Compounds that inhibit PI3K isoform alpha and methods for treating cancer - Patents.com

Abstract

The present disclosure provides compounds of formula (I), and pharma- ceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The present disclosure also provides compositions containing same, as well as methods of using and making same. JPEG2024533975000120.jpg48165

Description

[Technical field]

[0001] The present disclosure provides compounds of formula (I), and pharma- ceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The present disclosure also provides compositions containing same, as well as methods of using and making same. [Background technology]

[0002] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene, is part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several researchers have shown that the role of PI3K / AKT signaling is involved in physiological and pathophysiological functions that drive tumor progression, such as metabolism, cell growth, proliferation, angiogenesis, and metastasis (see Fruman, D.A. The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018, 15, 273-291). Inhibition of PI3K / AKT / TOR signaling (e.g., pharmacological or genetic) can lead to cancer cell death and regression of tumor growth.

[0003] The PI3K pathway can be activated, for example, via point mutation(s) in the PIK3CA gene or via inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30-50% of human cancers and contributes to resistance to various anticancer therapies (see Martini, M. et al., PI3K / AKT signaling pathway and cancer: An updated review. Ann. Med. 2014, 46, 372-383 and Bauer, TM et al., Targeting PI3 kinase in cancer. Pharmacol. Ther. 2015, 146, 53-60). PI3K consists of three subunits: p85 regulatory subunit, p55 regulatory subunit, and p110 catalytic subunit. According to their distinct structures and specific substrates, PI3Ks are classified into three classes: class I, II, and III. Class I PI3Ks include class IA and class IB PI3Ks. Class IA PI3Ks, heterodimers of p85 regulatory and p110 catalytic subunits, are the type most clearly associated with human cancer. Class IA PI3Ks contain p110α, p110β, and p110δ catalytic subunits produced by distinct genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ, produced by PIK3CG, represents the only catalytic subunit in class IB PI3Ks. PIK3CA, the gene encoding the p110α subunit, is frequently mutated or amplified in many human cancers, including breast, colon, gastric, cervical, prostate, and lung cancers (see Samuels Y, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554).

[0004] However, the development of PI3K inhibitors has been challenging for several reasons, including (i) adaptive molecular mechanisms upon therapeutic inhibition of PI3K, (ii) the lack of ability to specifically inhibit signaling through PIK3CA mutations while sparing endogenous p110α, (iii) the limitation of using these therapies in rational combinations, including those with reported strong mechanistic support, and (iv) dose-limiting toxicities that prevent sustained PI3K pathway inhibition (see Hanker et al., Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors, Cancer Discovery, April 2019;9:482-491). Additionally, there are other factors and compensatory pathways that affect PI3K signaling, such as HRAS and KRAS mutations that reduce sensitivity to PI3K inhibitors (and knockdown of these has been shown to improve sensitivity to PI3K inhibitors), derived from both clinical and in vitro basic studies (see Misrha, R.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci. 2021, 22, 3464). Domain deletions in PIK3CA can significantly activate PI3K signaling and also enhance sensitivity to PI3K inhibitors (see Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426-1435). Thus, targeting PI3Kα represents a strategy for the treatment of proliferative disorders such as cancer. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Fruman,DAThe PI3K Pathway in Human Disease.Cell 2017,170,605-635 [Non-licensed document 2] Janku,F.et al.,Targeting the PI3K pathway in cancer: Are we making headway? Nat.Rev.Clin.Oncol.2018,15,273-291 [Non-licensed document 3] Martini,M.et al.,PI3K / AKT signaling pathway and cancer:An updated review.Ann.Med.2014,46,372-383

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[0006] Some embodiments include a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is a C-C cycloalkyl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; X 1 , X 2 , X 3 , and X 4 each independently represents N, CH, or CR 4 where X 1 , X 2 , X 3 , and X 4 up to two of may be N; Each R 4 are independently halogen, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR AR B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), phenyl, 5- to 6-membered heteroaryl, and each of the R G and selected from the group consisting of 3-6 membered heterocyclyl or 3-6 membered cycloalkyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, R G C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), or -SO2(C1-C6 alkyl), optionally substituted with R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and -COH.

