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

Abstract

The present disclosure relates to the use of phosphoinositide 3-kinase (PI3K) inhibitors targeting allosteric and normal pockets of PI3K in methods of treating, preventing, or ameliorating diseases or conditions in which PI3K functions (or in use in treating, preventing, or ameliorating diseases or conditions). The PI3K inhibitors can be used in combination and can target allosteric or normal pockets of PI3K alpha simultaneously, separately, or sequentially. In some aspects of the disclosed methods, PI3K [alpha] inhibitors may target an allosteric or normal pocket of a PI3K [alpha] mutant that is resistant to treatment with another PI3K [alpha] inhibitor that targets a different pocket of PI3K [alpha].

Description

[0001] Cross-references to Related Patent Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 501,614, filed May 11, 2023, U.S. Provisional Application No. 63 / 382,980, filed November 9, 2022, and U.S. Provisional Application No. 63 / 382,029, filed November 1, 2022; the contents of which are incorporated herein by reference in their entirety.

[0003] References to sequence listings

[0004] This application is submitted 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 sequence listing information in ST.26 XML format is incorporated herein by reference in its entirety.

[0005] field

[0006] The present invention relates to inhibitors of phosphoinositide 3-kinase (PI3K) and combinations thereof, which can be used to treat diseases or conditions associated with PI3K regulation. The present invention also relates to allosteric chromone inhibitors of phosphoinositide 3-kinase (PI3K), which can be used to treat diseases or conditions associated with PI3K regulation, and the use of allosteric chromone inhibitors in combination with other allosteric or orthosteric inhibitors of PI3K in treating diseases or conditions associated with PI3K regulation. The present invention also relates to PI3K inhibitors and combinations thereof, methods (or uses) for treating diseases or conditions associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-associated 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 combined use or method of using a PI3K inhibitor with one or more additional cancer therapies.

[0007] background

[0008] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most heavily mutated systems in human cancer. PI3K signaling has also been 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.

[0009] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate 3'-OH groups on phosphatidylinositol or phosphoinositide. The PI3K family includes 15 kinases with different substrate specificities, expression patterns, and regulatory mechanisms. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and effectors in the Rho family GTPases pathway. Class II and class III PI3Ks play a key role in intracellular trafficking by synthesizing PI(3)P and PI(3,4)P2.

[0010] For example, PI3K isoforms are associated with a variety of human cancers and conditions. For example, the alpha (α) isoform of PI3K is associated with a variety of human cancers. It has been shown that angiogenesis requires the PI3Kα isoform to selectively control endothelial cell migration. Mutations in the PI3Kα gene or mutations that upregulate PI3Kα are believed to occur in many human cancers, such as lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Mutations in the PI3Kα gene are point mutations that cluster within several hotspots within the helical 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 PI3Kα, targeting this pathway offers valuable therapeutic opportunities. While other PI3K isoforms (such as PI3Kδ or PI3Kγ) are primarily expressed in hematopoietic cells, PI3Kα and PI3Kβ are constitutively expressed.

[0011] Due to the central role of PI3Kα in regulating glucose homeostasis, PI3K inhibition in patients often results in adverse events, including hyperglycemia and / or hyperinsulinemia. High levels of circulating insulin may have mitogenic and / or antiapoptotic effects on cancer cells, thereby counteracting the antiproliferative effects of PI3K inhibitors. In the setting of PI3Kα-mutant cancers, one approach to overcoming the problem of compensatory insulin and / or glucose production following systemic PI3Kα inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3Kα over wild-type PI3Kα. This would create a larger window for drug dosing 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 for higher doses and more complete inhibition of the drug target.

[0012] PI3Kα possesses an ATP-binding pocket, which serves as a target for modulating PI3Kα activity. PI3Kα must be bound to 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. The PI3Kα ATP-binding pocket is also referred to as the "PI3Kα orthosteric binding pocket."

[0013] Current PI3Kα inhibitors are nearly equipotent 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, mutation-selective inhibitors have been elusive. Therefore, inhibitors targeting a second peripheral binding pocket near known mutations (such as H1047R) could offer a path to selective PI3Kα inhibition.

[0014] The present invention provides a new class of kinase inhibitors that target a non-ATP binding pocket of PI3Kα, referred to herein as "PI3Kα allosteric pocket 1," and can interact with amino acid residues of PI3Kα, including R1047. The disclosed kinase inhibitors target PI3Kα allosteric 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.

[0015] The present invention also provides the characterization of another non-ATP binding pocket of PI3Kα (called "PI3Kα allosteric pocket 2"), and the interaction of PI3Kα inhibitors with PI3Kα allosteric pocket 2. The disclosed kinase inhibitors targeting PI3Kα allosteric pocket 1 can be used in combination therapy with PI3Kα inhibitors targeting PI3Kα allosteric pocket 2.

[0016] Summary

[0017] The present disclosure relates to methods of treating, preventing, or ameliorating diseases or conditions in which PI3K plays a role (or uses in treating, preventing, or ameliorating diseases or conditions) using phosphoinositide 3-kinase (PI3K) inhibitors that target the PI3K allosteric and orthosteric pockets. PI3K inhibitors can be used in combination and can target the allosteric pocket of phosphatidylinositol 3-kinase alpha (PI3Kα) referred to herein as "PI3Kα allosteric pocket 1," the allosteric pocket of PI3Kα referred to herein as "PI3Kα allosteric pocket 2," or the PI3Kα orthosteric pocket. (See Figure 1In some aspects of the disclosed methods, the PI3Kα inhibitor can target the PI3Kα allosteric pocket 1, the PI3Kα allosteric pocket 2, or the PI3Kα orthosteric pocket of a PI3Kα mutant that is resistant to treatment with another PI3Kα inhibitor, e.g., a PI3Kα inhibitor that targets different pockets of PI3Kα.

[0018] The method may comprise administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the invention or a combination of a PI3K inhibitor of the invention with other PI3K inhibitors, which may include other allosteric inhibitors of PI3K and orthosteric inhibitors of PI3K. The methods and PI3K inhibitors of the invention may be used to treat a variety of PI3K-dependent or PI3K-associated diseases and conditions.

[0019] In some aspects, the disclosed methods relate to methods of treating diseases or conditions associated with PI3Kα regulation. The methods can include 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.

[0020] In some aspects, the disclosed methods relate to methods of treating diseases or conditions associated with PI3Kα regulation. The methods can include 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.

[0021] In some aspects, the disclosed methods can include administering to a patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor binds to PI3Kα allosteric pocket 2.

[0022] In some aspects, the disclosed methods can include administering to a patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor, wherein the first PI3Kα selective inhibitor binds to PI3Kα allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor different from the first PI3Kα selective inhibitor, wherein the different second PI3Kα selective inhibitor binds to PI3Kα allosteric pocket 1. In some aspects, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor competitively bind to PI3Kα allosteric pocket 1.

[0023] 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.

[0024] In some aspects of the disclosed methods comprising administering a therapeutically effective amount of a first PI3Kα selective inhibitor and a therapeutically effective amount of a second PI3Kα selective inhibitor, an additive or synergistic effect can be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Kα selective inhibitor administered in the disclosed methods can 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 can 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.

[0025] In some aspects of the disclosed methods, a therapeutically effective amount of a first PI3Kα selective inhibitor can effectively 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 a second 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, hyperinsulinemia, diarrhea, dehydration, rash, lymphopenia, elevated alanine aminotransferase, fatigue, anemia, elevated 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.

[0026] In some aspects, the disclosed methods relate to methods of treating a disease or condition associated with PI3Kα regulation in a patient suffering from a disease or condition that is resistant to treatment with a PI3Kα selective inhibitor, which may be a PI3Kα selective allosteric inhibitor or a PI3Kα selective orthosteric inhibitor. The method may comprise administering to the patient a different PI3Kα selective inhibitor to which the disease or condition is not resistant, such as a PI3Kα selective allosteric inhibitor or a PI3Kα selective orthosteric inhibitor.

[0027] In some aspects, the disclosed methods relate to methods of treating a disease or condition associated with PI3Kα modulation in a patient, the patient having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor. In certain aspects, the disclosed methods relate to treating a disease or condition associated with PI3Kα modulation in a patient, the patient being identified as having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor, or being identified as having a disease or condition that exhibits an incomplete response to treatment with a PI3Kα selective orthosteric inhibitor. In some aspects, the method may comprise administering to a patient identified as having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor, or being identified as having a disease or condition that exhibits an incomplete response to treatment with a PI3Kα selective orthosteric inhibitor, a therapeutically effective amount of a PI3Kα selective allosteric inhibitor, wherein the PI3Kα selective allosteric inhibitor binds to the PI3Kα allosteric pocket 1. In some aspects, the method can include administering a therapeutically effective amount of a PI3Kα selective allosteric inhibitor to a patient identified as having a disease or condition that is resistant to treatment with a PI3Kα selective orthosteric inhibitor, or to a patient identified as having a disease or condition that exhibits an incomplete response to treatment with a PI3Kα selective orthosteric inhibitor, wherein the PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 2.

[0028] In some aspects, the disclosed methods relate to treating a disease or condition associated with PI3Kα regulation that is resistant to treatment with a first PI3Kα selective allosteric inhibitor, wherein the first PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 1. In some aspects, the method can include administering to a patient suffering from a 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 method can include administering to a patient suffering from a resistant disease or condition a therapeutically effective amount of a second, different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2. In some aspects, the method can include administering to a patient suffering from a resistant disease or condition a therapeutically effective amount of a PI3Kα selective inhibitor that binds to PI3Kα orthosteric pocket.

[0029] In some aspects, the disclosed methods relate to treating a disease or condition associated with PI3Kα regulation 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 method can include administering to a patient suffering from a 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 method can include administering to a patient suffering from a resistant disease or condition a therapeutically effective amount of a PI3Kα selective inhibitor that binds to PI3Kα orthosteric pocket.

[0030] In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with PI3Kα modulation 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 developed acquired resistance to treatment with the PI3Kα selective inhibitor. The method can include administering to the patient a different PI3Kα selective inhibitor to which the disease or condition is not resistant.

[0031] 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 allosteric inhibitor, wherein the PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 1 or PI3Kα allosteric pocket 2. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with the PI3Kα selective allosteric inhibitor, and the methods may include administering to the patient a therapeutically effective amount of the PI3Kα selective allosteric inhibitor. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1, and the methods may include administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2. In the disclosed methods, the patient's disease or condition may have conferred acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1. In the disclosed methods, the patient's disease or condition may have conferred acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1.

[0032] 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 allosteric inhibitor, wherein the PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 1 or PI3Kα allosteric pocket 2. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with the PI3Kα selective allosteric inhibitor, and the methods may include administering to the patient a therapeutically effective amount of the PI3Kα selective allosteric inhibitor. In the disclosed methods, the patient's disease or condition may have developed acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1, and the methods may include administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2. In the disclosed methods, the patient's disease or condition may have conferred acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1. In the disclosed methods, the patient's disease or condition may have conferred acquired resistance to treatment with a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1, and the method may comprise administering to the patient a therapeutically effective amount of a different PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1.

[0033] 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 suffers from 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). The method can include administering a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor to a patient suffering from the disease or condition. The method can include administering a therapeutically effective amount of a PI3Kα allosteric inhibitor to a patient suffering from 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), wherein the PI3Kα allosteric inhibitor binds to the PI3Kα allosteric pocket 1. The method can include administering to a patient 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) a therapeutically effective amount of a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2.

[0034] In certain aspects, the method relates to a method of treating a disease or condition associated with PI3Kα regulation in a patient in need thereof, e.g., a patient 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). The method can include determining whether the patient has 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), e.g., by arranging or performing genomic analysis. If the patient is found to have 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), 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 (e.g., an allosteric inhibitor that binds to PI3Kα allosteric pocket 1 and / or an allosteric inhibitor that binds to PI3Kα allosteric pocket 2), an orthosteric inhibitor, or a combination thereof, as disclosed herein.

[0035] In some aspects, the disclosed methods include selecting a patient for treatment with one or more PI3Kα selective inhibitors. In some aspects, patients are selected based on patients with 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, treatment can be administered to the selected patient, which treatment can include administering to the patient one or more PI3Kα selective inhibitors, which can include an allosteric inhibitor (e.g., an allosteric inhibitor that binds to the PI3Kα allosteric pocket 1 or an allosteric inhibitor that binds to the PI3Kα allosteric pocket 2), a positive inhibitor, or a combination thereof, as disclosed herein.

[0036] In the disclosed method, there is a patient in need who may suffer from cancer. In some aspects, there is a patient in need who may suffer from breast cancer. In some aspects, there is a patient in need who may suffer from PIK3CA mutation, late stage or metastatic breast cancer. In some aspects, there is a patient in need who may suffer from PIK3CA H1047R mutant late stage or metastatic breast cancer, which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[0037] 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 (which may include a PI3Kα selective inhibitor), and the patient may be administered a different therapeutic agent, which may include a different PI3Kα selective inhibitor.

[0038] In the disclosed methods, the patient may not have previously been administered a therapeutic agent for treating cancer, which may include a PI3Kα selective inhibitor. In certain aspects, the patient may be characterized as being naive to treatment with a PI3Kα selective inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Schematic diagram of PI3Kα(H1047R) showing the orthosteric pocket, allosteric pocket 1, and allosteric pocket 2.

[0041] Figure 2 Dose-response curve of apelisib in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0042] Figure 3 Dose response curve of compound 21 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0043] Figure 4 Dose response curve of compound N1 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0044] Figure 5 Dose response curve of compound N2 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0045] Figure 6 Dose response curve of compound 1 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0046] Figure 7 Dose response curve of compound HP1 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0047] Figure 8 Dose-response curve of apelisib in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0048] Figure 9 Dose response curve of compound HP1 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0049] Figure 10 Dose response curve of compound 1 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0050] Figure 11 Dose response curve of compound 21 in T47D (M1043I + H1047R) (double, cis, 6×) cell proliferation assay.

[0051] Figure 12 . Plot of the combination index of compound 21 and apelisib in T47D primary cells based on growth inhibition assay (CTG).

[0052] Figure 13 . Combination index plot of compound 21 and apelisib in T47D (M1043I + H1047R) (double, cis, 6×) cells based on growth inhibition assay (CTG).

[0053] Figure 14 . Combination index plot of compound 21 and compound HP1 in T47D primary cells based on growth inhibition assay (CTG).

[0054] Figure 15 . Combination index plot of compound 21 and compound HP1 in T47D (M1043I + H1047R) (double, cis, 6×) cells based on growth inhibition assay (CTG).

[0055] Figure 16 . Plot of the combination index of compound 21 and apelisib in MDA453 primary cells based on the growth inhibition assay (CTG).

[0056] Figure 17 . Plot of the combination index of compound 21 and apelisib in MDA453 (Cpd 21-R) (double, cis, 6×) cells based on growth inhibition assay (CTG).

[0057] Figure 18 . Combination index plot of compound 21 and compound HP1 in MDA453 primary cells based on growth inhibition assay (CTG).

[0058] Figure 19. Combination index plot of compound 21 and compound HP1 in MDA453 (Cpd 21-R) cells based on growth inhibition assay (CTG).

[0059] Figure 20 Graphical illustration of the interaction between PIKα_H1047R and compound 21 based on X-ray structure analysis. The interactions include direct hydrogen bonding between the carboxylic acid group of compound 21 and the side chains of R1047 and Q981; hydrogen bonding between the carboxylic acid group of compound 21, the bridging water molecule, and the side chain of Y985; and hydrogen bonding between the chromone exocyclic ketone group of compound 21, the bridging water molecule, and the side chain of H931 (as well as hydrogen bonding between the exocyclic ketone group of compound 21, the bridging water molecule, and the carbonyl backbone group of C901 (not shown)).

