 to 1200 mg oral dose administered twice daily. 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 PI3Kα specific inhibitor administered to the patient is 9 to 75 mg / kg oral dose, administered twice daily. Embodiment 39. The compound for use according to any one of Embodiments 1 to 38, wherein the disease or disorder is cancer. Embodiment 40. The compound for use according to any one of embodiments 1 to 39, wherein the disease or disorder is breast cancer. Embodiment 41. The compound for use in any one of embodiments 1 to 40, wherein the disease or disorder is PIK3CA mutant advanced or metastatic breast cancer. Embodiment 42. The compound for use in any one of embodiments 1 to 41, wherein the disease or disorder is PIK3CACA H1047R mutant advanced or metastatic breast cancer. Example 43. The compound for use in Example 42, wherein the PIK3CACA H1047R mutant advanced or metastatic breast cancer is estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-). Embodiment 44. The compound for use according to any one of embodiments 1 to 43, wherein the patient is a postmenopausal female. Embodiment 45. The compound for use according to any one of embodiments 1 to 44, wherein the patient suffers from type II diabetes. Example 46. The compound for use in any one of Examples 1 to 45, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). Example 47. The compound as used in Example 46, wherein the SERD is selected from ilustrant, fulvestrant, giredostat, ansonostat, retostat, elastatrant, comistran, LSZ102, Zn-c5 and D-0502. Example 48. The compound for use as in Example 46 or 47, wherein the therapeutically effective amount of the SERD is a 500 mg dose administered on Day 1, Day 15, and Day 29. Embodiment 49. The compound for use in any one of embodiments 1 to 48, wherein the second PI3Kα specific inhibitor is administered after the disease or disorder has developed resistance to the first PI3Kα specific inhibitor. Illustrative compounds The following are illustrative compounds that can be used in some aspects of the disclosed subject matter. In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: in R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6, R 7 and R 8 is as defined in the summary for formula (I). In another aspect, The compound of formula (I) wherein R 8 is H has formula (II) or a pharmaceutically acceptable salt thereof: in R. R 1 、 R 2 、 R 3 、 R 4, R 5, R 6 and R 7 is as defined in the summary for formula (I). In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; R 2 is a group of the following formula: ; R 3 is -H; halogen; -CN; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 3-C 5-cycloalkyl; a heterocycle having 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or a heteroaryl having 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 2-C 6 alkenyl; optionally substituted C 2-C 6 alkynyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; R 2 is a group of the following formula: ; R 3 is -H, -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C 1-C 3 alkyl; R 1 is a group of the following formula: ; R 2 is a group of the following formula: ; R 3 is -H, -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 4, R 5 and Each of R 6 is independently -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; R 8 is -H or C 1-C 6 alkyl; each R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-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 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 2-C 6 alkenyl; optionally substituted C 2-C 6 alkynyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or iodine; an optionally substituted phenyl; an optionally substituted 1,3-benzodioxole; an optionally substituted 2,3-dihydro-1,4-benzodioxine; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl, C 2-C 6 alkenyl or C 2-C 6 alkynyl groups are each optionally substituted by -CN, -OH, oxetane or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -SO 2R 11 、-NR 11 R 11 , -OH or -CN. In the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6Alkoxy;-SO 2R 11 ;-CONR 11 R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; and optionally substituted C 3-C 5-cycloalkyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H, -CN, halogen, C 1-C 6 haloalkyl, C 1-C 6Alkoxy, -SO 2R 11 、-C(O)OC 1-C 3-alkyl, -CONR 11 R 11 , depending on the situation via -CN or -CONR 11 R 11 Replaced by C 1-C 6 alkyl (each R 11 C is preferred 1-C 3 alkyl), optionally C 1-C 3 alkyl or -CN substituted C 3-cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, an optionally substituted phenyl (preferably an optionally substituted phenyl substituted with -CN), or an optionally substituted heteroaryl selected from pyrazole or oxazole. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each R 10 are independently -H, -CN, halogen, C 1-C 6 haloalkyl, C 1-C 6Alkoxy, -SO 2R 11 、-CONR 11 R 11 , C substituted by -CN as appropriate 1-C 6 alkyl, optionally C 1-C 3 alkyl or -CN substituted C 3 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, or an optionally substituted heteroaryl selected from pyrazole or oxazole. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each R 10 Independently . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each R 10 Independently 、 、 、 、 、 、 、 、 、 、 、 、 or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a group of the following formula: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, halogen, -CN, -N(H)(CH 2CH 2CO 2H), -C(O)C 1-C 3 alkyl, C 1-C 6 alkyl, C 1-C 6-haloalkyl, oxetane, isoxazole or pyridine (preferably 3-pyridine). In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H; halogen; -CN; C 1-C 6 alkyl; C 1-C 6 haloalkyl; C 3-C 5-cycloalkyl; a heterocycle having 3 to 5 ring atoms, which contains 1, 2 or 3 ring heteroatoms independently selected from N, O or S; or a heteroaryl having 5 ring atoms, which contains 1, 2 or 3 ring heteroatoms independently selected from N, O or S. In yet another compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, oxetane or isoxazole. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 6 alkyl or C 1-C In another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl); best R 3 is -H or methyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is H or halogen, preferably R 4 is H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl; preferred R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 5 is -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 6 is -H or halogen. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), and R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), and R 2 is a group of the following formula: ; ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, methyl or trifluoromethyl (preferably R 3 is -H or methyl), and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the following formula: ; ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl groups, and R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 2 is a group of the following formula: ; ; ;or . Preferably, each R10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, methyl or trifluoromethyl, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 6 is -H or halogen, and R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN; and each R 11 are independently -H or C 1-C 3 alkyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 6 is -H or halogen, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 4 is H or halogen; more preferably R 3 is -H, -CN or C 1-C 3 alkyl groups, and R 4 is H; best R 3 is -H or methyl, and R 4 is H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), and R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 3 is -H or methyl, and R 5 is -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), and R 6 is -H or halogen; more preferably R 3 is -H or methyl, and R 6 is -H or halogen. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), and R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; preferred R 5 is -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), and R 6 is -H or halogen. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 6 is -H or halogen; preferably R 5 is -H, halogen, methyl or trifluoromethyl, and R 6 is H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 4 is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 5 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl groups, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 5 is -H, halogen, methyl or trifluoromethyl, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; or Better R 3 is -H or methyl, R 6 is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 2 is a group of the following formula: ; ; ;or Better R 5 is -H, halogen, methyl or trifluoromethyl, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or Better R 4 and R 6 is each -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or Better R 5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), and R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 3 is -H or methyl, R 4 is -H, and R 5 is -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), and R 6 is -H or halogen; more preferably R 3 is -H or methyl, and R 4 and R 6 is each H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen; more preferably R 3 is -H or methyl, R 5 is -H, halogen, methyl or trifluoromethyl, and R 6 is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen (preferably R 4 is -H), and R 6 is -H or halogen; more preferably R 5 is -H, halogen, methyl or trifluoromethyl, and R 4 and R 6 is each H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), R 5 is -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl or C 1-C 6 alkoxy groups, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 4 is -H, R 5 is -H, halogen, methyl or trifluoromethyl, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 4 and R 6 is each -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 5 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl groups, R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, and R 2 is a group of the following formula: ; ; ;or Better R 5 is -H, halogen, methyl or trifluoromethyl, R 4 is -H, R 6 is -H or halogen, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, and R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 3 is -H or methyl, R 4 and R 6 is each -H, and R 5 is -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 4 is -H, R 6 is -H or halogen, R 5 is -H, halogen, methyl or trifluoromethyl, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 6 alkyl or C 1-C 6 haloalkyl; preferred R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 7 is -CN, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 8 is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), and R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 8 is H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), and R 8 is H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 8 and Each R is -H. In yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), and R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 8 is -H, R is -H, and R 2 is a group of the following formula: ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), R 8 is -H, R is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H or methyl, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), and R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 4. R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is C 1-C 3 alkyl groups (preferably methyl groups), and R 4, R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 7 is -CN, methyl or trifluoromethyl, and R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 8 and Each R is -H. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl (preferably R 3 is -H, -CN or C 1-C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), R 6 is -H or halogen, R 5 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl groups, R 7 is -CN, methyl or trifluoromethyl, R 8 is -H, R is -H, and R 2 is a group of the following formula: ; ; ;or Better R 3 is -H or methyl, R 4 is -H, R 6 is -H or halogen, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is a methyl group, R 8 is -H, R is -H, and R 2 is a group of the following formula: ; ;or . Preferably, each R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11 R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C 1-C 6 alkyl optionally through -CN, -OH or C 1-C 3 alkoxy substituted; optionally substituted C 3-C 5-cycloalkyl, phenyl, heterocyclic or heteroaryl are each optionally substituted by one to three substituents independently selected from the following: halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3-haloalkoxy, -NR 11 R 11 , -OH or -CN. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, -CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl; preferably R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-cycloalkyl; preferably R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl; more preferably R9 is independently -H, halogen, methyl, trifluoromethyl, methoxy or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl; preferably R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; preferably R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; preferably R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-cycloalkyl. Preferably, each R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl. More preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-cycloalkyl. Preferably, each R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups. More preferably, each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the formula ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-cycloalkyl; preferably R 9 is independently -H, halogen, -CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl; more preferably R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the formula ; ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy or C 3-C 5-cycloalkyl; preferably R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl; more preferably R9 is independently -H, halogen, methyl, trifluoromethyl, methoxy or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; Each of them R 9 is independently -H, halogen, -CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 1-C 3 alkoxy groups. Preferably, each R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups. More preferably, each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen, -CN, C 1-C 3 haloalkyl or C 1-C 3 alkoxy. Preferably, R 9 is -H, halogen or C 1-C 3 haloalkyl. More preferably, R 9 is -H or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen, -CN, C 1-C 3 haloalkyl or C 1-C 3 alkoxy. Preferably, R 9 is -H, halogen or C 1-C 3 haloalkyl. More preferably, R 9 is -H or halogen. Even more preferably, R 9 is -H or fluorine. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen, -CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl. Preferably, R 9 is -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl. More preferably, R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen or C 1-C 3 haloalkyl. Preferably, R 9 is independently halogen or trifluoromethyl. More preferably, R 9 is chloro or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen, -CN, C 1-C 6 alkyl, C 1-C 6 haloalkyl or C 1-C 6 alkoxy. Preferably, R 9 is -H, halogen, C 1-C 6 alkyl or C 1-C 6 haloalkyl. More preferably, R 9 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ;in R 9 is -H, halogen, -CN, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy or C 3-C 5-cycloalkyl. Preferably, R 9 is -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl. More preferably, R 9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or . In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen, R 6 is -H or halogen, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 1 is a group of the following formula: ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl. More preferably, each R 9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. Preferably, R 3 is -H, methyl or trifluoromethyl, R 4 is -H or halogen, R 6 is -H or halogen, R 5 is -H, halogen, methyl or trifluoromethyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4 is -H, R 6 is -H or halogen, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 1 is a group of the following formula: ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl. Preferably, R 3 is -H or methyl, R 4 is -H, R 6 is -H or halogen, R 5 is -H, halogen, methyl or trifluoromethyl, and each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, methyl or trifluoromethyl, R 8 and Each R is -H, and R 1 is a group of the following formula: ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl; more preferably R 7 is a methyl group, R 8 and R is each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 7 is -CN, methyl or trifluoromethyl, R 8 and Each R is -H, and R 1 is a group of the following formula: ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 7 is a methyl group, R 8 and R is each -H, and each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl; more preferably R 3 is -H, methyl or trifluoromethyl, R 4 is -H or halogen, R 6 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; more preferably R 3 is -H or methyl, R 4, R 6, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; preferred R 3 is -H, methyl or trifluoromethyl, R 4 is -H or halogen, R 6 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and each R 9 is independently -H, halogen, methyl or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen or C 1-C 3 haloalkyl; preferred R 3 is -H or methyl, R 4, R 6, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is -H or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen or C 1-C 3 haloalkyl; preferred R 3 is -H or methyl, R 4, R 6, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is -H or halogen, more preferably R 9 is -H or fluorine. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl; preferred R 3 is -H, methyl or trifluoromethyl, R 4 is -H or halogen, R 6 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen or C 1-C 3 haloalkyl; preferred R 3 is -H or methyl, R 4, R 6, R 8 and R each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is independently halogen or trifluoromethyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN or C 1-C 3 alkyl, R 4, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl; preferred R 3 is -H or methyl, R 4, R 6, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 3 is -H, -CN, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 4 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the following formula: ;in R 9 is -H, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl or C 3-C 5-cycloalkyl; preferred R 3 is -H, methyl or trifluoromethyl, R 4 is -H or halogen, R 6 is -H or halogen, R 8 and R is each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 7 is methyl, and R 9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl. In yet another compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, R 1 is a group of the following formula: ; ; ; ;or ; Each of them R 9 is independently -H, halogen, C 1-C 3 alkyl or C 1-C 3 haloalkyl groups, and R 2 is a group of the following formula: Among them R 10 are independently -H; -CN; halogen; C 1-C 6 haloalkyl; C 1-C 6 alkoxy; C 1-C 6-haloalkoxy; -SO 2R 11 ;-CONR 11R 11 ;-NR 11 R 11 ;-NR 11 -CO 2R 11 ; replaced by C as appropriate 1-C 6 alkyl; optionally substituted C 3-C 5-cycloalkyl; an optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or thiophene; an optionally substituted phenyl; or an optionally ...