[0007] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0008] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0009] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the PIK3CA gene, the PI3K alpha protein, or any of the expression or activity or levels thereof; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) provided herein or a pharma- ceutical composition thereof.

[0010] Provided herein is a method for treating a PI3Kα-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated disease or disorder a therapeutically effective amount of a compound of formula (I) provided herein or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition.

[0011] The present disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising determining that a cancer in the subject is a PI3Kα-associated disease or disorder, and administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0013] The present disclosure also provides a method of treating a PI3K alpha-associated cancer in a subject, the method comprising determining that the cancer in the subject is a PI3K alpha-associated cancer, and administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0014] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I) provided herein or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition, to a subject having medical records indicating that the subject has a dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them.

[0015] The disclosure also provides a method for inhibiting PI3K alpha in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0016] Other embodiments include those described in the detailed description and / or claims.

[0017] Additional definitions To facilitate understanding of the disclosure set forth herein, some additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout this specification and the appendix is ​​incorporated herein by reference in its entirety.

[0018] The term "about" when referring to a number or numerical range means that the number or numerical range referred to is approximate, e.g., within experimental variation and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% of the specified number or numerical range.

[0019] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject being treated.

[0020] The term "inhibit" or "inhibition of" means to reduce by a measurable amount or to prevent completely (eg, 100% inhibition).

[0021] "API" refers to active pharmaceutical ingredient.

[0022] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of the chemical substance being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to cause a clinically meaningful reduction in disease symptoms. The appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0023] The term "excipient" or "pharmaceutical acceptable excipient" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutical acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of prudent medical judgment, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0024] The term "pharmaceutical acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In certain cases, a pharmaceutical acceptable salt is obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, a pharmaceutical acceptable salt is obtained by reacting a compound having an acidic group described herein with a base to form a salt, for example, an alkali metal salt such as an ammonium salt, a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid such as arginine, lysine, etc., or by other methods previously determined. A pharmacologically acceptable salt is not particularly limited as long as it can be used in medicine. Examples of salts that the compounds described herein form with bases include their salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; their salts with organic bases such as methylamine, ethylamine, and ethanolamine; their salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0025] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0026] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as, for example, a human.

[0027] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0028] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0029] The term "hydroxyl" refers to the --OH radical.

[0030] The term "cyano" refers to the -CN radical.

[0031] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1-10indicates that the group may have 1 to 10 (including the endpoints) carbon atoms in it. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means that there are only single bonds between the constituent carbon atoms and other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0032] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo.

[0033] The term "alkoxy" refers to an -O-alkyl radical (eg, -OCH3).

[0034] The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group in which at least one ring in the system is aromatic (e.g., a 6 carbon monocyclic, a 10 carbon bicyclic, or a 14 carbon tricyclic aromatic ring system) and 0, 1, 2, 3, or 4 atoms of each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0035] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

[0036] The term "heteroaryl" as used herein refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having from 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, where at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and where at least one ring in the system is aromatic (but need not be a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., where the oxo group (i.e., "=O") is a component of a heteroaryl ring), pyridones (e.g., [ka] Pyrimidones (e.g. [ka] Pyridazinones (e.g. [ka] Pyrazinones (e.g. [ka] and imidazolone (e.g. [ka] Also includes one or more of:

[0037] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms, having 1 to 3 heteroatoms in the case of a monocyclic, 1 to 6 heteroatoms in the case of a bicyclic, or 1 to 9 heteroatoms in the case of a tricyclic or polycyclic (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system), in which the heteroatoms are selected from O, N, or S (e.g., carbon atoms and or 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively, when tricyclic, where valences permit, one or more ring atoms can be substituted by 1-3 oxo (e.g., to form a lactam), one or more N or S atoms can be substituted by 1-2 oxides (e.g., to form an N-oxide, S-oxide, or S,S-dioxide), and 0, 1, 2, or 3 atoms of each ring can be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyls may include multiple fused and bridged rings.Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[4.1.0]hexane, 5-azabicyclo[4.1.0]hexane, 3-azabicyclo[4.1.0]hexane, 7 ... Heterocyclyl includes spiro[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2. 1.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0038] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0039] As used herein, when a ring is described as being "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation due to the ring itself, e.g., one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0040] For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are understood to include those in which the points of fusion are (i) located on adjacent ring atoms (e.g., [xx0] ring systems (where 0 represents zero atom bridges) (e.g., [ka] (ii) those located on a single ring atom (spiro-fused ring systems) (e.g., [ka] or (iii) located on a contiguous sequence of ring atoms (bridged ring systems where the total bridge length is >0) (e.g., [ka] It is understood that this includes those having fused rings, including:

[0041] In addition, atoms constituting the compounds of the present invention are intended to include all isotopes of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include: 13 C and 14 Contains C.

[0042] In addition, the compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: [ka] Compounds containing the moiety: [ka] Similarly, a pyridinyl or pyrimidinyl moiety depicted as optionally substituted by hydroxyl includes the pyridone or pyrimidone tautomeric forms.

[0043] The compounds provided herein may include various stereochemical forms.The compounds also include mixtures of enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures and diastereomeric mixtures, as well as individual enantiomers and diastereomers, resulting from structural asymmetry in a particular compound.Unless otherwise indicated, when a disclosed compound is designated or depicted by structure without specifying a stereochemical structure (e.g., a "flat" structure), and has one or more chiral centers, it is understood that it represents all possible stereoisomers of the compound.

[0044] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The present disclosure provides compounds of formula (I), and pharma- ceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The present disclosure also provides compositions containing same, as well as methods of using and making same.

[0046] Compounds of formula (I) Some embodiments include a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is a C-C cycloalkyl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; X 1 , X 2 , X 3 , and X 4 each independently represents N, CH, or CR 4 where X 1 , X 2 , X 3 , and X 4 up to two of may be N; Each R 4 are independently halogen, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), phenyl, 5- to 6-membered heteroaryl, and each of the R G and selected from the group consisting of 3-6 membered heterocyclyl or 3-6 membered cycloalkyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, R G C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), or -SO2(C1-C6 alkyl), optionally substituted with R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and -COH.

[0047] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0048] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] It is.

[0049] In some embodiments, each R 1 is an independently selected halogen. In some embodiments, each R 1 is independently selected from fluoro and chloro. 1is fluoro.

[0050] In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro.

[0051] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0052] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.

[0053] In some embodiments, R 2 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with two fluoros. In some embodiments, R 2 is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with two fluoros. In some embodiments, R 2 is unsubstituted C-C cycloalkyl. In some embodiments, R 2is cyclopropyl.

[0054] In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 is N or CH. In some embodiments, X 1 , X 2 , X 3 , and X 4 Two of them are independently selected CR 4 and the other two X 1 , X 2 , X 3 , and X 4 is N or CH. In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 is CH. In some embodiments, X 1 , X 2 , X 3 , and X 4 Two of them are independently selected CR 4 and the other two X 1 , X 2 , X 3 , and X 4 is CH. In some embodiments, X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 is N. In some embodiments, X 1 , X 2 , X3 , and X 4 Two of them are independently selected CR 4 and the other two X 1 , X 2 , X 3 , and X 4 is N.

[0055] In some embodiments, X 1 , X 2 , X 3 , and X 4 X 1 and X 4 together with the adjacent carbon atom form a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl ring.

[0056] In some embodiments, the compound of formula (I) has the formula (Ia): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (wherein hydrogen is present at position 1) X 2 and X 4 are each independently N or CH.

[0057] In some embodiments, the compound of formula (Ia) is [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, X 2 and X 4 are each independently N or CH.

[0058] In some embodiments, the compound of formula (I) has formula (Ib): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0059] In some embodiments, the compound of formula (Ib) is [ka] or a pharma- ceutical acceptable salt thereof, wherein R 1A are halogens.

[0060] In some embodiments, the compound of formula (I) has the formula (Ic): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0061] In some embodiments, the compound of formula (Ic) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R1A are halogens.

[0062] In some embodiments, the compound of formula (I) has the formula (Id): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0063] In some embodiments, the compound of formula (Id) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R 1A are halogens.

[0064] In some embodiments, the compound of formula (I) has the formula (Ie): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0065] In some embodiments, the compound of formula (Ie) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R 1A are halogens.