[0060] Figure 21 Graphical illustration of the interaction between PIKα_H1047R and compound 172 based on X-ray structure analysis. The interactions include direct hydrogen bonding between the carboxylic acid group of compound 172 and the side chains of R1047 and Q981; hydrogen bonding between the chromone exocyclic ketone group of compound 172, the bridging water molecule, and the side chain of H931; hydrogen bonding between the cyano group of compound 172 and the side chain of Y1021; core π-π stacking between the chromone core of compound 172 and the side chain of F954; and π-πT stacking between the 4-cyanophenyl group of compound 172 and the side chain of F909.

[0061] Figure 22 Graphical illustration of the interaction between PIKα_H1047R and compound N3 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the carboxylic acid group of compound N3 and the side chains of R1047 and Q981; core π-π stacking between the chromone core of compound N3 and the side chain of F954; and π-πT stacking between the phenyl group of compound N3 and the side chain of F954.

[0062] Figure 23 Graphical representation of the interaction between PIKα_H1047R and compound N4 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the carboxylic acid group of compound N4 and the side chains of R1047 and Q981, as well as hydrogen bonding between the chromone exocyclic ketone group of compound N4, the bridging water molecule, and the side chain of H931.

[0063] Figure 24Graphical representation of the interaction between PIKα_H1047R and compound N5 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the carboxylic acid group of compound N5 and the side chains of R1047 and Q981; direct hydrogen bonding between the isoxazole group of compound N5 and the side chain of H931; and core π-π stacking between the isoxazole core of compound N5 and the side chain of F954.

[0064] Figure 25 Graphical illustration of the interaction between PIKα_M1043I_H1047R and compound HP1 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the nitrogen atom of the isoindolin-1-one core of compound HP1 and the carbonyl backbone group of D1018; core-π-π stacking between the 3-trifluoromethyl, 5-fluorophenyl core of compound HP1 and the side chain of F937; and π-πT stacking between the 3-trifluoromethyl, 5-fluorophenyl core of compound HP1 and the side chain of F1002.

[0065] Figure 26 Graphical illustration of the interaction between PIKα_M1043I_H1047R and compound HP2 based on X-ray structural analysis. The interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-1-one core of compound HP2 and the carbonyl backbone group of D1018; core-π-πT stacking between the 3-trifluoromethyl, 5-fluorophenyl core of compound HP2 and the side chain of F1002; and chlorine-carbonyl interactions between the chlorine atom of the 2-chloro, 5-fluorophenyl group of compound HP2 and the side chain carbonyl group of E1012.

[0066] Figure 27 Graphical illustration of the interactions between PIKα_H1047R, compound N6, and compound HP2 in their respective allosteric pockets based on X-ray structure analysis.

[0067] Figure 28 Effects of Compound 21 (37.5 mg / kg), Apelixitide (12.5 mg / kg), and Fulvestrant (5 mg / animal) in T47D xenografts (H1047+ / 1, ER+, PR+, HER2-).

[0068] Figure 29 Effects of Compound 21 (37.5 mg / kg), Apelixitide (6.25 mg / kg), and Fulvestrant (5 mg / animal) in T47D xenografts (H1047+ / 1, ER+, PR+, HER2-).

[0069] Figure 30Naive cells and compound 21-resistant MDA453 cells (having the M1043I second site mutation) were treated with compound 21, apelisib, or compound HP1.

[0070] Figure 31 . Primary cells and engineered T47D cells (with a 6xM1043I second-site mutation) were treated with compound 21, apelisib, or compound HP1.

[0071] Figure 32 Parental SUM185PE cells and Compound 21-resistant SUM185PE cells were treated with Compound 21, Compound 1, apelisib, or Compound HP1.

[0072] Figure 33 MDA453 primary cells were treated with compound 21 in combination with apelisib.

[0073] Figure 34 Synergy plot of MDA453 primary cells treated with compound 21 in combination with apelisib.

[0074] Figure 35 MDA453 primary cells were treated with compound 21 in combination with compound HP1.

[0075] Figure 36 Synergy plot of MDA453 primary cells treated with compound 21 in combination with compound HP1.

[0076] Figure 37 MDA453 primary cells were treated with apelisib in combination with compound HP1.

[0077] Figure 38 MDA453 primary cells were treated with apelisib in combination with compound HP1.

[0078] Figure 39 . H1047R homozygous SUM185PE cells were treated with compound 21 in combination with apelisib.

[0079] Figure 40 Compound 21-resistant SUM185PE cells were treated with a combination of Compound 21 and apelisib.

[0080] Figure 41 . H1047R homozygous SUM185PE cells were treated with compound 21 in combination with compound HP1.

[0081] Figure 42 H1047R homozygous SUM185PE cells were treated with apelisib in combination with compound HP1.

[0082] Figure 43. T47D cells were treated with compound 21 in combination with apelisib.

[0083] Figure 44 . T47D cells were treated with compound 21 in combination with compound HP1.

[0084] Figure 45 T47D cells treated with apelisib in combination with compound HP1.

[0085] Figure 46 T47D primary cells treated with compound 21 in combination with apelisib.

[0086] Figure 47 . T47D 6x H1043I cells were treated with compound 21 in combination with apelisib.

[0087] Figure 48 Parental SUM185PE cells and Cpd-21-R SUM185PE cells were treated with Compound 21, Apelixitide, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.

[0088] Figure 49 .T47D cells (5×H1047R / 1×WT) or engineered T47D cells with a second site mutation (5×H1047R / 6×C901F or 6×H1047R / M1043I) were treated with Compound 21, Apelix, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.

[0089] Figure 50 . T47D cells were treated with compound 21 in combination with compound HP6.

[0090] Figure 51 . T47D cells were treated with compound 21 in combination with compound HP6.

[0091] Figure 52 . Combination index graph of compound 21 and compound HP6 in T47D cells.

[0092] Figure 53 .SUM185PE cells were treated with compound 21 in combination with compound HP6.

[0093] Figure 54 . Combination index graph of compound 21 and compound HP6 in SUM185PE cells.

[0094] Figure 55 . T47D cells were treated with compound 21 in combination with compound HP5.

[0095] Figure 56. Combination index graph of compound 21 and compound HP5 in T47D cells.

[0096] Figure 57 .SUM185PE cells were treated with compound 21 in combination with compound HP5.

[0097] Figure 58 . Combination index graph of compound 21 and compound HP5 in SUM185PE cells.

[0098] Detailed description

[0099] 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 diseases or conditions are dependent on or associated with PI3K activity. In the disclosed methods and uses, a therapeutically effective amount of a PI3K inhibitor or a combination of PI3K inhibitors, which may include both 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.

[0100] In some embodiments of the disclosed methods and uses, the disease or condition is cancer, e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. In some embodiments, diseases or conditions associated with PI3K include, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, 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, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0101] The details of the present invention are set forth in the following description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the present invention will be apparent from the description and claims. In the specification and the appended claims, the singular also includes the plural, unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. All patents and publications cited in this specification disclose PI3Kα inhibitor compounds and methods for preparing and using PI3Kα inhibitor compounds, and are incorporated herein by reference in their entirety.

[0102] definition

[0103] 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. For example, "an element" means one element, or more than one element.

[0104] Unless stated otherwise, the term "and / or" means "and" or "or".

[0105] The terms "administering," "dosing," or "taking" 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 "dosing" 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 a patient. "Administering" or "dosing" can be performed by a patient, e.g., wherein the patient administers a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or a composition to themselves.

[0106] The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl.

[0107] The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms and containing 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.

[0108] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0109] 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, or hexynyl.

[0110] The term "aromatic" refers to a planar ring having 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a connected p-orbital system having delocalized electrons, and the system may contain lone electron pairs.

[0111] The term "aryl", unless otherwise clearly defined, refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl. When containing two aromatic rings (bicyclic etc.), the aromatic ring of the aryl can be connected (such as biphenyl) or fused (such as naphthyl) by a single point. In addition, when containing two fused rings, the aryl defined herein can have one or more saturated or partially undersaturated rings fused with completely unsaturated aromatic rings. The exemplary ring systems of these aryls include but are not limited to phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl and tetrahydrobenzoannulyl.

[0112] The term "carrier" encompasses vehicles, excipients, and diluents, and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, used to carry or transport an agent from one organ or body part of a patient to another.

[0113] The term "cyano" refers to a substituent in which a carbon atom is triple bonded to a nitrogen atom, ie, C≡N.

[0114] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, bicyclo[2.2.2]octyl, and bicyclo[2.2.2]octenyl.

[0115] Unless otherwise indicated, the term "disorder" refers to, and is used interchangeably with, the terms disease, condition, or ailment.

[0116] The term "haloalkoxy" refers to an alkoxy group, as defined herein, substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0117] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0118] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0119] The term "heteroaryl", unless otherwise expressly defined, refers to 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 spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise expressly defined, "fused" means that two rings share two ring atoms. Unless otherwise expressly defined, "spiro-fused" means that two rings share one ring atom. Heteroaryl as defined herein also refers to bicyclic heteroaromatic groups, wherein heteroatoms are selected from N, O, S, P or B, preferably N, O or S. Heteroaryl as defined herein also refers to tricyclic heteroaromatic groups, which contain one or more ring heteroatoms selected from N, O, S, P or B, preferably N, O or S. Heteroaryl as defined herein also refers to tetracyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P or B, preferably N, O or S.Examples of heteroaromatic groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c] pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolinyl, indolinonyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4 -b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-b]pyridinyl, [1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and 3H-indolyl. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to the saturated or partially unsaturated rings 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 is optionally substituted with one or more oxo groups. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7 ,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborola-1(3H)-onyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0120] The term "heterocyclyl", "heterocycle" or "heterocycloalkyl" refers to a monocyclic or polycyclic ring containing 3 to 24 atoms, preferably 3 to 10 atoms, including carbon and one or more heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 heteroatoms selected from N, O and S, and wherein the ring is not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, aza Oxalic acid Base, diazepine alkyl, tropanyl, oxazolidinone and homotropanyl.

[0121] The term "hydroxyalkyl" refers to an alkyl group as defined herein substituted with a hydroxy group.

[0122] The term "cis" when referring to two different mutations means that the two different mutations are located on the same chromosome.

[0123] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or the arrangement of their atoms in space. Isomers whose atoms differ in their arrangement in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images of one another are called "enantiomers." When a compound has an asymmetric center, for example, it is bound to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0124] The term "regulate" or "modulate" refers to the inhibition and / or activation of the biological activity of a compound or substrate of PI3K. Modulation may include inhibition.

[0125] The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human.

[0126] The term "therapeutically effective amount" when used in connection with a compound refers to that amount or dosage of the compound which, when administered to a patient in single or multiple doses, provides the desired effect on the patient being diagnosed or treated.

[0127] One skilled in the art can determine the effective amount by using known techniques and by observing the results obtained under similar circumstances. In determining the effective amount for a patient, the attending diagnostician considers many factors, including, but not limited to: the type of patient; their size, age, and general health; the specific disease or condition involved; the extent or severity of the disease or condition involved; the response of the individual patient; the specific compound being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; the use of concomitant medications; and other relevant circumstances.

[0128] For a patient, the term "treatment" includes inhibiting, slowing, stopping or reversing the progression or severity of an existing symptom or condition. For a patient, the term "treatment" may include prescribing a therapeutic agent to be administered to the patient or formulating a treatment regimen for the patient. For a patient, the term "treatment" may include arranging a diagnostic test for the patient. Diagnostic testing may include genomic analysis to identify mutations present in PI3Kα, such as C901 mutations (e.g., C901F), M1043 mutations (e.g., M1043I / L) and / or H1047 mutations (e.g., H1047R), which may be cis (i.e., on the same allele), as disclosed herein.

[0129] With respect to a patient, the term "prevent" can refer to 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 for 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.

[0130] For 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 average patient survival time following treatment.

[0131] The term "PI3K" refers to "phosphoinositide 3-kinase." The term "PI3Kα" refers to phosphoinositide 3-kinase alpha, which belongs to class I PI3K and comprises the PI3k catalytic alpha polypeptide (p110-α) encoded by the gene PIK3CA. The p110-α polypeptide may also be referred to as "PIK3CA." The p110-α polypeptide comprises 1068 amino acids and has the amino acid sequence set forth in SEQ ID NO: 1:

[0132] p110-α (SEQ ID NO: 1)

[0133]

[0134] The Enzyme Commission (EC) number for the catalytic activity of PI3Kα is 2.7.1.153. The catalytic activity of PI3Kα includes phosphatidylinositol-4,5-bisphosphate 3-kinase activity, in which a phosphate group of adenosine triphosphate (ATP) is transferred to phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). PI3Kα catalyzes the addition of the 3-phosphate group from ATP to PIP2 by binding ATP to the ATP-binding pocket within the kinase catalytic domain of the p100α subunit of PI3Kα.

[0135] 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 to or near the ATP binding pocket of PI3Kα, which can 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 aNon-ATP Pocket for Potential Allosteric Modulation of PI3Kα, J. Phys. Chem. B 2015, 119, 1002-1016, published on October 9, 2014; and Fairhurst et al., Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazoleand 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3kinase alpha inhibitors, Biorg. & Medic. Chem. Lett. 25 (2015) 3575-3581, published on June 26, 2015). The ATP binding pocket is located in the cleft between the N-terminal and C-terminal lobes of the catalytic domain of p100α kinase. The ATP binding pocket may comprise one or more amino acid residues selected from the group consisting of R770, M772, P778, W780, 1800, K802, D810, Y836, 1848, V850, V851, S854, Q859, N920, M922, F930, 1932, and D933.

[0136] Orthosteric inhibitors of PI3Kα can bind to PI3Kα at or near the ATP binding pocket of PI3Kα and can interact with one or more amino acids selected from R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933. Interactions may include, but are not limited to, hydrogen bonding, π-πT stacking, and coplanar core π-π stacking, either directly or through bridging water molecules. Orthosteric inhibitors of PI3Kα are known and may include, but are not limited to, alpelisib, inavolisib, and serabelisib, which are selective inhibitors of PI3Kα.

[0137] The disclosed inhibitors can inhibit PI3Kα by binding to or near a pocket of PI3Kα that is not the ATP binding pocket of PI3Kα, which can be referred to as an "allosteric pocket". The disclosed inhibitors can act as allosteric inhibitors of PI3Kα. PI3Kα allosteric inhibitors 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 / 018636, WO2023 / 039532, WO2023 / 056407, WO2023 / 060262, WO2023 / 288242, WO2023 / 081209, WO2023 / 081757, WO2023 / 081759, WO2023 / 078401, WO2023 / 104111, WO2023 / 109870, WO2023 / 159155, WO2023 / 168378, WO2023 / 173124, and WO2023 / 192416 and WO2023 / 288242, the contents disclosed therein regarding PI3Kα inhibitor compounds and methods of making and using PI3Kα inhibitor compounds are incorporated herein by reference in their entirety.