Claims

1. Use of a selective PI3Kα inhibitor bound to PI3Kα allosite pocket 2 for manufacturing a pharmaceutical product for treating cancers associated with regulation of phosphatidylinositol 3-kinase α (PI3Kα) that are resistant to treatment with abexib, wherein the selective PI3Kα inhibitor is: or a pharmaceutically acceptable salt thereof.

2. Use of a selective PI3Kα inhibitor for manufacturing a pharmaceutical product for treating cancers associated with regulation of phosphatidylinositol 3-kinase α (PI3Kα) in patients in need, wherein the patients have cancers comprising a cis-M1043I / L mutation with H1047R mutation and / or a cis-C901F mutation with H1047R mutation, and wherein the selective PI3Kα inhibitor is: or a pharmaceutically acceptable salt thereof.

3. As requested in claim 1 or 2, wherein the cancer is breast cancer.

4. As requested in claim 1 or 2, wherein the cancer is PIK3CA-mutated advanced or metastatic breast cancer.

5. For the purposes of claim 1 or 2, wherein the cancer is PIK3CA H1047R mutant advanced or metastatic breast cancer.

6. As requested in paragraph 1 or 2, wherein the cancer is an estrogen receptor-positive (ER+) human, epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer.

7. As requested in item 1 or 2, wherein the patient is a postmenopausal woman.

8. For the purposes of claim 1 or 2, wherein the patient has type II diabetes.

9. As claimed in claim 1 or 2, wherein the treatment further comprises administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

10. As requested in paragraph 9, wherein the SERD is selected from imlunestrant, fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, and camizestrant.

11. As requested in claim 10, wherein the effective therapeutic dose of the SERD is 500 mg administered on days 1, 15 and 29.

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