[0066] In some embodiments, the compound of formula (I) has the formula (If): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (wherein hydrogen is present at position 1) X 2 and X 4 are each independently N or CH.

[0067] In some embodiments, the compound of formula (If) is [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, X 2 and X 4 are each independently N or CH.

[0068] In some embodiments, the compound of formula (I) has the formula (Ig): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1BIf absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0069] In some embodiments, the compound of formula (Ig) is [ka] or a pharma- ceutical acceptable salt thereof, wherein R 1A are halogens.

[0070] In some embodiments, the compound of formula (I) has the formula (Ih): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0071] In some embodiments, the compound of formula (Ih) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R 1A are halogens.

[0072] In some embodiments, the compound of formula (I) has the formula (Ii): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1Bis a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0073] In some embodiments, the compound of formula (Ii) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R 1A are halogens.

[0074] In some embodiments, the compound of formula (I) has the formula (Ij): [ka] or a pharma- ceutical acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent (i.e., R 1B If absent, R is used to satisfy the valence. 1B (There is a hydrogen atom at the position.)

[0075] In some embodiments, the compound of formula (Ij) is [ka] or a pharma- ceutical acceptable salt thereof; In the formula, R 1A are halogens.

[0076] In some embodiments, R 1A and R 1B Each is an independently selected halogen. In some embodiments, R 1A and R 1B Each is fluoro. In some embodiments, R 1Ais fluoro and R 1B is chloro. In some embodiments, R 1A is fluoro and R 1B is absent (in which case the hydrogen is R 1B (Replaces ).

[0077] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0078] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.

[0079] In some embodiments, R 2 is halogen. In some embodiments, R 2 is chloro.

[0080] In some embodiments, R 2 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 2 is unsubstituted C-C cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl.

[0081] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is isopropyl.

[0082] In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is trifluoromethyl. In some embodiments, R 3 is difluoromethyl.

[0083] In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl.

[0084] In some embodiments, R 4 is halogen. In some embodiments, R 4 is fluoro. In some embodiments, R 4 is chloro.

[0085] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C4 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl or isopropyl. In some embodiments, R 4 is n-butyl, sec-butyl, iso-butyl, or tert-butyl.

[0086] In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is ethoxy. In some embodiments, R 4 is isopropyloxy.

[0087] In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is trifluoromethyl. In some embodiments, R 4 is difluoromethyl.

[0088] In some embodiments, R 4 is hydroxyl.

[0089] In some embodiments, R 4 is cyano or -COH.

[0090] In some embodiments, R 4 -NR A RB In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B The other of R G In some embodiments, R is a C1-C6 alkyl optionally substituted with A and R B is hydrogen, and R A and R B The other of R G In some embodiments, R A and R B is hydrogen, and R A and R B The other of the two is fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 R selected from the group consisting of -COH G is a C1-C3 alkyl substituted with

[0091] In some embodiments, R 4 teeth, [ka] R G is fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and -COH.

[0092] In some embodiments, R A and R B is hydrogen, and R A and RB The other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B The other of these is methyl.

[0093] In some embodiments, R A and R B Each is C1-C6 alkyl. In some embodiments, R A and R B Each is C1-C3 alkyl. In some embodiments, R A and R B Each is methyl. In some embodiments, R A and R B is hydrogen, and R A and R B The other of R is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B The other of R is C1-C3 haloalkyl. A and R B Each is C1-C6 haloalkyl. In some embodiments, R A and R B Each is C1-C3 haloalkyl. In some embodiments, R A and R B one of which is C1-C6 alkyl, and R A and R B The other of the two is C1-C6 haloalkyl.

[0094] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0095] In some embodiments, R 4 is -C(=O)NR C R D In some embodiments, R C and R D Each is hydrogen. In some embodiments, R C and R D is hydrogen, and R C and R D The other of R is C1-C6 alkyl. C and R D is hydrogen, and R C and R D The other of R is C1-C4 alkyl. C and R D is hydrogen, and R C and R D The other of R is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. C and R D Each is C1-C6 alkyl. In some embodiments, R C and R D Each is C1-C4 alkyl. In some embodiments, R C and R D are each methyl, ethyl, propyl, or butyl.