[0138] In some aspects, the allosteric inhibitors disclosed herein can bind to PI3Kα at or near the PI3Kα allosteric pocket (referred to herein as "PI3Kα allosteric pocket 1"). In some aspects, the allosteric inhibitors of PI3Kα can bind to the PI3Kα allosteric pocket 1 and can interact with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The interactions may include, but are not limited to, hydrogen bonding, π-πT stacking, and coplanar core π-π stacking, either directly or through bridging water molecules. Specific interactions can 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 chromone exocyclic ketone group of the inhibitor, the bridging water molecule and the side chain of H931; hydrogen bonding between the chromone 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 π-π stacking between the chromone core of the inhibitor and the side chain of F954; π-πT-stacking between the phenyl core group of the inhibitor (e.g., the core in the substituent at the C2 position of the chromone core) and the side chain of F909; direct hydrogen bonding between the C3 substituent on the chromone core of the inhibitor and the side chain of H931; and core π-π stacking between the inhibitor core (e.g., the core of the substituent at the C3 position of the chromone core) and the side chain of F954. WO2021 / 202964, WO2022 / 235574, WO2022 / 235575, WO2022 / 251482, WO2023 / 056407, WO2023 / 060262 and WO2023 / 078401 disclose PI3Kα allosteric inhibitors that bind to PI3Kα allosteric pocket 1, and the contents disclosed in these patents regarding PI3Kα inhibitor compounds and methods for preparing and using PI3Kα inhibitor compounds are incorporated herein by reference in their entirety.

[0139] In some aspects, the allosteric inhibitors disclosed herein can bind to PI3Kα at or near the PI3Kα allosteric pocket (referred to herein as "PI3Kα allosteric pocket 2"). In some aspects, the allosteric inhibitors of PI3Kα can bind to PI3Kα allosteric pocket 2 and can interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. The interactions can include, but are not limited to, hydrogen bonding, π-πT stacking, and coplanar core π-π stacking, either directly or through bridging water molecules. Specific interactions may include one or more of the following interactions: direct hydrogen bonding between the nitrogen atom of the inhibitor's isoindolin-1-one core and the carbonyl backbone group of D1018; core π-π stacking binding between the inhibitor's 3-trifluoromethyl, 5-fluorophenyl core and the F937 side chain; π-πT stacking between the inhibitor's 3-trifluoromethyl, 5-fluorophenyl core and the F1002 side chain; and chloro-carbonyl interactions between the chlorine atom of the compound 2-chloro, 5-fluorophenyl and the side chain carbonyl of E1012.

[0140] 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 are incorporated herein by reference in their entirety for disclosures regarding PI3Kα inhibitor compounds and methods of making and using PI3Kα inhibitor compounds. In some embodiments, the disclosed methods may utilize the PI3Kα allosteric specific inhibitors disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, which optionally may bind to PI3Kα allosteric pocket 2.

[0141] In some embodiments of the methods disclosed herein, the methods may utilize the PI3Kα allosteric specific inhibitors disclosed in Table 1 on pages 162-855 of WO2021 / 222556 and referred to as compounds I-1 to I-2704 or pharmaceutically acceptable salts thereof.

[0142] In some embodiments, the method may utilize an allosteric specific inhibitor of PI3Kα selected from the group consisting of:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157] or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the method may utilize a PI3Kα allosteric specific inhibitor as disclosed in Table 1 of WO2021 / 222556, selected from:

[0159]

[0160] or a pharmaceutically acceptable salt thereof.

[0161] In some aspects of the methods disclosed herein, the methods may utilize the PI3Kα allosteric specific inhibitors disclosed in Tables AD on pages 175-259 of WO2022 / 265993. In some embodiments, the methods may utilize the PI3Kα allosteric specific inhibitors disclosed in WO2022 / 265993 selected from:

[0162]

[0163] or a pharmaceutically acceptable salt thereof.

[0164] In some aspects, the PI3Kα inhibitor used in the disclosed method can bind to PI3Kα simultaneously. In some aspects, the disclosed inhibitor combination can bind to one or more allosteric pockets (e.g., PI3Kα allosteric pocket 1 and / or PI3Kα allosteric pocket 2), and the disclosed inhibitor combination can bind to the PI3Kα positive-stable pocket at the same time. In some aspects, the disclosed inhibitor combination can bind to the first allosteric pocket (e.g., one of PI3Kα allosteric pocket 1 and PI3Kα allosteric pocket 1), and the disclosed inhibitor combination can bind to the second allosteric pocket (e.g., another of PI3Kα allosteric pocket 1 and PI3Kα allosteric pocket 2) at the same time. In some aspects, the disclosed inhibitor combination can bind to the first allosteric pocket (e.g., PI3Kα allosteric pocket 1), the disclosed inhibitor combination can bind to the second or allosteric pocket (e.g., PI3Kα allosteric pocket 2), and the disclosed inhibitor combination can bind to the PI3Kα positive-stable pocket at the same time.

[0165] 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 allosteric pockets (e.g., PI3Kα allosteric pocket 1 and / or PI3Kα allosteric pocket 2).

[0166] In some aspects, PI3Kα selective inhibitors (which may include PI3Kα selective allosteric inhibitors and PI3Kα selective orthosteric inhibitors) can inhibit the activity of PI3Kα, such as the phosphorylation activity of PI3Kα. Phosphorylation activity can be determined 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. 50 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 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 allosteric inhibitors and PI3Kα selective orthosteric inhibitors) can inhibit the growth of cancer cells whose growth is dependent on PI3Kα activity. Growth inhibition can be determined using methods including those disclosed herein, including the use of 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 .

[0167] In some aspects, the disclosed subject matter relates to methods for treating diseases and disorders associated with PI3K α regulation using a plurality of PI3K α inhibitors or a combination of PI3K α inhibitors. As used herein, the terms "a plurality of PI3K α inhibitors" or "a combination of PI3K α inhibitors" should be interpreted as referring to "two or more different PI3K α inhibitors". A plurality of PI3K α inhibitors can inhibit PI3K α by binding at or near the same PI3K α pocket (e.g., at or near the PI3K α allosteric pocket), or a plurality of PI3K α inhibitors can inhibit PI3K α by binding at or near different PI3K α pockets (e.g., one inhibitor binds at or near the allosteric pocket of PI3K α, while another inhibitor binds at or near the orthosteric pocket of PI3K α, or one inhibitor binds at or near the allosteric pocket of PI3K α, while another inhibitor binds at or near a different allosteric pocket of PI3K α).

[0168] The disclosed methods may include administering a PI3Kα selective inhibitor. A PI3Kα selective inhibitor may be defined as a PI3Kα inhibitor whose inhibitory activity against PI3Kα is greater than its inhibitory activity against one or more of PI3Kβ, PI3Kγ, and PI3Kδ. In some aspects, a PI3Kα selective inhibitor has an IC of 0.001 for PI3Kα in a phosphorylation assay. 50 Value or EC 50 The values may be lower than the IC values for one or more of PI3Kβ, PI3Kγ, and PI3Kδ in a phosphorylation assay, respectively. 50 Value or EC 50 Used to determine the IC values for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ 50 Suitable phosphorylation assays for the values of PI3Kα may include, but are not limited to, in vitro biochemical 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 0.001 for PI3Kα in a phosphorylation assay. 50 Value or EC 50 The values are the IC values for one or more of PI3Kβ, PI3Kγ, and PI3Kδ in phosphorylation assays. 50 Value or EC50 At least 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 40, 1 / 50, 1 / 100, 1 / 500, or 1 / 1000 of the value.

[0169] The disclosed PI3Kα selective inhibitors can exhibit selectivity for mutant forms of PI3Kα relative to wild-type forms of PI3Kα. In some aspects, the disclosed PI3Kα selective inhibitors can exhibit selectivity for H1047R mutant PI3Kα relative to wild-type PI3Kα. In some aspects, the PI3Kα selective inhibitors have an IC of 0.001 for H1047R mutant PI3Kα in a phosphorylation assay. 50 Value or EC 50 The values were less than the IC values for wild-type PI3Kα in the phosphorylation assay. 50 Value or EC 50 In some aspects, the PI3Kα selective inhibitor has an IC value of less than about 100 nM, 50 nM, 10 nM, or 1 nM for 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 for 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 values are the IC values for wild-type PI3Kα in phosphorylation assays. 50 Value or EC 50 The value of the H1047R mutant PI3Kα is at least 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 40, 1 / 50, 1 / 100, 1 / 500, or 1 / 1000 times greater. 50 Value or EC 50 Suitable phosphorylation assays for the value may include, but are not limited to, in vitro biochemical or cell-based phosphorylation assays.

[0170] 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 in the disclosed methods, the first PI3Kα selective inhibitor be administered before (e.g., in time) the second PI3Kα selective inhibitor. In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor may be administered simultaneously or substantially simultaneously (e.g., less than about 12, 6, 2, 1, 0.5, 0.25, or 0.1 hours apart from each other), separately or at substantially different times (e.g., more than 12, 24, 48, or 72 hours apart, or more than 1, 2, 3, or 4 weeks apart, or more than 1, 2, 3, or 4 months apart), or sequentially (e.g., 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).

[0171] In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor can be administered by the same participant. In some aspects, a caregiver (e.g., the patient's physician or the patient's non-physician caregiver) 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 different participants. In some aspects, a caregiver administers one of the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor, and different caregivers administer the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor. In some aspects, a caregiver administers one of the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor to the patient, and the patient administers the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor to themselves.

[0172] In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα selective inhibitor can effectively reduce the patient's PI3Kα activity without causing 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 blood glucose greater than about 100, 105, 110, 115, 120, or 125 mg / dL when fasting (e.g., after not eating for at least 8 hours), or blood glucose greater than about 155, 160, 165, 170, 175, or 180 mg / dL one to two hours after eating. Adverse events may include, but are not limited to, hyperinsulinemia, diarrhea, dehydration, rash, lymphopenia, elevated alanine aminotransferase, fatigue, anemia, elevated serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemia, alopecia, prolonged activated partial thromboplastin time, kidney disease with reduced glomerular filtration rate (GFR), acute abdominal pain, and abnormal liver function tests.

[0173] In some aspects of the disclosed methods, a therapeutically effective amount of a PI3Kα selective inhibitor is administered to a patient in need, 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 100-1200 mg oral dose (e.g., BID (twice daily)). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose (e.g., 37.5 mg / kg oral dose BID).

[0174] The PI3Kα selective allosteric 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 amount of compound actually administered will be determined by the physician based on relevant circumstances, including the condition to be treated, the selected 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.

[0175] In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 200 mg to 2400 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 400 mg to 2000 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 600 mg to 1200 mg.

[0176] In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 200 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 300 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 400 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 500 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 600 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 700 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 800 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 900 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1000 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1100 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1200 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1300 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1400 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1500 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1600 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1700 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1800 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 1900 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 2000 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 2100 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 2200 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 2300 mg. In one embodiment, the total daily dose of the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is 2400 mg.

[0177] In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 200 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 300 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 400 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 500 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 600 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 700 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 800 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 900 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1000 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1100 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1200 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1300 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1400 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1500 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1600 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1700 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1800 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 1900 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2000 mg for a 28-day cycle.In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2100 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2200 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2300 mg for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a total daily dose of 2400 mg for a 28-day cycle.

[0178] In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg to 1200 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg to 1000 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg to 600 mg twice daily.

[0179] In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 150 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 250 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 350 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 400 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 450 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 500 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 550 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 600 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 650 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 700 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 750 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 800 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 850 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 900 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 950 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1150 mg twice daily. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice daily.

[0180] In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg to 1200 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg to 1000 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 100 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 150 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 250 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 300 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 350 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 400 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 450 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 500 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 550 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 600 mg twice daily for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 650 mg twice a day for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 700 mg twice a day for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 750 mg twice a day for a period of 28 days. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 800 mg twice a day for a period of 28 days.In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 850 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 900 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 950 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1050 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1100 mg twice daily for a 28-day cycle. In one embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1150 mg twice daily for a 28-day cycle. In one embodiment, the PI3K alpha selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1200 mg twice daily for a period of 28 days.

[0181] In a preferred embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 200 mg twice a day for a period of 28 days. In another preferred embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 400 mg twice a day for a period of 28 days. In another preferred embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 600 mg twice a day for a period of 28 days. In another preferred embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 800 mg twice a day for a period of 28 days. In another preferred embodiment, the PI3Kα selective allosteric inhibitor or a pharmaceutical salt thereof is administered at a dose of 1000 mg twice a day for a period of 28 days.

[0182] In some aspects, the therapeutically effective amount of the PI3K alpha selective allosteric 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 the range defined by any of these values. In some aspects, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose (e.g., QD or BID 37.5 mg / kg). In some aspects, the therapeutically effective amount of the PI3K alpha selective allosteric inhibitor administered to the patient is less than about 75, 70, 65, 60, 55, 50, 45, 40, 37.5, 30, 35, 30, 25, 30, 15, 9, 8, 7, 6 or 5 mg / kg oral dose (e.g., QD or BID).

[0183] 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 oral dose QD (i.e., once daily administration) or less than about 300 mg oral dose QD, for example, less than about 250, 200, 150, 100, or 50 mg QD. In certain aspects, the therapeutically effective amount of the PI3Kα selective orthosteric inhibitor administered to the patient is 50 mg / kg oral dose QD (i.e., administered once a day) or less than about 50 mg / kg oral dose QD, e.g., less than about 30, 12.5, 6.25, or 3.125 mg / kg oral dose QD, e.g., when the PI3Kα selective orthosteric inhibitor is administered simultaneously, separately, or sequentially with a PI3Kα selective allosteric inhibitor (e.g., a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 1 or PI3Kα allosteric pocket 2).

[0184] The disclosed methods may involve 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 suffers from 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 suffers from a disease or condition that is resistant to treatment with a PI3Kα selective inhibitor and the patient has not previously received treatment with a PI3Kα selective inhibitor.

[0185] The disclosed methods may involve patients with a disease or condition that results in acquired resistance to a PI3Kα selective inhibitor. In vitro characterization of acquired resistance can be performed by methods including, but not limited to, growth inhibition of ECs. 50shifts, such as measured by cell viability assays; changes in phosphorylation inhibition, such as measured by Western blotting and quantification of phosphorylated bands, or by determining the IC in phosphorylation assays 50 Value determination; and stability of cell colonies under non-selective conditions. The in vivo or clinical characteristic of acquired resistance may be the observation of relapse after the patient receives treatment with a PI3Kα selective inhibitor and the patient previously showed remission. For patients with cancer, the clinical characteristic of acquired resistance may be the observation of relapse after a remission was previously observed when the patient was treated with a PI3Kα selective inhibitor. For patients with cancer, the clinical characteristic of acquired resistance may be the observation of increased cancer growth after a decrease in cancer growth was previously observed following treatment with a PI3Kα selective inhibitor. For patients with cancer, the clinical characteristic of acquired resistance may be the observation of recurrence of cancer at a different site in the patient's body than the site where the cancer was first observed prior to treatment with the PI3Kα selective inhibitor.

[0186] In the disclosed method, a therapeutically effective amount of one or more PI3Kα selective inhibitors can be administered to the patient, which may include a combination of an allosteric inhibitor and / or a positive inhibitor. In some aspects, the disclosed method also includes administering a therapeutically effective amount of another therapeutic agent to the patient. In some aspects of the disclosed method, a therapeutically effective amount of a selective estrogen receptor degrader (SERD) is also 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 method, the therapeutically effective amount of SERD is a dosage of 500 mg, which can be administered on the 1st, 15th, and 29th days or in a treatment regimen.