[0096] In some embodiments, R C and R D is hydrogen, and R C and R D The other of R is C1-C6 haloalkyl. C and R D is hydrogen, and R C and R D The other of R is C1-C3 haloalkyl. C and R DEach is C1-C6 haloalkyl. In some embodiments, R C and R D Each is C1-C3 haloalkyl. In some embodiments, R C and R D one of which is C1-C6 alkyl, and R C and R D The other of these is C1-C6 haloalkyl.

[0097] In some embodiments, one R 4 is -SO2(NR E R F In some embodiments, R E and R F Each is hydrogen. In some embodiments, R E and R F is hydrogen, and R E and R F The other of R is C1-C6 alkyl. E and R F is hydrogen, and R E and R F The other of R is C1-C4 alkyl. E and R F is hydrogen, and R E and R F The other of R E and R F Each is C1-C6 alkyl. In some embodiments, R E and R F Each is C1-C3 alkyl. In some embodiments, R E and R F Each is methyl. In some embodiments, R E and R F is hydrogen, and R E and R F The other of R is C1-C6 haloalkyl. E and R Fis hydrogen, and R E and R F The other of R is C1-C3 haloalkyl. E and R F Each is C1-C6 haloalkyl. In some embodiments, R E and R F Each is C1-C3 haloalkyl. In some embodiments, R E and R F one of which is C1-C6 alkyl, and R E and R F The other of R is C1-C6 haloalkyl. 4 is -SO2(C1-C6 alkyl). In some embodiments, R 4 is -SO2(C1-C3 alkyl). In some embodiments, R 4 is -SOMe. In some embodiments, R 4 is -SO2Et.

[0098] In some embodiments, R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, R 4 is -S(=O)(=NH)Me.

[0099] In some embodiments, R 4 is -C(=O)(C1-C6 alkyl). In some embodiments, R 4 is -C(=O)(C1-C3 alkyl). In some embodiments, R 4 is -C(=O)Me.

[0100] In some embodiments, R 4 is -CO2(C1-C6 alkyl). In some embodiments, R 4 is -CO2(C1-C4 alkyl). In some embodiments, R 4is -CO2Me.

[0101] In some embodiments, R 4 is one to two independently selected R G In some embodiments, R is phenyl optionally substituted with 4 is one R G In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 is two independently selected R G In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 is unsubstituted phenyl.

[0102] In some embodiments, R 4 is one to two independently selected R G In some embodiments, R is a 5-6 membered heteroaryl optionally substituted with 4 is a 5-membered heteroaryl. In some embodiments, R 4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. 4 is a 6-membered heteroaryl. In some embodiments, R 4 is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0103] In some embodiments, R 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl optionally substituted with 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 is one R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 is two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 is one or two independently selected R G In some embodiments, R is a 3-6 membered cycloalkyl optionally substituted with 4 is one or two independently selected R G In some embodiments, R 4 is one R G In some embodiments, R 4 is two independently selected R G In some embodiments, R 4 is an unsubstituted 3-6 membered cycloalkyl.

[0104] In some embodiments, one R G is fluoro. In some embodiments, one R G is cyano. In some embodiments, one R G is hydroxyl. In some embodiments, one R G is C1-C6 alkyl. In some embodiments, one R G is C1-C3 alkyl. In some embodiments, one R G is methyl.

[0105] In some embodiments, one R G is C1-C6 alkoxy. In some embodiments, one R G is C1-C3 alkoxy. In some embodiments, one R G is methoxy.

[0106] In some embodiments, one R G is -COH.

[0107] In some embodiments, one R G -NR A1 R B1 In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 The other of R is C1-C6 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 The other of R is C1-C3 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 The other of R A1 and R B1 Each is C1-C6 alkyl. In some embodiments, R A1 and R B1 Each is methyl.

[0108] In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 The other of R is C1-C6 haloalkyl. A1 and R B1is hydrogen, and R A1 and R B1 The other of R is C1-C3 haloalkyl. A1 and R B1 Each is C1-C6 haloalkyl. In some embodiments, R A1 and R B1 one of which is C1-C6 alkyl, and R A1 and R B1 The other of these is C1-C6 haloalkyl.