[0187] In the disclosed method, there is a patient in need who may suffer from cancer. In some aspects, there is a patient in need who may suffer from breast cancer. In some aspects, there is a patient in need who may suffer from PIK3CA mutation, late stage or metastatic breast cancer. The cancer of PIK3CA mutation may include a cancer with one or more mutations selected from but not limited to: E542K, E545K, E453Q / K, E726K, C901F, M1043I / L and H1047R, optionally wherein the one or more mutations are cis (i.e., on the same allele). In some aspects, there is a patient in need who may suffer from PIK3CACA H1047R mutation late stage or metastatic breast cancer, which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[0188] In some aspects of the disclosed methods, the patient in need thereof is a postmenopausal female.

[0189] In some aspects of the disclosed methods, the patient has type 2 diabetes.

[0190] IA Combination of allosteric and orthosteric inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of PI3K-related Use in regulating related diseases and conditions

[0191] In some aspects, the disclosed methods relate to methods for treating diseases or conditions associated with PI3Kα regulation. The methods may include administering to a patient in need: (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 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 the PI3Kα orthosteric pocket. The disclosed methods may include administering a first PI3Kα selective inhibitor (which is a PI3Kα selective allosteric inhibitor) and a second PI3Kα selective inhibitor (which is a PI3Kα selective orthosteric inhibitor). In the disclosed methods, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor may be administered simultaneously, separately, or sequentially.

[0192] In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor of Formula I:

[0193]

[0194] or a pharmaceutically acceptable salt thereof, wherein:

[0195] R is -H or C1-C3 alkyl;

[0196] R1 is a group of the formula:

[0197]

[0198]

[0199] R2 is a group of the formula:

[0200]

[0201] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0202] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0203] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0204] R8 is -H or C1-C6 alkyl;

[0205] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0206] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0207] R 11 Each is independently -H or C1-C3 alkyl.

[0208] In some aspects of the disclosed method, the allosteric inhibitor is of the formula:

[0209]

[0210] or a pharmaceutically acceptable salt thereof.

[0211] The second PI3Kα selective inhibitor used in the disclosed methods binds to the PI3Kα orthosteric pocket and can function as an orthosteric inhibitor. In certain aspects, the orthosteric inhibitor is apelisib or a pharmaceutically acceptable salt thereof. In certain aspects, the orthosteric inhibitor is inavulisib or a pharmaceutically acceptable salt thereof. In certain aspects, the orthosteric inhibitor is cerabelicip or a pharmaceutically acceptable salt thereof.

[0212] 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 100-1200 mg oral dose BID (i.e., twice daily administration). In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg or less than about 37 mg / kg).

[0213] 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 oral dose QD (i.e., administered once daily) or less than about 300 mg oral dose QD.

[0214] 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 that would be 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 that would be required in a treatment method in which the allosteric inhibitor is not administered.

[0215] 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 causing 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 causing adverse events, or while minimizing the risk of adverse events.

[0216] 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 apelisib.

[0217] In the disclosed method, the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor can be applied in sequence. In some aspects, the method includes applying the second PI3Kα selective inhibitor after the disease or condition develops resistance to the first PI3Kα selective inhibitor. In some aspects, after the disease or condition develops resistance to the first PI3Kα selective inhibitor, the second PI3Kα selective inhibitor is initially applied. In some aspects, the second PI3Kα selective inhibitor is not applied until the disease or condition develops resistance to the first PI3Kα selective inhibitor. In some aspects, resistance is characterized by the presence of M1043 mutations (e.g., M1043I or M1043L) and / or C901 mutations (e.g., C901F). Patients who exhibit resistance may suffer from a disease or condition comprising M1043I / L mutations and / or C901F mutations and H1047R mutations (optionally, wherein M1043I / L mutations and C901F mutations are cis with H1047R mutations on the same allele).

[0218] IB Combination of a first allosteric inhibitor and a second allosteric inhibitor of phosphoinositide 3-kinase (PI3K) for the treatment of The invention relates to a method for treating diseases and conditions associated with PI3K regulation, wherein the first allosteric inhibitor and the second allosteric inhibitor are different Allosteric pocket binding

[0219] 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. 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 allosteric pocket 1 and optionally 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 a different allosteric pocket of PI3Kα, such as PI3Kα allosteric pocket 2, and optionally can interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. The disclosed methods can include 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.

[0220] In the disclosed methods, the first PI3Kα selective inhibitor can be an allosteric inhibitor of Formula I:

[0221]

[0222] or a pharmaceutically acceptable salt thereof, wherein:

[0223] R is -H or C1-C3 alkyl;

[0224] R1 is a group of the formula:

[0225]

[0226] R2 is a group of the formula:

[0227]

[0228] R3 is -H, halogen, CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0229] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0230] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0231] R8 is -H or C1-C6 alkyl;

[0232] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0233] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0234] R 11 Each is independently -H or C1-C3 alkyl.

[0235] In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor of the formula:

[0236]

[0237] or a pharmaceutically acceptable salt thereof.

[0238] 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 disclosures of which regarding PI3Kα inhibitor compounds and methods of making and using the same are incorporated herein by reference in their entireties.

[0239] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor of Formula IV:

[0240]

[0241] or a pharmaceutically acceptable salt thereof, wherein:

[0242] 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)-;

[0243] Q is CH, C(R Q ) or N;

[0244] X is CH, C(R x ) or N;

[0245] Y is CH, C(R Y ) or N;

[0246] Z is CH, C(R Z ) or N;

[0247] R 1 Yes-L 1 -R 1A ;

[0248] R 2 Yes-L 2 -R 2A ;

[0249] R E Each instance of is independently H or -L E -R EA ;

[0250] R Q Yes-L Q -R QA ;

[0251] R X Yes-L X -R XA ;

[0252] R Y Yes-L Y -R YA ;

[0253] R Z Yes-L Z -R ZA ;or

[0254] R ETwo examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0255] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0256] R Y and R Z Together with the atoms between them, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0257] R 1A Is R 1C r 1 R A or R B ;

[0258] R 2A Is R 2C r 2 RA or R B ;

[0259] R EA Is R EC r 3 R A or R B ;

[0260] R QA Is R QC r 4 R A or R B ;

[0261] R XA Is R XC r 5 R A or R B ;

[0262] R YA Is R YC r 6 R A or R B ;

[0263] R ZA Is R ZC r 7 R A or R B ;

[0264] R L Is R LC r 8 R A or R B ;

[0265] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0266] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0267] R 1C 、R 2C 、R EC 、R QC 、R XC 、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZC each instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0268] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0269] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each independently is 0, 1, 2, 3, 4 or 5.

[0270] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor of Formula XXVIII:

[0271]

[0272] or a pharmaceutically acceptable salt thereof.

[0273] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor of the formula:

[0274]

[0275] or a pharmaceutically acceptable salt thereof.

[0276] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein

[0277] R 1 yes

[0278] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0279] 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 1-3 halogens 1-3 Aliphatic group.

[0280] 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)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0281] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0282] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R 2C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0283] 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 1-3 halogens 1-3 Aliphatic group.

[0284] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0285] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA for

[0286]

[0287] In some aspects, the second PI3Kα selective inhibitor has a middle R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C1-3 aliphatic) or C 1-3 an aliphatic group, wherein each C 1-3 The aliphatic group is optionally substituted with one or more halogen atoms.

[0288] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor has a formula selected from the group consisting of:

[0289]

[0290] or a pharmaceutically acceptable salt thereof.

[0291] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from:

[0292]

[0293] or a pharmaceutically acceptable salt thereof.

[0294] 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 100-1200 mg oral dose BID (i.e., administered twice a day). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg).

[0295] In some aspects of the disclosed methods, which include administering a therapeutically effective amount of a first allosteric inhibitor and a therapeutically effective amount of a second allosteric inhibitor, a synergistic effect can be observed. In some aspects of the disclosed methods, the therapeutically effective amount of the first allosteric inhibitor administered to the patient can be less than the therapeutically effective amount of the first allosteric inhibitor required in a method without administering the second allosteric inhibitor. In some aspects of the disclosed methods, the therapeutically effective amount of the second allosteric inhibitor administered to the patient can be less than the therapeutically effective amount of the second allosteric inhibitor required in a method without administering the first allosteric inhibitor.

[0296] In some aspects of the disclosed methods, a therapeutically effective amount of the first allosteric inhibitor is effective to reduce PI3Kα activity in a patient without causing an adverse event, or while minimizing the risk of an adverse event. In some aspects of the disclosed methods, a therapeutically effective amount of the second allosteric inhibitor is effective to reduce PI3Kα activity in a patient without causing an adverse event, or while minimizing the risk of an adverse event.

[0297] In the disclosed method, the first allosteric inhibitor and the second allosteric inhibitor can be sequentially applied. In some respects, the method is included in applying the second allosteric inhibitor after disease or illness produces resistance to the first allosteric inhibitor. In some respects, after disease or illness produces resistance to the first allosteric inhibitor, the second allosteric inhibitor is initially applied. In some respects, the second allosteric inhibitor is just applied after disease or illness produces resistance to the first allosteric inhibitor. In some respects, the feature of resistance is that there is M1043 mutation (for example, M1043I or M1043L) and / or C901 mutation (for example, C901F). In some respects, the patient suffers from the disease or illness (optionally wherein M1043I / L mutation and C901F mutation and H1047R mutation are cis on the same allele) comprising M1043I / L mutation and / or C901F mutation and H1047R mutation.

[0298] Combination of a first allosteric inhibitor and a second allosteric inhibitor of phosphoinositide 3-kinase (PI3K) for the treatment of The invention relates to a method for treating diseases and conditions associated with PI3K regulation, wherein the first allosteric inhibitor and the second allosteric inhibitor are combined with the same allosteric inhibitor. Pocket combination

[0299] The disclosed methods may relate to methods of 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 the PI3Kα allosteric 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 the PI3Kα allosteric 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 include 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.

[0300] In some aspects of the disclosed methods, the first PI3Kα selective inhibitor is an allosteric inhibitor of Formula I:

[0301]

[0302] or a pharmaceutically acceptable salt thereof, wherein:

[0303] R is -H or C1-C3 alkyl;

[0304] R1 is a group of the formula:

[0305]

[0306] R2 is a group of the formula:

[0307]

[0308] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0309] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0310] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0311] R8 is -H or C1-C6 alkyl;

[0312] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0313] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0314] R 11 Each is independently -H or C1-C3 alkyl.

[0315] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor of Formula I:

[0316]

[0317] or a pharmaceutically acceptable salt thereof, wherein:

[0318] R is -H or C1-C3 alkyl;

[0319] R1 is a group of the formula:

[0320]

[0321] R2 is a group of the formula:

[0322]

[0323] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0324] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0325] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0326] R8 is -H or C1-C6 alkyl;

[0327] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0328] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0329] R 11 Each is independently -H or C1-C3 alkyl.

[0330] In certain aspects of the disclosed methods, the first allosteric inhibitor of Formula I and the second allosteric inhibitor of Formula I are different.

[0331] In certain aspects of the disclosed methods, the first allosteric inhibitor has the formula:

[0332]

[0333] or a pharmaceutically acceptable salt thereof.

[0334] In certain aspects of the disclosed methods, the second PI3Kα selective inhibitor does not have the formula:

[0335]

[0336] or a pharmaceutically acceptable salt thereof.

[0337] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is an allosteric inhibitor of the formula:

[0338]

[0339] or a pharmaceutically acceptable salt thereof.

[0340] In some aspects of the disclosed methods, the second allosteric inhibitor has a formula selected from:

[0341]

[0342]

[0343] or a pharmaceutically acceptable salt thereof.

[0344] 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 100-1200 mg oral dose BID (i.e., twice daily administration). In some aspects, the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg / kg oral dose BID (e.g., 37.5 mg / kg).

[0345] In the disclosed method, the first allosteric inhibitor and the second allosteric inhibitor can be sequentially applied. In some respects, the method is included in applying the second allosteric inhibitor after disease or illness produces resistance to the first allosteric inhibitor. In some respects, after disease or illness produces resistance to the first allosteric inhibitor, the second allosteric inhibitor is initially applied. In some respects, the second allosteric inhibitor is applied until disease or illness produces resistance to the first allosteric inhibitor. In some respects, the second allosteric inhibitor is applied after disease or illness produces resistance to the first allosteric inhibitor. In some respects, resistance is characterized by the presence of M1043 mutation (for example, M1043I or M1043L) and / or C901 mutation (for example, C901F). In some respects, the patient may suffer from the disease or illness (optionally, wherein M1043I / L mutation and C901F mutation and H1047R mutation are cis on the same allele) comprising M1043I / L mutation and / or C901F mutation and H1047R mutation.

[0346] ID(i). Use of allosteric inhibitors for treating diseases or conditions resistant to treatment with orthosteric inhibitors

[0347] In some aspects, the disclosed methods relate to methods for treating a disease or condition associated with PI3Kα regulation that is resistant to treatment with a PI3Kα selective orthosteric inhibitor. The methods can include administering to a patient suffering from the disease or condition a therapeutically effective amount of a PI3Kα selective allosteric inhibitor, wherein the PI3Kα selective allosteric inhibitor binds to the PI3Kα allosteric pocket 1 and optionally can interact with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0348] In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant 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 become resistant to treatment with an orthosteric inhibitor, wherein the patient has not been previously treated with the orthosteric inhibitor.

[0349] In some aspects of the disclosed methods, the disease or condition is resistant to treatment with apelisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with inavolini or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with cerabelicip or a pharmaceutically acceptable salt thereof.

[0350] In some aspects of the disclosed methods, the allosteric inhibitor has Formula I:

[0351]

[0352] or a pharmaceutically acceptable salt thereof, wherein:

[0353] R is -H or C1-C3 alkyl;

[0354] R1 is a group of the formula:

[0355]

[0356] R2 is a group of the formula:

[0357]

[0358] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0359] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0360] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0361] R8 is -H or C1-C6 alkyl;

[0362] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0363] R 10Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0364] R 11 Each is independently -H or C1-C3 alkyl.

[0365] In some aspects of the disclosed methods, the allosteric inhibitor does not have the formula:

[0366]

[0367] or a pharmaceutically acceptable salt thereof.

[0368] In some aspects of the disclosed methods, the allosteric inhibitor has the formula:

[0369]

[0370] or a pharmaceutically acceptable salt thereof.

[0371] In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from:

[0372]

[0373] or a pharmaceutically acceptable salt thereof.

[0374] The disclosed methods may include administering a therapeutically effective amount of a PI3Kα selective allosteric inhibitor to a patient suffering from a disease or condition resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further include administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient.

[0375] ID(ii). Use of other allosteric inhibitors for treating diseases or conditions resistant to orthosteric inhibitors

[0376] In some aspects, the disclosed methods relate to methods of treating a disease or condition associated with PI3Kα regulation that is resistant to treatment with a PI3Kα selective orthosteric inhibitor. The methods can include administering to a patient suffering from the disease or condition a therapeutically effective amount of a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2 and optionally can form one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0377] In some aspects of the disclosed methods, the patient develops a disease or condition that is resistant to treatment with an orthosteric inhibitor after prior treatment with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that exhibits de novo resistance to treatment with an orthosteric inhibitor, wherein the patient has not been previously treated with the orthosteric inhibitor.

[0378] In some aspects of the disclosed methods, the disease or condition is resistant to treatment with apelisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with inavolini or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or condition is resistant to treatment with cerabelicip or a pharmaceutically acceptable salt thereof.

[0379] 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 PI3Kα inhibitor compounds and methods of making and using PI3Kα inhibitor compounds.

[0380] In some aspects of the disclosed methods, the allosteric inhibitor has Formula IV:

[0381]

[0382] or a pharmaceutically acceptable salt thereof, wherein:

[0383] 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)-;

[0384] Q is CH, C(R Q ) or N;

[0385] X is CH, C(R x ) or N;

[0386] Y is CH, C(R Y ) or N;

[0387] Z is CH, C(R Z ) or N;

[0388] R 1 Yes-L 1 -R 1A ;

[0389] R 2 Yes-L 2 -R 2A ;

[0390] R E Each instance of is independently H or -L E -R EA ;

[0391] R Q Yes-L Q -R QA ;

[0392] R X Yes-L X -R XA ;

[0393] R Y Yes-L Y -R YA ;

[0394] R Z Yes-L Z -R ZA ;or

[0395] R ETwo examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0396] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0397] R Y and R Z Together with the intervening atoms, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0398] R 1A To be R 1C r 1 R A or R B ;

[0399] R 2A To be R 2C r 2 RA or R B ;

[0400] R EA Is R EC r 3 R A or R B ;

[0401] R QA Is R QC r 4 R A or R B ;

[0402] R XA Is R XC r 5 R A or R B ;

[0403] R YA Is R YC r 6 R A or R B ;

[0404] R ZA Is R ZC r 7 R A or R B ;

[0405] R L To be R LC r 8 R A or R B ;

[0406] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0407] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0408] R 1C 、R 2C 、R EC 、R QC 、R XC 、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZC each instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0409] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0410] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each independently is 0, 1, 2, 3, 4 or 5.

[0411] In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII:

[0412]

[0413] or a pharmaceutically acceptable salt thereof.

[0414] In some aspects of the disclosed methods, the allosteric inhibitor has the formula:

[0415]

[0416] or a pharmaceutically acceptable salt thereof.

[0417] In some aspects, the allosteric inhibitor has the formula, wherein

[0418] R 1 yes

[0419] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0420] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0421] In some aspects, the allosteric inhibitor has the formula, wherein R2 -N(H)C(O)-R 2A 、-N(H)C(O)N(H)-R 2A 、-C(O)N(H)-R 2A 、-N(H)-R 2A 、-S(O)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0422] In some aspects, the allosteric inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0423] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0424] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0425] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0426] In some aspects, the allosteric inhibitor has the formula, wherein R YA for

[0427]

[0428] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic) or C 1-3 Aliphatic group, where C 1-3 The aliphatic groups are each optionally substituted with one or more halogen atoms.

[0429] In some aspects of the disclosed methods, the allosteric inhibitor has a formula selected from:

[0430] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor has a formula selected from the group consisting of:

[0431]

[0432] or a pharmaceutically acceptable salt thereof.

[0433] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from:

[0434]

[0435] or a pharmaceutically acceptable salt thereof.

[0436] The disclosed methods may include administering a therapeutically effective amount of a PI3Kα selective allosteric inhibitor to a patient suffering from a disease or condition resistant to treatment with an orthosteric inhibitor. In some aspects, the disclosed methods further include administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient.

[0437] ID(iii) Use of allosteric inhibitors for treating diseases or conditions resistant to other allosteric inhibitors

[0438] In some aspects, the disclosed methods relate to methods of treating a disease or condition associated with PI3Kα regulation that is resistant to treatment with a first PI3Kα selective allosteric inhibitor, wherein the first PI3Kα selective allosteric inhibitor binds to the PI3Kα allosteric pocket 1 and optionally can form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The method can include administering to a patient suffering from the disease or condition a therapeutically effective amount of a second, different, PI3Kα selective allosteric inhibitor that binds to the PI3Kα allosteric pocket 1 and optionally can form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0439] In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant to treatment with the first allosteric inhibitor after the patient was previously treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant to treatment with the first allosteric inhibitor de novo, wherein the patient has not been previously treated with the first allosteric inhibitor.

[0440] In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor of Formula I:

[0441]

[0442] or a pharmaceutically acceptable salt thereof, wherein:

[0443] R is -H or C1-C3 alkyl;

[0444] R1 is a group of the formula:

[0445]

[0446] R2 is a group of the formula:

[0447]

[0448] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0449] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0450] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0451] R8 is -H or C1-C6 alkyl;

[0452] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0453] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0454] R 11 Each is independently -H or C1-C3 alkyl.

[0455] In some aspects of the disclosed methods, the disease or condition is resistant to treatment with an allosteric inhibitor of the formula:

[0456]

[0457] or a pharmaceutically acceptable salt thereof.

[0458] In some aspects of the disclosed methods, a patient resistant to treatment with a first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor of Formula I:

[0459]

[0460] or a pharmaceutically acceptable salt thereof, wherein:

[0461] R is -H or C1-C3 alkyl;

[0462] R1 is a group of the formula:

[0463]

[0464] R2 is a group of the formula:

[0465]

[0466] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0467] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0468] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0469] R8 is -H or C1-C6 alkyl;

[0470] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0471] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0472] R 11 Each is independently -H or C1-C3 alkyl.

[0473] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has the formula:

[0474]

[0475] or a pharmaceutically acceptable salt thereof.

[0476] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from:

[0477]

[0478] or a pharmaceutically acceptable salt thereof.

[0479] The disclosed methods may include administering a therapeutically effective amount of a PI3Kα selective allosteric inhibitor to a patient suffering from a disease or condition resistant to treatment with a different PI3Kα selective allosteric inhibitor. In some aspects, the disclosed methods further include administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient.

[0480] ID(iv) Allosteric inhibitors are used to treat a disease or condition that has acquired resistance to another allosteric inhibitor. Uses of

[0481] In some aspects, the disclosed methods relate to methods of treating a disease or condition associated with PI3Kα regulation that is resistant to treatment with a first PI3Kα selective allosteric inhibitor, wherein the first PI3Kα selective allosteric inhibitor binds to PI3Kα allosteric pocket 1 and optionally can form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. The method can include administering to a patient suffering from the disease or condition a therapeutically effective amount of a different second PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2 and optionally can form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0482] In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant to treatment with the first allosteric inhibitor after the patient was previously treated with the first allosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or condition that has become resistant to treatment with the first allosteric inhibitor de novo, wherein the patient has not been previously treated with the first allosteric inhibitor.

[0483] In some aspects of the disclosed methods, the patient is resistant to treatment with a first allosteric inhibitor of Formula I:

[0484]

[0485] or a pharmaceutically acceptable salt thereof, wherein:

[0486] R is -H or C1-C3 alkyl;

[0487] R1 is a group of the formula:

[0488]

[0489] R2 is a group of the formula:

[0490]

[0491] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0492] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0493] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0494] R8 is -H or C1-C6 alkyl;

[0495] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0496] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0497] R 11 Each is independently -H or C1-C3 alkyl.

[0498] In some aspects of the disclosed methods, the disease or condition is resistant to treatment with an allosteric inhibitor of the formula:

[0499]

[0500] or a pharmaceutically acceptable salt thereof.

[0501] In some aspects of the disclosed methods, a patient who is resistant to treatment with a first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor, such as disclosed in WO2021 / 222556, WO2022 / 265993, WO2023 / 018636, WO2023 / 039532, WO2023 / 288242, WO2023 / 081757, or WO2023 / 081759, the disclosures of which regarding PI3Kα inhibitor compounds and methods of making and using PI3Kα inhibitor compounds are incorporated herein by reference in their entireties. In some aspects of the disclosed methods, the second allosteric inhibitor has Formula IV:

[0502]

[0503] or a pharmaceutically acceptable salt thereof, wherein:

[0504] 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)-;

[0505] Q is CH, C(R Q ) or N;

[0506] X is CH, C(R x) or N;

[0507] Y is CH, C(R Y ) or N;

[0508] Z is CH, C(R Z ) or N;

[0509] R 1 Yes-L 1 -R 1A ;

[0510] R 2 Yes-L 2 -R 2A ;

[0511] R E Each instance of is independently H or -L E -R EA ;

[0512] R Q Yes-L Q -R QA ;

[0513] R X Yes-L X -R XA ;

[0514] R Y Yes-L Y -R YA ;

[0515] R Z Yes-L Z -R ZA ;or

[0516] R E Two examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0517] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0518] R Y and RZ Together with the intervening atoms, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0519] R 1A To be R 1C r 1 R A or R B ;

[0520] R 2A To be R 2C r 2 R A or R B ;

[0521] R EA Is R EC r 3 R A or R B ;

[0522] R QA Is R QC r 4 R A or R B ;

[0523] R XA Is R XC r 5 R A or RB ;

[0524] R YA Is R YC r 6 R A or R B ;

[0525] R ZA Is R ZC r 7 R A or R B ;

[0526] R L To be R LC r 8 R A or R B ;

[0527] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0528] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0529] R 1C 、R 2C 、R EC 、R QC 、RXC 、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZC each instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0530] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0531] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8Each independently is 0, 1, 2, 3, 4 or 5.

[0532] In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII:

[0533]

[0534] or a pharmaceutically acceptable salt thereof.

[0535] In some aspects of the disclosed methods, the allosteric inhibitor has the formula:

[0536]

[0537] or a pharmaceutically acceptable salt thereof.

[0538] In some aspects, the allosteric inhibitor has the formula, wherein

[0539] R 1 yes

[0540] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0541] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0542] 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)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0543] In some aspects, the allosteric inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0544] In some aspects, the allosteric inhibitor has the formula, wherein R2C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0545] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0546] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0547] In some aspects, the allosteric inhibitor has the formula, wherein R YA for

[0548]

[0549] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic) or C 1-3 an aliphatic group, wherein each C 1-3 The aliphatic group is optionally substituted with one or more halogen atoms.

[0550] In some aspects of the disclosed methods, the allosteric inhibitor administered to the patient has a formula selected from:

[0551]

[0552] or a pharmaceutically acceptable salt thereof.

[0553] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from the group consisting of:

[0554]

[0555] or a pharmaceutically acceptable salt thereof.

[0556] The disclosed methods may include administering a therapeutically effective amount of a PI3Kα selective allosteric inhibitor to a patient suffering from a disease or condition resistant to treatment with another PI3Kα selective allosteric inhibitor. In some aspects, the disclosed methods further include administering a therapeutically effective amount of a selective estrogen receptor degrader (SERD) to the patient.

[0557] IE is an orthosteric inhibitor for the treatment of M1043I / L+H1047R cancers

[0558] In certain aspects, the disclosed methods relate to treating a disease or condition associated with PI3Kα regulation in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), optionally after the patient has previously been 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, optionally, can interact 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 allosteric inhibitor, or the patient may have a cancer that exhibits de novo resistance to treatment with a PI3Kα-selective allosteric inhibitor; and in the disclosed methods, a therapeutically effective amount of a PI3Kα-selective orthosteric inhibitor may be administered to the patient.

[0559] In some aspects of the disclosed methods, the patient was previously treated with a PI3Kα selective allosteric inhibitor of Formula I, or a pharmaceutically acceptable salt thereof:

[0560]

[0561] in:

[0562] R is -H or C1-C3 alkyl;

[0563] R1 is a group of the formula:

[0564]

[0565] R2 is a group of the formula:

[0566]

[0567] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted 3 to 5 ring atom heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted 5 or 6 ring atom heteroaryl 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0568] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0569] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0570] R8 is -H or C1-C6 alkyl;

[0571] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0572] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0573] R 11 Each is independently -H or C1-C3 alkyl.

[0574] In some aspects of the disclosed methods, the patient has previously been treated with a therapeutically effective amount of a PI3Kα selective allosteric inhibitor of the formula:

[0575]

[0576] In some aspects of the disclosed methods, the therapeutically effective amount of the PI3Kα selective allosteric inhibitor administered to the patient is a 100-1200 mg oral dose administered twice daily. In some aspects of the disclosed methods, the therapeutically effective amount of the first PI3Kα selective inhibitor administered to the patient is a 9-75 mg / kg oral dose administered twice daily (e.g., a 37.5 mg / kg oral dose administered twice daily). In the disclosed methods, the patient may have acquired resistance to treatment with the PI3Kα selective allosteric inhibitor administered at the indicated dose.

[0577] 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 oral dose QD (i.e., administered once daily) or less than about 300 mg oral dose QD, such as less than about 250, 200, 150, 100, or 50 mg oral dose QD.

[0578] In some aspects, the disclosed methods include administering to a patient a therapeutically effective amount of a PI3Kα selective orthosteric inhibitor, and the disclosed methods further include administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, the administered PI3Kα selective orthosteric inhibitor is selected from apelisib, inavulisib, cerabelic acid, or a pharmaceutically acceptable salt thereof.

[0579] IF(i). Allosteric inhibitors for the treatment of M1043I / L+H1047R cancers

[0580] 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 a cancer comprising an M1043 mutation with an H1047R mutation (e.g., M1043I / L, optionally in cis) and / or a C901 mutation with an H1047R mutation (e.g., C901F, optionally in cis). The method comprises administering to the patient a therapeutically effective amount of a PI3Kα selective allosteric inhibitor that binds to PI3Kα allosteric pocket 2 and optionally can interact with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.

[0581] In some aspects, the PI3Kα selective allosteric inhibitor administered to the patient has Formula IV:

[0582]

[0583] or a pharmaceutically acceptable salt thereof, wherein:

[0584] 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)-;

[0585] Q is CH, C(R Q ) or N;

[0586] X is CH, C(R x ) or N;

[0587] Y is CH, C(R Y ) or N;

[0588] Z is CH, C(R Z ) or N;

[0589] R 1 Yes-L 1 -R 1A ;

[0590] R 2 Yes-L 2 -R 2A ;

[0591] R E Each instance of is independently H or -L E -R EA ;

[0592] R Q Yes-L Q -R QA ;

[0593] R X Yes-L X -R XA ;

[0594] R Y Yes-L Y -R YA ;

[0595] R Z Yes-L Z -R ZA ;or

[0596] R E Two examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0597] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0598] R Y and R Z Together with the intervening atoms, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6heterocycloalkylene, -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-;

[0599] R 1A To be R 1C r 1 R A or R B ;

[0600] R 2A To be R 2C r 2 R A or R B ;

[0601] R EA Is R EC r 3 R A or R B ;

[0602] R QA Is R QC r 4 R A or R B ;

[0603] R XA Is R XC r 5 R A or R B ;

[0604] R YA Is R YC r 6 R A or R B ;

[0605] R ZA Is R ZC r 7 R A or R B ;

[0606] R L To be R LC r 8 R A or R B ;

[0607] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0608] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0609] R 1C 、R 2C 、R EC 、R QC 、R XC 、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZCeach instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0610] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0611] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each independently is 0, 1, 2, 3, 4 or 5.

[0612] In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII:

[0613]

[0614] or a pharmaceutically acceptable salt thereof.

[0615] In some aspects of the disclosed methods, the allosteric inhibitor has the formula:

[0616]

[0617] or a pharmaceutically acceptable salt thereof.

[0618] In some aspects, the allosteric inhibitor has the formula, wherein

[0619] R 1 yes

[0620] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0621] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0622] 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)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0623] In some aspects, the allosteric inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0624] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6The aliphatic group is optionally substituted with one or more halogen atoms.

[0625] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0626] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0627] In some aspects, the allosteric inhibitor has the formula, wherein R YA for

[0628]

[0629] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic) or C 1-3 an aliphatic group, wherein each C 1-3 The aliphatic group is optionally substituted with one or more halogen atoms.

[0630] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient has a formula selected from:

[0631]

[0632] or a pharmaceutically acceptable salt thereof.