[0109] In some embodiments, one R G is -C(=O)NR C1 R D1 In some embodiments, R C1 and R D1 Each is hydrogen. In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1 The other of R is C1-C6 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 The other of R is C1-C3 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 The other of R C1 and R D1 Each is C1-C6 alkyl. In some embodiments, R C1 and R D1 Each is C1-C3 alkyl. In some embodiments, R C1 and R D1 Each is methyl. In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1The other of R is C1-C6 haloalkyl. C1 and R D1 is hydrogen, and R C1 and R D1 The other of R is C1-C3 haloalkyl. C1 and R D1 Each is C1-C6 haloalkyl. In some embodiments, R C1 and R D1 one of which is C1-C6 alkyl, and R C1 and R D1 The other of these is C1-C6 haloalkyl.

[0110] In some embodiments, R 4 is an unsubstituted 3- to 6-membered heterocyclyl.

[0111] In some embodiments, R 4 is one or two independently selected R G In some embodiments, R is a 4-6 membered heterocyclyl optionally substituted with 4 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or tetrahydropyranyl. 4 is 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, or 4-tetrahydropyranyl. 4 is 1-azetidinyl, 1-pyrrolidinyl, or 1-piperidinyl.

[0112] In some embodiments, R 4 teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is fluoro, hydroxyl, cyano, -C(=O)NR C1 R D1or -COH, G is optionally replaced by

[0113] In some embodiments, [ka] is azetidinyl. In some embodiments, [ka] is pyrrolidinyl. In some embodiments, [ka] is piperidinyl.

[0114] In some embodiments, [ka] is unsubstituted. In some embodiments, [ka] is one R G In some embodiments, [ka] is two independently selected R G is replaced by.

[0115] In some embodiments, one R G is fluoro. In some embodiments, one R G is hydroxyl. In some embodiments, one R G is cyano. In some embodiments, one R Gis -C(=O)NR C1 R D1 In some embodiments, one R G is -CONH. In some embodiments, one R G is -COH.

[0116] In some embodiments, one to two independently selected R G is attached to the position of ring B distal to the nitrogen. In some embodiments, [ka] teeth, [ka] wherein one or two independently selected R G is attached at the 3-position of the azetidine. [ka] teeth, [ka] wherein one or two independently selected R G is attached at the 3-position of the pyrrolidine. [ka] teeth, [ka] wherein one or two independently selected R G is attached at the 4-position of the piperidine.

[0117] In some embodiments, Z is O.

[0118] In some embodiments, Z is NR x It is.

[0119] In some embodiments, R x is hydrogen.

[0120] In some embodiments, R x is C1-C6 alkyl. In some embodiments, R x is C1-C3 alkyl. In some embodiments, R x is methyl.

[0121] In some embodiments, R x is C-C cycloalkyl. In some embodiments, R x is C-C cycloalkyl. In some embodiments, R x is cyclopropyl. In some embodiments, R x is cyclobutyl.

[0122] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-5 (eg, compounds 1-7), or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table A, or a pharma- ceutically acceptable salt thereof. [Table 4]

[0124] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table B, or a pharma- ceutically acceptable salt thereof. [Table 5]

[0125] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table C, or a pharma- ceutically acceptable salt thereof. [Table 6]

[0126] Pharmaceutical Compositions and Administration General Provisions In some embodiments, the chemical entity (e.g., a compound that inhibits PI3K alpha, or a pharma- ceutically acceptable salt thereof) is administered as a pharmaceutical composition comprising a chemical entity described herein and one or more pharma- ceutically acceptable excipients, and optionally one or more additional therapeutic agents.

[0127] In some embodiments, the chemical substance can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens®, poloxamers, or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared containing the chemicals described herein in the range of 0.005% to 100%, with the remainder consisting of non-toxic excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80% of the chemicals provided herein. Actual methods of preparing such dosage forms will be known or apparent to those skilled in the art. For example, see Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0128] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraintestinal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0129] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes.Typically, such compositions can be prepared as injections, either as liquid solutions or suspensions, and solid forms suitable for use in preparing solutions or suspensions by adding liquid prior to injection can also be prepared, and preparations can also be emulsified.The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[0130] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be easily injected. It must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0131] The carrier may also be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable composition can be brought about by using an agent that delays absorption, for example, aluminum monostearate and gelatin, in the composition.