[0633] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from:

[0634]

[0635] or a pharmaceutically acceptable salt thereof

[0636] 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 prior treatment with a therapeutically effective amount of a first PI3Kα selective allosteric 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 received a therapeutically effective amount of a first PI3Kα selective allosteric 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.

[0637] In some aspects of the disclosed methods, the patient has a cancer that 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 allosteric inhibitor of Formula I or a pharmaceutically acceptable salt thereof.

[0638]

[0639] in:

[0640] R is -H or C1-C3 alkyl;

[0641] R1 is a group of the formula:

[0642]

[0643] R2 is a group of the formula:

[0644]

[0645] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; wherein each optionally substituted heterocycle or heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0646] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0647] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0648] R8 is -H or C1-C6 alkyl;

[0649] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0650] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0651] R 11 Each is independently -H or C1-C3 alkyl.

[0652] In certain aspects of the disclosed methods, the therapeutically effective amount of the PI3Kα selective allosteric inhibitor of Formula I administered to the patient is 100-1200 mg oral doses administered twice daily. In certain aspects of the disclosed methods, the therapeutically effective amount of the PI3Kα selective allosteric inhibitor of Formula I administered to the patient is 9-75 mg / kg oral doses administered twice daily (e.g., 37.5 mg / kg oral doses administered twice daily). In the disclosed methods, the patient may have a cancer that develops acquired resistance after administration of the PI3Kα selective allosteric inhibitor at a specified dose.

[0653] In some aspects of the disclosed methods, the patient has previously been treated with a therapeutically effective amount of a PI3Kα selective inhibitor of the formula:

[0654]

[0655] 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 also 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 estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0656] In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Kα selective allosteric inhibitor, and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0657] IF(ii). Other allosteric inhibitors for the treatment of M1043I / L+H1047R cancers

[0658] 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 a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation). The method comprises administering to the patient a therapeutically effective amount of a 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.

[0659] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient has Formula I:

[0660]

[0661] or a pharmaceutically acceptable salt thereof, wherein:

[0662] R is -H or C1-C3 alkyl;

[0663] R1 is a group of the formula:

[0664]

[0665] R2 is a group of the formula:

[0666]

[0667] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted heteroaryl of 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0668] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0669] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0670] R8 is -H or C1-C6 alkyl;

[0671] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0672] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0673] R 11 Each is independently -H or C1-C3 alkyl.

[0674] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient does not have the formula:

[0675]

[0676] or a pharmaceutically acceptable salt thereof.

[0677] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor of Formula I administered to the patient has the formula:

[0678]

[0679] or a pharmaceutically acceptable salt thereof.

[0680] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor of Formula I administered to the patient is selected from:

[0681]

[0682] or a pharmaceutically acceptable salt thereof.

[0683] In the disclosed methods, the patient may have a cancer comprising a mutation M1043I / L (optionally in cis with a H1047R mutation) and / or a C901 mutation (e.g., C901F, optionally in cis with a H1047R mutation), and the patient may also 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 estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0684] In some aspects, the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3Kα selective allosteric inhibitor, and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0685] Diagnosis and treatment of patients with M1043X+H1047R cancer or C901X+H1047R cancer

[0686] In certain aspects, the method relates to a method of treating a disease or condition associated with PI3Kα regulation in a patient in need thereof, e.g., 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 include determining whether 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), e.g., by arranging or performing genomic analysis to identify mutations (e.g., M1043I / L and / or C901F and / or H1047R, optionally in cis) in the patient's cancer. Suitable genomic analysis may include one or more steps, for example: arranging genomic analysis to identify M1043 mutations, C901 mutations and / or H1047R mutations (optionally in cis); PCR amplifying 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 whether 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 can further comprise administering to the patient a treatment, which can comprise administering to the patient one or more PI3Kα selective inhibitors.

[0687] 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:

[0688]

[0689] or a pharmaceutically acceptable salt thereof.

[0690] 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 orthosteric inhibitor. In some aspects, the PI3Kα selective orthosteric inhibitor is selected from apelisib, inavulisib, cerabelic acid, or a pharmaceutically acceptable salt thereof.

[0691] In some aspects of the disclosed methods, if the patient has a cancer comprising an M1043 mutation (M1043I / L is optionally cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F is optionally cis with an H1047R mutation), the method may include administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor, wherein the PI3Kα selective inhibitor binds to the PI3Kα allosteric 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 allosteric inhibitor is a compound disclosed in WO2021 / 222556 (e.g., any one of compounds I-1 to I-2704 in Table 1, pages 162-855). In some aspects, the PI3Kα selective allosteric inhibitor is a compound disclosed in WO2022 / 265993, Table AD, pages 175-259.

[0692] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient has Formula IV:

[0693]

[0694] or a pharmaceutically acceptable salt thereof, wherein:

[0695] 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)-;

[0696] Q is CH, C(R Q ) or N;

[0697] X is CH, C(R x ) or N;

[0698] Y is CH, C(R Y) or N;

[0699] Z is CH, C(R Z ) or N;

[0700] R 1 Yes-L 1 -R 1A ;

[0701] R 2 Yes-L 2 -R 2A ;

[0702] R E Each instance of is independently H or -L E -R EA ;

[0703] R Q Yes-L Q -R QA ;

[0704] R X Yes-L X -R XA ;

[0705] R Y Yes-L Y -R YA ;

[0706] R Z Yes-L Z -R ZA ;or

[0707] R E Two examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0708] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0709] R Y and R ZTogether with the intervening atoms, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6 heterocycloalkylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)C(NOR)-, -N(R)C(NCN)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-;

[0710] R 1A To be R 1C r 1 R A or R B ;

[0711] R 2A To be R 2C r 2 R A or R B ;

[0712] R EA Is R EC r 3 R A or R B ;

[0713] R QA Is R QC r 4 R A or R B ;

[0714] R XA Is R XC r 5 R A or R B;

[0715] R YA Is R YC r 6 R A or R B ;

[0716] R ZA Is R ZC r 7 R A or R B ;

[0717] R L To be R LC r 8 R A or R B ;

[0718] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0719] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0720] R 1C 、R 2C 、R EC 、R QC 、R XC、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZC each instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0721] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0722] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each independently is 0, 1, 2, 3, 4 or 5.

[0723] In some aspects of the disclosed methods, the allosteric inhibitor has Formula XXVIII:

[0724]

[0725] or a pharmaceutically acceptable salt thereof.

[0726] In some aspects of the disclosed methods, the allosteric inhibitor has the formula:

[0727]

[0728] or a pharmaceutically acceptable salt thereof.

[0729] In some aspects, the allosteric inhibitor has the formula, wherein

[0730] R 1 yes

[0731] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0732] In some aspects, the allosteric inhibitor has the formula, wherein R 1C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0733] 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)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0734] In some aspects, the allosteric inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0735] In some aspects, the allosteric inhibitor has the formula, wherein R 2CEach instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0736] In some aspects, the allosteric inhibitor has the formula, wherein R 2C Each instance of is independently halogen or C optionally substituted with 1-3 halogens 1-3 Aliphatic group.

[0737] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0738] In some aspects, the allosteric inhibitor has the formula, wherein R YA for

[0739]

[0740] In some aspects, the second PI3Kα selective inhibitor has the formula, wherein R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic) or C 1-3 an aliphatic group, wherein each C 1-3 The aliphatic group is optionally substituted with one or more halogen atoms.

[0741] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient has a formula selected from:

[0742]

[0743] or a pharmaceutically acceptable salt thereof.

[0744] In some aspects of the disclosed methods, the second PI3Kα selective inhibitor is disclosed in WO2022 / 265993 and has a formula selected from:

[0745]

[0746] or a pharmaceutically acceptable salt thereof.

[0747] In some aspects of the disclosed methods, if the patient has a cancer comprising an M1043 mutation (e.g., M1043I / L optionally in cis with an H1047R mutation) and / or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), the method can include administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor that binds to the PI3Kα allosteric pocket 1 and can form interactions with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.

[0748] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor administered to the patient has Formula I:

[0749]

[0750] or a pharmaceutically acceptable salt thereof, wherein:

[0751] R is -H or C1-C3 alkyl;

[0752] R1 is a group of the formula:

[0753]

[0754] R2 is a group of the formula:

[0755]

[0756] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted heteroaryl of 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0757] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0758] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0759] R8 is -H or C1-C6 alkyl;

[0760] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0761] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11 Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0762] R 11 Each is independently -H or C1-C3 alkyl.

[0763] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor of Formula I has the formula:

[0764]

[0765] or a pharmaceutically acceptable salt thereof.

[0766] In some aspects of the disclosed methods, the PI3Kα selective allosteric inhibitor of Formula I administered to the patient is selected from the group consisting of:

[0767]

[0768] or a pharmaceutically acceptable salt thereof.

[0769] 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 also 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 estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0770] Compounds used for treatment

[0771] In some aspects, the disclosed subject matter relates to a first PI3Kα specific inhibitor for use in simultaneous, separate, or sequential combination with a second PI3Kα specific inhibitor to treat a disease or condition associated with the regulation of phosphatidylinositol 3-kinase α (PI3Kα). The disclosed compounds for use in treatment can be further illustrated by the following embodiments.

[0772] Embodiment 1. A PI3Kα specific inhibitor compound having the following formula:

[0773]

[0774] or a pharmaceutically acceptable salt thereof, wherein:

[0775] R is -H or C1-C3 alkyl;

[0776] R1 is a group of the formula:

[0777]

[0778] R2 is a group of the formula:

[0779]

[0780] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl), -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or optionally substituted heteroaryl of 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 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl or C1-C3 haloalkyl;

[0781] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0782] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0783] R8 is -H or C1-C6 alkyl;

[0784] R9 are each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0785] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl are each optionally replaced by -CN, -OH, oxetanyl, C1-C3 alkoxy or -CONR 11 R 11Substitution; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0786] R 11 Each is independently -H or C1-C3 alkyl;

[0787] It is used in simultaneous, separate or sequential combination with a second PI3Kα specific inhibitor for the treatment of diseases or disorders associated with the regulation of phosphatidylinositol 3-kinase α (PI3Kα), wherein the second PI3Kα specific inhibitor is a PI3Kα specific orthosteric inhibitor.

[0788] Embodiment 2. The compound for use according to embodiment 1, wherein the second PI3Kα specific inhibitor is apelisib or a pharmaceutically acceptable salt thereof.

[0789] Embodiment 3. The compound for use according to embodiment 1, wherein the second PI3Kα specific inhibitor is inavulisib or a pharmaceutically acceptable salt thereof.

[0790] Embodiment 4. The compound for use according to any one of embodiments 1-3, wherein the dosage of the second PI3Kα specific inhibitor is an oral dosage of less than about 300 mg administered per day.

[0791] 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.

[0792] Embodiment 6. The compound for use according to embodiment 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 oral dose administered daily.

[0793] Embodiment 7. PI3Kα specific inhibitor compound of formula I:

[0794]

[0795] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in embodiment 1; which is combined simultaneously, separately or sequentially with a second PI3Kα-specific inhibitor that binds to the PI3Kα allosteric pocket 2 for the treatment of a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation.

[0796] Embodiment 8. The compound for use according to embodiment 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.

[0797] Embodiment 9. The compound for use according to embodiment 7 or 8, wherein the second PI3Kα specific inhibitor has the following formula:

[0798]

[0799] or a pharmaceutically acceptable salt thereof, wherein:

[0800] 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)-;

[0801] Q is CH, C(R Q ) or N;

[0802] X is CH, C(R x ) or N;

[0803] Y is CH, C(R Y ) or N;

[0804] Z is CH, C(R Z ) or N;

[0805] R 1 Yes-L 1 -R 1A ;

[0806] R 2 Yes-L 2 -R 2A ;

[0807] R E Each instance of is independently H or -L E -R EA ;

[0808] R Q Yes-L Q -R QA ;

[0809] R X Yes-L X -R XA ;

[0810] R Y Yes-L Y -R YA ;

[0811] R Z Yes-L Z -R ZA ;or

[0812] R E Two examples of together with the atoms between them form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R EEC Replace n instances of ;

[0813] R Q and R 1 Together with the atoms between them, they form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each ring is R Q1C Replace p instances of ;

[0814] R Y and R Z Together with the intervening atoms, they form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by R YZC q instances of L 1 , L 2 , L E , L Q , L X , L Y and L Z Each independently is 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 replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, C 3-6heterocycloalkylene, -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-;

[0815] R 1A To be R 1C r 1 R A or R B ;

[0816] R 2A To be R 2C r 2 R A or R B ;

[0817] R EA Is R EC r 3 R A or R B ;

[0818] R QA Is R QC r 4 R A or R B ;

[0819] R XA Is R XC r 5 R A or R B ;

[0820] R YA Is R YC r 6 R A or R B ;

[0821] R ZA Is R ZC r 7 R A or R B ;

[0822] R L To be R LC r 8 R A or R B ;

[0823] R A Each instance of is independently oxo, deuterium, halogen, -CN, -NO2, -OR, -SF5, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)2F, -S(O)R, -S(O)NR2, -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O )NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2. -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -P(O)R2, -P(O)(R)OR or -B(OR)2;

[0824] R B Each instance of C is independently 1-6 aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 5-12 membered saturated or partially unsaturated bicyclic carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0825] R 1C 、R 2C 、R EC 、R QC 、R XC 、R YC 、R ZC 、R LC 、R EEC 、R Q1C and R YZCeach instance of is independently oxo, deuterium, halogen, -CN, -NO, -OR, -SF, -SR, -NR, -S(O)R, -S(O)NR, -S(O)F, -S(O)R, -S(O)NR, -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, -P(O)R, -P(O)(R)OR, -B(OR), or an optionally substituted group selected from: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from the following: C 1-6 Aliphatic group (wherein the C 1-6 The aliphatic group is optionally selected from C 1-3 Alkyl, C 1-3 substituted with a substituent selected from haloalkyl and halogen), phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or

[0826] Two R groups on the same nitrogen, taken together with the intervening atoms, form a 4-7 membered saturated, partially unsaturated, or heteroaromatic ring having 0-3 heteroatoms other than nitrogen independently selected from nitrogen, oxygen, and sulfur; and

[0827] n, p, q, r 1 、r 2 、r 3 、r 4 、r 5 、r 6 、r 7 and r 8 Each independently is 0, 1, 2, 3, 4 or 5.

[0828] Embodiment 10. The compound for use according to any one of embodiments 7-9, wherein the second PI3Kα selective inhibitor has the formula:

[0829]

[0830] or a pharmaceutically acceptable salt thereof.

[0831] Embodiment 11. The compound for use according to any one of embodiments 7-10, wherein the second PI3Kα selective inhibitor has the formula:

[0832]

[0833] or a pharmaceutically acceptable salt thereof.

[0834] Embodiment 12. The compound for use according to any one of embodiments 7-11, wherein the second PI3Kα selective inhibitor has the formula, wherein

[0835] R 1 yes

[0836] Embodiment 13. The compound for use according to any one of embodiments 7-12, wherein the second PI3Kα selective inhibitor has the formula, wherein R 1C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0837] Embodiment 14. The compound for use according to any one of embodiments 7-13, 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)2CH2-R 2A 、-CH2S(O)2-R 2A or -C(H)(CH3)OH.

[0838] Embodiment 15. The compound for use according to any one of embodiments 7-14, wherein the second PI3Kα selective inhibitor has the formula, wherein R 2A is optionally replaced by C at one or more positions 1-3 an aliphatic group (eg, methyl group), a haloalkyl group (eg, trifluoromethyl group or difluoromethyl group), or a phenyl group substituted with halogen.

[0839] Embodiment 16. The compound for use according to any one of embodiments 7-15, wherein the second PI3Kα selective inhibitor has the formula, wherein R2C Each instance of is independently halogen, -CN, -O-(C 1-6 aliphatic) or C 1-6 aliphatic group; wherein each C 1-6 The aliphatic group is optionally substituted with one or more halogen atoms.

[0840] Embodiment 17. The compound for use according to any one of embodiments 7-16, wherein the second PI3Kα selective inhibitor has the formula, wherein R YA is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each of which is replaced by R YC r 6 Instances replaced.

[0841] Embodiment 18. The compound for use according to any one of embodiments 7-17, wherein the second PI3Kα selective inhibitor has the formula, wherein R YA for

[0842]

[0843] Embodiment 19. The compound for use according to any one of embodiments 7-18, wherein the second PI3Kα selective inhibitor has the formula, wherein R YC Each instance of is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic) or C 1-3 an aliphatic group, wherein each C 1-3 The aliphatic group is optionally substituted with one or more halogen atoms.

[0844] Embodiment 20. The compound for use according to embodiment 19, wherein the second PI3Kα selective inhibitor has a formula selected from the group consisting of:

[0845]

[0846]

[0847] or a pharmaceutically acceptable salt thereof, or a second PI3Kα selective inhibitor having a formula selected from the group consisting of:

[0848]

[0849] or a pharmaceutically acceptable salt thereof.

[0850] Embodiment 21. PI3Kα specific inhibitor compound of formula I:

[0851]

[0852] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1; which is combined simultaneously, separately or sequentially with a second PI3Kα specific inhibitor of Formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the first PI3Kα specific inhibitor and the second PI3Kα specific inhibitor are different compounds.

[0853] Embodiment 22. The compound for use according to embodiment 21, wherein the second PI3Kα specific inhibitor does not have the following formula:

[0854]

[0855] Embodiment 23. The compound for use according to embodiment 21 or 22, wherein the second PI3Kα specific inhibitor has the following formula:

[0856]

[0857] or a pharmaceutically acceptable salt thereof.

[0858] Embodiment 24. The compound for use according to any one of embodiments 21-23, wherein the second PI3Kα specific inhibitor has a formula selected from the group consisting of:

[0859]

[0860] or a pharmaceutically acceptable salt thereof.

[0861] Embodiment 25. The compound for use according to any one of embodiments 1-24, wherein the therapeutically effective amount of the first PI3Kα specific inhibitor is effective to reduce PI3Kα activity in the patient without inducing hyperglycemia in the patient.

[0862] Embodiment 26. The compound for use according to any one of embodiments 1-25, wherein the therapeutically effective amount of the second PI3K alpha specific inhibitor is effective to reduce PI3K alpha activity in the patient without inducing hyperglycemia in the patient.

[0863] Embodiment 27. A PI3Kα specific inhibitor compound of formula I:

[0864]

[0865] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in Embodiment 1; for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient resistant to treatment with apelicild or inavolinid.

[0866] Embodiment 28. A PI3Kα-specific inhibitor that binds to the 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 treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in patients who are resistant to treatment with apelisib or inavolinisib.

[0867] Embodiment 29. The PI3Kα specific inhibitor for use according to embodiment 28, wherein the inhibitor is a compound of the following formula:

[0868]

[0869] or a pharmaceutically acceptable salt thereof, wherein R1, R2, E, Q, X, Y, Z are as defined in embodiment 9, or a PI3Kα specific inhibitor for use according to embodiment 28, wherein the inhibitor is a compound selected from the following formula:

[0870]

[0871] or a pharmaceutically acceptable salt thereof.

[0872] Embodiment 30. A PI3Kα specific inhibitor, which is a PI3Kα specific orthosteric inhibitor, for use in treating a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the patient has previously been treated with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0873]

[0874] wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in Embodiment 96, and the patient has a cancer that has acquired an M1043I / L mutation in cis with an H1047R mutation and / or a C901F mutation in cis with an H1047R mutation.

[0875] Embodiment 31. A PI3Kα specific inhibitor that binds to PI3Kα allosteric pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012 and D1018, for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation 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.

[0876] Embodiment 32. PI3Kα specific inhibitor compound of formula I:

[0877]

[0878] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in Embodiment 1, for treating a disease or condition associated with the regulation of phosphatidylinositol 3-kinase alpha (PI3Kα) in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047R mutation.

[0879] Embodiment 33. PI3Kα specific inhibitor compound of formula I:

[0880]

[0881] or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in Embodiment 1, for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, comprising assaying a blood sample from the patient to determine whether the patient has a cancer comprising an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047R mutation, and if an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047R mutation is present, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0882] Embodiment 34. A PI3Kα specific inhibitor selected from apelisib and inavolinisib for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, comprising assaying a sample from the patient to determine whether the patient has cancer comprising an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047 mutation, and if an M1043I / L mutation in cis with the H1047R mutation and / or a C901F mutation in cis with the H1047 mutation is present, administering to the patient a therapeutically effective amount of apelisib, inavolinisib, or a pharmaceutically acceptable salt thereof.

[0883] Embodiment 35. A PI3Kα specific inhibitor that binds to PI3Kα allosteric pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012 and D1018, for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, comprising assaying a blood sample from the patient to determine 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 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 the PI3Kα specific inhibitor or a pharmaceutically acceptable salt thereof.

[0884] Embodiment 36. The compound for use according to any one of embodiments 1-27, 30, 32 and 33, wherein the compound of formula I has the following formula:

[0885]

[0886] or a pharmaceutically acceptable salt thereof.

[0887] Embodiment 37. The compound for use according to any one of embodiments 1-27, 30, 32 and 33, wherein the therapeutically effective amount of the compound of formula I administered to the patient is an oral dose of 100-1200 mg administered twice daily.

[0888] Embodiment 38. The compound for use according to any one of embodiments 1-27, 30, 32 and 33, wherein the therapeutically effective amount of the first PI3Kα specific inhibitor administered to the patient is an oral dose of 9-75 mg / kg administered twice daily.

[0889] Embodiment 39. The compound for use according to any one of embodiments 1 to 38, wherein the disease or disorder is cancer.

[0890] Embodiment 40. The compound for use according to any one of embodiments 1 to 39, wherein the disease or disorder is breast cancer.

[0891] Embodiment 41. A compound for use according to any one of embodiments 1 to 40, wherein the disease or condition is PIK3CA mutated, advanced or metastatic breast cancer.

[0892] Embodiment 42. A compound for use according to any one of embodiments 1 to 41, wherein the disease or condition is PIK3CACA H1047R mutant advanced or metastatic breast cancer.

[0893] Embodiment 43. The compound for use according to embodiment 42, wherein the PIK3CACA H1047R mutant advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).

[0894] Embodiment 44. The compound for use according to any one of embodiments 1-43, wherein the patient is a postmenopausal female.

[0895] Embodiment 45. The compound for use according to any one of embodiments 1 to 44, wherein the patient suffers from type 2 diabetes.

[0896] Embodiment 46. The compound for use according to any one of embodiments 1-45, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).

[0897] Embodiment 47. The compound for use according to embodiment 46, wherein the SERD is selected from the group consisting of imidestrant, fulvestrant, gileadatran, amidestrant, lintostrant, erastrant, camidestrant, LSZ102, Zn-c5 and D-0502.

[0898] Embodiment 48. The compound for use according to embodiment 46 or 47, wherein the therapeutically effective amount of the SERD is a dose of 500 mg administered on days 1, 15 and 29.

[0899] Embodiment 49. The compound for use according to any one of embodiments 1-48, wherein the second PI3K alpha specific inhibitor is administered after the disease or condition has developed resistance to the first PI3K alpha specific inhibitor.

[0900] Exemplary compounds

[0901] The following are exemplary compounds that can be used in certain aspects of the disclosed subject matter.

[0902] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0903]

[0904] wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the summary of formula (I).

[0905] In another aspect, the compound of formula (I) wherein R8 is H has formula (II), or a pharmaceutically acceptable salt thereof:

[0906]

[0907] wherein R, R1, R2, R3, R4, R5, R6 and R7 are as defined in the summary of formula (I).

[0908] In the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0909] R is -H or C1-C3 alkyl;

[0910] R1 is a group of the formula:

[0911]

[0912] R2 is a group of the formula:

[0913]

[0914] R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S;

[0915] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0916] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0917] R8 is -H or C1-C6 alkyl;

[0918] R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0919] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and

[0920] R 11 Each is independently -H or C1-C3 alkyl.

[0921] In the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0922] R is -H or C1-C3 alkyl;

[0923] R1 is a group of the formula:

[0924]

[0925] R2 is a group of the formula:

[0926]

[0927] R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0928] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0929] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0930] R8 is -H or C1-C6 alkyl;

[0931] R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0932] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and

[0933] R 11 Each is independently -H or C1-C3 alkyl.

[0934] In the compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0935] R is -H or C1-C3 alkyl;

[0936] R1 is a group of the formula:

[0937]

[0938] R2 is a group of the formula:

[0939]

[0940] R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0941] R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0942] R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0943] R8 is -H or C1-C6 alkyl;

[0944] R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;

[0945] R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and

[0946] R 11 Each is independently -H or C1-C3 alkyl.

[0947] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0948]

[0949] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl wherein the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN.

[0950] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0951]

[0952] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and R 11Each is independently -H or C1-C3 alkyl.

[0953] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0954]

[0955] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0956] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0957]

[0958] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0959] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 、-CONR 11 R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0960] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 、-C(O)OC1-C3 alkyl、-CONR 11 R 11 , optionally -CN or CONR 11 R 11 Substituted C1-C6 alkyl (preferably each R 11 is C1-C3 alkyl), C1-C3 cycloalkyl optionally substituted by C1-C3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, an optionally substituted phenyl (preferably an optionally substituted phenyl substituted by -CN), or an optionally substituted heteroaryl selected from pyrazole or oxazole.

[0961] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 、-CONR 11 R 11 , C1-C6 alkyl optionally substituted by -CN, C3 cycloalkyl optionally substituted by C1-C3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, or an optionally substituted heteroaryl selected from pyrazole or oxazole.

[0962] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 10 Each independently

[0963]

[0964] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R 10 Each independently

[0965]

[0966] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0967]

[0968]

[0969]

[0970] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula:

[0971]

[0972]

[0973] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R is -H, halogen, -CN, -N(H)(CHCHCOH), -C(O)C-Calkyl, C-Calkyl, C-Chaloalkyl, oxetane, isoxazole, or pyridine (preferably 3-pyridine). In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R is -H, halogen, -CN, C-Calkyl, C-Chaloalkyl, C-Ccycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane or isoxazole. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl); most preferably R3 is -H or methyl.

[0974] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or halogen, preferably R4 is H.

[0975] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; preferably R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R5 is -H, halogen, methyl or trifluoromethyl.

[0976] In yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or halogen.

[0977] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), and R2 is a group of the formula:

[0978]

[0979] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl.

[0980] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), and R2 is a group of the formula:

[0981]

[0982] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0983] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, methyl or trifluoromethyl (preferably R3 is -H or methyl), and R2 is a group of the formula:

[0984]

[0985] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0986] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula:

[0987]

[0988] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl.

[0989] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula:

[0990]

[0991] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0992] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula:

[0993]

[0994] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[0995] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and R2 is a group of the formula:

[0996]

[0997] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl.

[0998] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula:

[0999]

[1000] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1001] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, methyl or trifluoromethyl, and R2 is a group of the formula:

[1002]

[1003] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1004] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen, and R2 is a group of the formula:

[1005]

[1006] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl.

[1007] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen, and R2 is a group of the formula:

[1008]

[1009] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1010] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen, and R2 is a group of the formula:

[1011]

[1012] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1013] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, and R4 is H or halogen; more preferably, R3 is -H, -CN or C1-C3 alkyl, and R4 is H; most preferably, R3 is -H or methyl, and R4 is H.

[1014] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN or C1-C3 alkyl), and R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R3 is -H or methyl, and R5 is -H, halogen, methyl or trifluoromethyl.

[1015] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN or C1-C3 alkyl), and R6 is -H or halogen; more preferably R3 is -H or methyl, and R6 is -H or halogen.

[1016] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), and R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R5 is -H, halogen, methyl or trifluoromethyl.

[1017] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H) and R6 is -H or halogen.

[1018] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R6 is -H or halogen; preferably R5 is -H, halogen, methyl or trifluoromethyl, and R6 is H.

[1019] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), and R2 is a group of the formula: Preferably, R3 is -H or methyl, R4 is -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1020] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN or C1-C3 alkyl), R5 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl or trifluoromethyl, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1021] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, (preferably R3 is -H, -CN or C1-C3 alkyl), R6 is -H or halogen, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R6 is -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1022] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula: More preferably, R5 is -H, halogen, methyl or trifluoromethyl, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1023] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, and R2 is a group of the formula: More preferably, R4 and R6 are each -H, and R2 is a group of the formula:

[1024] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1025] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, and R2 is a group of the formula: Preferably, R5 is -H, halogen, methyl or trifluoromethyl, R6 is -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1026] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), and R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably, R3 is -H or methyl, R4 is -H, and R5 is -H, halogen, methyl or trifluoromethyl.

[1027] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), and R6 is -H or halogen; more preferably R3 is -H or methyl, and R4 and R6 are each H.

[1028] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen; more preferably R3 is -H or methyl, R5 is -H, halogen, methyl or trifluoromethyl, and R6 is H.

[1029] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably R4 is -H), and R6 is -H or halogen; more preferably R5 is -H, halogen, methyl or trifluoromethyl, and R4 and R6 are each H.

[1030] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R5 is -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R4 is -H, R5 is -H, halogen, methyl or trifluoromethyl, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1031] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R4 and R6 are each -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH, or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl is each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1032] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R5 is -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, R6 is -H or halogen, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl or trifluoromethyl, R6 is -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1033] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, and R2 is a group of the formula: More preferably, R5 is -H, halogen, methyl or trifluoromethyl, R4 is -H, R6 is -H or halogen, and R2 is a group of the formula:

[1034] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1035] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is -H, -CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, and R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably, R3 is -H or methyl, R4 and R6 are each -H, and R5 is -H, halogen, methyl or trifluoromethyl.

[1036] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is a group of the formula: More preferably, R3 is -H or methyl, R4 is -H, R6 is -H or halogen, R5 is -H, halogen, methyl or trifluoromethyl, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1037] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R is -H.

[1038] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; preferably R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R7 is -CN, methyl or trifluoromethyl.

[1039] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R8 is -H.

[1040] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R is -H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R is -H.

[1041] In yet another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R8 and R are each -H.

[1042] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R8 is H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 is H.

[1043] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R8 and R are each -H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[1044] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl, R8 is -H, R is -H, and R2 is a group of the formula:

[1045] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), R8 is -H, R is -H, and R2 is a group of the formula: Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1046] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R8 and R are each -H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H or methyl, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[1047] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R4, R8, and R are each -H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, R8, and R are each -H.

[1048] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R7 is -CN, methyl, or trifluoromethyl, and R8 and R9 are each -H. In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R8 and R9 are each -H.