[0132] Sterile injection is prepared by incorporating the required amount of active compound into a suitable solvent that contains various other ingredients as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other ingredients as listed above.For the preparation of sterile powder for sterile injection, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains the powder of active ingredient with any additional desired ingredients from the solution of the previous sterile filter.

[0133] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" Neoplasia. 2006, 10, 788-795.

[0134] Pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols such as Vaseline, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, glyceryl ether ... caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0135] In certain embodiments, suppositories may be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0136] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for localized delivery to the digestive or GI tract using oral administration (eg, solid or liquid dosage form).

[0137] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0138] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a diluent such as lactose, sucrose, dicalcium phosphate, etc., a lubricant such as magnesium stearate, etc., and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc., together with the chemical entity provided herein. In another solid dosage form, a powder, a marume, a solution or a suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Also contemplated are unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated, such as, for example, a capsule (or tablet in a capsule) containing granules of each drug, a bilayer tablet, a bicompartment gel capsule, etc. Enteric coating or delayed release oral dosage forms are also contemplated.

[0139] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0140] In certain embodiments, the excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional well-known sterilization techniques. For excipients of various oral dosage forms, such as tablets and capsules, sterility is not required. USP / NF standards are usually sufficient.

[0141] In certain embodiments, the solid oral dosage form may further comprise one or more components that chemically and / or structurally direct the composition to facilitate delivery of the chemical to the stomach or lower GI, for example, the ascending colon and / or the transverse colon and / or the distal colon and / or the small intestine. Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0142] Examples include upper GI targeting techniques such as accordion pills (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0143] Other examples include lower GI targeting techniques. Several enteric / pH-responsive coatings and excipients are available to target various regions in the intestinal tract. These materials are typically polymers designed to dissolve or erode at a specific pH range, selected based on the GI region where drug release is desired. These materials also function to protect acid-labile drugs from gastric juices or limit exposure when the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other techniques include dosage forms that respond to localized bacterial flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0144] Intraocular compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic® (triblock copolymer), cyclodextrin), preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (a stabilized oxychloro complex; Allergan, Inc.)).

[0145] Topical compositions may include ointments and creams. Ointments are semi-solid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and fatty alcohols such as cetyl or stearyl alcohol, and the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a moisturizer. Emulsifiers in cream formulations are generally non-ionic, anionic, cationic, or amphoteric surfactants. As with other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0146] In any of the above-described embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0147] Dosage Dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the particular compound being used. The determination of the proper dosage for a particular situation can be determined by a medical practitioner. The total daily dosage may be divided and administered in small amounts throughout the day, or by any means that provides continuous delivery.

[0148] In some embodiments, the compounds described herein are administered in a dose range of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg, about 0.01 mg / Kg to about 200 mg / Kg, about 0.01 mg / Kg to about 150 mg / Kg, about 0.01 mg / Kg to about 100 mg / Kg, about 0.01 mg / Kg to about 50 mg / Kg, about 0.01 mg / Kg to about 10 mg / Kg, about 0.01 mg / Kg to about 5 mg / Kg, about 0.01 mg / Kg to about 1 mg / Kg, / Kg, about 0.01 mg / Kg to about 0.5 mg / Kg, about 0.01 mg / Kg to about 0.1 mg / Kg, about 0.1 mg / Kg to about 200 mg / Kg, about 0.1 mg / Kg to about 150 mg / Kg, about 0.1 mg / Kg to about 100 mg / Kg, about 0.1 mg / Kg to about 50 mg / Kg, about 0.1 mg / Kg to about 10 mg / Kg, about 0.1 mg / Kg to about 5 mg / Kg, about 0.1 mg / Kg to about 1 mg / Kg, about 0.1 mg / Kg to about 0.5 mg / Kg).

[0149] Regimen The dosages described above can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every second day, every third day, weekly, twice weekly, biweekly, monthly).