[1049] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably R3 is -H, -CN, or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is -H or halogen, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R7 is -CN, methyl, or trifluoromethyl, R8 is -H, R is -H, and R2 is a group of the formula:

[1050]

[1051] Herein, R3 is -H or methyl, R4 is -H, R6 is -H or halogen, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, R8 is -H, R is -H, and R2 is a group of the formula:

[1052]

[1053] Preferably, R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH or -CN.

[1054] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1055]

[1056] wherein R9 is each independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl; preferably R9 is each independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy or cyclopropyl.

[1057] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1058] wherein R9 is each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; preferably R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl; more preferably R9 is each independently -H, halogen, methyl, trifluoromethyl, methoxy or cyclopropyl.

[1059] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1060] wherein R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; preferably R9 is each independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1061] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1062]

[1063] wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1064] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1065]

[1066] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1067]

[1068] wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably, R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1069] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl. Preferably, R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl. More preferably, R9 is each independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1070] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl. Preferably, R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. More preferably, R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1071] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula

[1072] wherein R9 is each independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; preferably, R9 is each independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl; more preferably, R9 is each independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy or cyclopropyl.

[1073] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula

[1074]

[1075] wherein R9 is each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; preferably, R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl; more preferably, R9 is each independently -H, halogen, methyl, trifluoromethyl, methoxy or cyclopropyl.

[1076] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is each independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy. Preferably, R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. More preferably, R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1077] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl or C1-C3 alkoxy. Preferably, R9 is -H, halogen or C1-C3 haloalkyl. More preferably, R9 is -H or trifluoromethyl.

[1078] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl, or C1-C3 alkoxy. Preferably, R9 is -H, halogen, or C1-C3 haloalkyl. More preferably, R9 is -H or halogen. Even more preferably, R9 is -H or fluorine.

[1079] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl. Preferably, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl. More preferably, R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1080] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is -H, halogen or C1-C3 haloalkyl. Preferably, R9 is independently halogen or trifluoromethyl. More preferably, R9 is chlorine or trifluoromethyl.

[1081] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: wherein R9 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Preferably, R9 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. More preferably, R9 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[1082] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1083] wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl. Preferably, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl. More preferably, R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1084] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1085]

[1086]

[1087] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1088]

[1089] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R1 is a group of the formula:

[1090] Wherein R9 is each independently of one another-H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl.More preferably R9 is each independently of one another-H, halogen, methyl, trifluoromethyl or cyclopropyl.Preferably R3 is-H, methyl or trifluoromethyl, R4 is-H or halogen, R6 is-H or halogen, R5 is-H, halogen, methyl or trifluoromethyl, and R9 is each independently of one another-H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1091] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN or C1-C3 alkyl, R4 is -H, R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R1 is a group of the formula:

[1092] wherein R9 is independently of one another-H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.Preferred R3 is-H or methyl, R4 is-H, R6 is-H or halogen, R5 is-H, halogen, methyl or trifluoromethyl, and R9 is independently of one another-H, halogen, methyl or trifluoromethyl.

[1093] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula:

[1094] wherein R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; more preferably R7 is methyl, R8 and R9 are each -H, and R9 is each independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1095] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula:

[1096] wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R7 is methyl, R8 and R9 are each -H, and R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1097] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula:

[1098] wherein R9 is each independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; more preferably R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is each independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1099] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl, R4, R8, and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula: wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1100] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula:

[1101] wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is each independently -H, halogen, methyl or trifluoromethyl.

[1102] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl, R4, R8, and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula: wherein R9 is -H, halogen or C1-C3 haloalkyl; preferably R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H or trifluoromethyl.

[1103] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl, R4, R8, and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula: wherein R9 is -H, halogen or C1-C3 haloalkyl; preferably R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H or halogen, more preferably R9 is -H or fluorine.

[1104] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula:

[1105] wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; preferably R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1106] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl, R4, R8, and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula: wherein R9 is -H, halogen or C1-C3 haloalkyl; preferably R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is independently halogen or trifluoromethyl.

[1107] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl, R4, R8, and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula: wherein R9 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R3 is -H or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[1108] In another compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R1 is a group of the formula:

[1109] wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; preferably R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[1110] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[1111]

[1112] wherein R9 is each independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the formula:

[1113]

[1114] where R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted by -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl are each optionally substituted by 1 to 3 sub...

Claims

1. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, the method comprising administering to the patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor of the formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor is a PI3Kα selective orthosteric inhibitor selected from apelisib, inavulisib, or a pharmaceutically acceptable salt thereof; wherein the therapeutically effective amount of the first PI3Kα selective inhibitor and the therapeutically effective amount of the second PI3Kα selective inhibitor are administered simultaneously, separately or sequentially. 2 . The method of claim 1 , wherein the second PI3Kα selective inhibitor is apelisib or a pharmaceutically acceptable salt thereof. 3 . The method of claim 1 , wherein the second PI3Kα selective inhibitor is inavulixib or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the dose of the second PI3Kα selective inhibitor is less than about 300 mg oral dose administered daily. 5 . The method of claim 4 , wherein the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor are administered substantially simultaneously.

6. The method of any one of claims 1-5, wherein the dose of the second PI3Kα selective inhibitor is less than about 50, 30, 12.5, 6.25, or 3.125 mg / kg oral dose administered daily. 7 . The method of claim 6 , wherein the first PI3K alpha selective inhibitor and the second PI3K alpha selective inhibitor are administered substantially simultaneously.

8. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, the method comprising administering to the patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor that binds to PI3Kα allosteric pocket 1 and has the following formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor, wherein the second PI3Kα selective inhibitor is selected from: and pharmaceutically acceptable salts thereof; wherein the first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor are administered simultaneously, separately or sequentially.

9. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, the method comprising administering to the patient: (i) a therapeutically effective amount of a first PI3Kα selective inhibitor of the formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl; and (ii) a therapeutically effective amount of a second PI3Kα selective inhibitor of the formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl, provided that the second PI3Kα selective inhibitor is not a compound of the formula: The first PI3Kα selective inhibitor and the second PI3Kα selective inhibitor are different and are used simultaneously, separately or sequentially.

10. The method of claim 9, wherein the second PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 or 10, wherein the second PI3Kα selective inhibitor has a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1-11, wherein the first PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

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

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

15. The method of any one of claims 1-14, wherein the first PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

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

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

18. The method of any one of claims 1-17, wherein the method comprises administering the second PI3Kα specific inhibitor after the disease or condition becomes resistant to the first PI3Kα specific inhibitor.

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

20. A method of treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation that is resistant to treatment with apelisib, the method comprising administering to a patient in need thereof a therapeutically effective amount of a PI3Kα selective inhibitor of the formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl, provided that the PI3Kα selective inhibitor administered in the method is not a compound of the formula:

21. The method of claim 20, wherein the PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

22. The method of claim 20 or 21, wherein the second PI3Kα selective inhibitor has a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. A method of treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation, said disease or condition being resistant to treatment with apelisib, said method comprising administering to a patient in need thereof a therapeutically effective amount of a PI3Kα selective inhibitor that binds to allosteric pocket 2 of PI3Kα, said PI3Kα selective inhibitor being selected from the group consisting of: and pharmaceutically acceptable salts thereof.

24. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, wherein the patient has previously been treated with a therapeutically effective amount of a first PI3Kα selective inhibitor, or a pharmaceutically acceptable salt thereof, wherein the first PI3Kα selective inhibitor has the formula: in: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl; The patient suffers from cancer that has acquired M1043I / L mutation and H1047R mutation in cis and / or C901F mutation and H1047R mutation in cis, and the method comprises administering to the patient a therapeutically effective amount of a second PI3Kα selective inhibitor selected from apelisib, inavulisib, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the first PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

26. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis, the method comprising administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor that binds to PI3Kα allosteric pocket 2, the PI3Kα selective inhibitor being selected from: and pharmaceutically acceptable salts thereof.

27. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis, the method comprising administering to the patient a therapeutically effective amount of a PI3Kα selective inhibitor having the formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 are each independently -H or C1-C3 alkyl, provided that the PI3Kα selective inhibitor administered in the method is not a compound of the formula:

28. The method of claim 27, wherein the PI3Kα selective inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

29. The method according to claim 27 or 28, wherein the PI3Kα selective inhibitor is selected from: or a pharmaceutically acceptable salt thereof.

30. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, the method comprising: The patient is determined to have a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis, and a therapeutically effective amount of a PI3Kα selective inhibitor selected from apelisib and inavulisib is administered to the patient.

31. A method for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, the method comprising: The patient is determined to have a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis, and the patient is administered a therapeutically effective amount of a PI3Kα selective inhibitor, wherein the PI3Kα selective inhibitor binds to the PI3Kα allosteric pocket 2 and is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

32. A method of selecting a patient suffering from a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation for treatment with a therapeutically effective amount of a PI3Kα specific inhibitor compound of the formula: Wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1, the method comprising assaying a sample from a patient, wherein the patient is selected if an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047 mutation in cis are present in the sample.

33. A method for selecting a patient having a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation for treatment with a therapeutically effective amount of a PI3Kα specific inhibitor selected from apelisib and inavolinisib, the method comprising assaying a sample from the patient, wherein the patient is selected if the sample contains an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047 mutation in cis.

34. A method of selecting a patient suffering from a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation for treatment with a therapeutically effective amount of a PI3Kα specific inhibitor that binds to allosteric pocket 2 of PI3Kα, the PI3Kα specific inhibitor being selected from the group consisting of: and pharmaceutically acceptable salts thereof; If the sample contains M1043I / L mutation and H1047R mutation in cis and / or C901F mutation and H1047 mutation in cis, the patient will be selected.

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

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

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

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

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

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

41. The method of any one of claims 1-39, wherein the patient has type 2 diabetes.

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

43. The method of claim 42, wherein the SERD is selected from the group consisting of imidestrant, fulvestrant, gilead, amidestrant, lintostrant, erastran, camidestrant, LSZ102, Zn-c5, and D-0502.

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

45. A PI3Kα specific inhibitor compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the formula: R2 is a group of the formula: R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S, or a heteroaryl of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O or S; R4, R5 and R6 are each independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; R9 are each independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; R 10 Each is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 、-CONR 11 R 11 、-NR 11 R 11 、-NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole; wherein the optionally substituted C1-C6 alkyl , C2-C6 alkenyl or C2-C6 alkynyl are each optionally substituted by -CN, -OH, oxetanyl or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl are each optionally substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 、-NR 11 R 11 , -OH or -CN; and R 11 Each is independently -H or C1-C3 alkyl; It is used in combination with a second PI3Kα specific inhibitor simultaneously, separately or sequentially for the treatment of diseases or conditions related to phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the second PI3Kα specific inhibitor is a PI3Kα specific orthosteric inhibitor selected from apelisib, inavulisib or a pharmaceutically acceptable salt thereof.

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

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

48. The compound for use according to any one of claims 45 to 47, wherein the dose of the second PI3K alpha specific inhibitor is less than an oral dose of about 300 mg administered per day.

49. The compound for use according to any one of claims 45 to 48, wherein the first PI3K alpha specific inhibitor and the second PI3K alpha specific inhibitor are administered substantially simultaneously.

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

51. A PI3Kα specific inhibitor compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45; which is used in combination simultaneously, separately or sequentially with a second PI3Kα specific inhibitor that binds to the PI3Kα allosteric pocket 2 for the treatment of a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the second PI3Kα specific inhibitor is selected from and pharmaceutically acceptable salts thereof.

52. A PI3Kα specific inhibitor compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45; which is combined simultaneously, separately or sequentially with a second PI3Kα specific inhibitor of Formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the first PI3Kα specific inhibitor and the second PI3Kα specific inhibitor are different.

53. The compound for use according to claim 52, wherein the second PI3Kα specific inhibitor does not have the formula:

54. The compound for use according to claim 52 or 53, wherein the second PI3Kα specific inhibitor has the formula: or a pharmaceutically acceptable salt thereof.

55. A compound for use according to any one of claims 52 to 54, wherein the second PI3Kα specific inhibitor has a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

56. The compound for use according to any one of claims 52-55, wherein the therapeutically effective amount of the first PI3K alpha specific inhibitor is effective to reduce PI3K alpha activity in the patient without inducing hyperglycemia in the patient.

57. The compound for use according to any one of claims 52 to 56, wherein the therapeutically effective amount of the second PI3K alpha specific inhibitor is effective to reduce PI3K alpha activity in the patient without inducing hyperglycemia in the patient.

58. A PI3Kα specific inhibitor compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45; for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in patients resistant to treatment with apelisib or inavolinisib.

59. A PI3Kα specific inhibitor that binds to PI3Kα allosteric pocket 2, selected from: and pharmaceutically acceptable salts thereof for use in treating diseases or conditions associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in cancer patients resistant to treatment with apelisib or inavolinisib.

60. A PI3Kα specific inhibitor, which is a PI3Kα specific orthosteric inhibitor selected from apelisib or inavolinisib for use in treating a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation, wherein the patient has previously been treated with a compound of formula I or a pharmaceutically acceptable salt thereof. wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45, and the patient has a cancer that has acquired an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis.

61. A PI3Kα specific inhibitor that binds to PI3Kα allosteric pocket 2, selected from: and pharmaceutically acceptable salts thereof for use in treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis.

62. PI3Kα specific inhibitor compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45, for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, wherein the patient has a cancer comprising an M1043I / L mutation and an H1047R mutation in cis and / or a C901F mutation and an H1047R mutation in cis.

63. A PI3Kα specific inhibitor compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 45, for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, comprising assaying a blood sample from the patient to determine whether the patient has a cancer comprising M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutation in cis, and if the patient has a cancer comprising M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutation in cis, administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

64. A PI3Kα specific inhibitor selected from apelisib and inavolinisib for treating a disease or condition associated with phosphatidylinositol 3-kinase α (PI3Kα) regulation in a patient in need thereof, comprising assaying a sample from the patient to determine whether the patient has a cancer comprising M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutation in cis, and if the patient has a cancer comprising the presence of M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutation in cis, administering a therapeutically effective amount of apelisib, inavolinisib or a pharmaceutically acceptable salt thereof to the patient.

65. A PI3Kα specific inhibitor that binds to PI3Kα allosteric pocket 2, selected from: and pharmaceutically acceptable salts thereof for treating a disease or condition associated with phosphatidylinositol 3-kinase alpha (PI3Kα) regulation in a patient in need thereof, comprising assaying a blood sample from the patient to determine whether the patient suffers from a cancer comprising M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutations in cis, and if the patient suffers from a cancer comprising M1043I / L and H1047R mutations in cis and / or C901F mutation and H1047 mutations in cis, administering a therapeutically effective amount of a PI3Kα specific inhibitor or a pharmaceutically acceptable salt thereof to the patient.

66. The compound for use according to any one of 45-58, 60, 62 and 63, wherein the compound of formula I has the following formula: or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

72. A compound for use according to any one of claims 45 to 71, wherein the disease or condition is PIK3CACAH1047R mutant advanced or metastatic breast cancer.

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

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

75. A compound for use according to any one of claims 45 to 74, wherein the patient suffers from type 2 diabetes.

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

77. The compound for use according to claim 76, wherein the SERD is selected from the group consisting of imidestrant, fulvestrant, gileadastrant, amidestrant, lintostrant, erastrant, camidestrant, LSZ102, Zn-c5 and D-0502.

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

79. The compound for use according to any one of claims 45 to 78, wherein the second PI3K alpha specific inhibitor is administered after the disease or condition has developed resistance to the first PI3K alpha specific inhibitor.

Images