[0150] In some embodiments, the administration period of the compounds described herein extends over 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the therapeutic compound is administered to an individual for a period of time, followed by a separate period of time. In another embodiment, the therapeutic compound is administered for a first period of time, followed by a second period of time during which administration is suspended, followed by a third period of time during which administration of the therapeutic compound is initiated, followed by a fourth period of time during which administration is suspended. In some aspects of this embodiment, the period of administration of the therapeutic compound followed by the period of cessation of administration is repeated for a determined or undetermined period of time. In further embodiments, the period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.In further embodiments, the period during which administration is suspended spans 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0151] Treatment Indications Provided herein is a method for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα) encoded by the PIK3CA gene. Provided herein is an inhibitor of PI3Kα useful for treating or preventing, for example, diseases or disorders associated with dysregulation of the expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them (i.e., PI3Kα-associated diseases or disorders), such as PIK3CA-associated overgrowth syndrome (PROS, see, for example, Venot, et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., as megalencephaly-capillary malformation syndrome (MCAP) and hemimegalencephaly), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-associated cancer).

[0152] As used herein, a "PI3K alpha inhibitor" includes any compound that exhibits (e.g., inhibits or reduces) PI3K alpha inactivation activity. In some embodiments, the PI3K alpha inhibitor may be selective for PI3K alpha having one or more mutations.

[0153] The ability of a test compound to act as an inhibitor of PI3K alpha can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3K alpha inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of the kinase. An alternative in vitro assay quantifies the ability of an inhibitor to bind to the protein kinase, which can be measured either by radiolabeling the compound prior to binding, isolating the compound / kinase complex, and determining the amount of radiolabel bound, or by performing a competition experiment in which a new compound is incubated with a kinase bound to a known radioligand.

[0154] The efficacy of the PI3Kα inhibitors provided herein is shown to be 50 A lower EC value when determined under substantially similar conditions can be determined. 50 Compounds with higher EC 50 In some embodiments, the substantially similar conditions include determining PI3Kα-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells, A594 cells, U2OS cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing wild-type PI3Kα, mutant PI3Kα, or any fragment thereof).

[0155] The efficacy of the PI3Kα inhibitors provided herein was also evaluated by IC 50 A lower IC value when determined under substantially similar conditions may also be determined. 50 Compounds with higher IC 50In some embodiments, the substantially similar conditions include determining PI3Kα-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3Kα, mutant PI3Kα, or any fragment thereof, SKOV3, T47D, CAL33, BT20, HSC2, OAW42, NCI, HCC1954, NCIH1048, Detroit562, A594 cells, U2OS cells, A431 cells, A594 cells, U2OS cells, Ba / F3 cells, or 3T3 cells).

[0156] Selectivity between wild-type PI3Kα and PI3Kα containing one or more of the mutations described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorescence-based binding assays, as well as cellular assays such as levels of pAKT, a biomarker of PI3Kα activity, or proliferation assays in which cell proliferation is dependent on mutant PI3Kα kinase activity.

[0157] In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of PI3K alpha. For example, the compounds provided herein may bind to the catalytic domain of the helical phosphatidylinositol kinase homology domain of PI3K alpha. In some embodiments, the compounds provided herein may exhibit nanomolar potency against PI3K alpha kinases that contain one or more mutations, for example, the mutations in Tables 1 and 2.

[0158] In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of mutant PI3Kα. For example, the compounds provided herein may bind to an allosteric site in the kinase domain. In some embodiments, the compounds provided herein may exhibit nanomolar potency against PI3Kα proteins containing activating mutations, with minimal activity against related kinases (e.g., wild-type PI3Kα). Inhibition of wild-type PI3Kα may cause undesirable side effects (e.g., hyperglycemia and skin rashes) that may affect quality of life and compliance. In some cases, inhibition of wild-type PI3Kα may also lead to dose-limiting toxicity. See, e.g., Hanker, et al., Cancer Disc. 2019, 9, 4, 482-491.

[0159] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, can selectively target PI3K alpha, e.g., the compound of formula (I), or a pharma- ceutically acceptable salt thereof, can selectively target PI3K alpha over another kinase or non-kinase target.

[0160] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit greater inhibition of PI3Kα containing one or more mutations described herein (e.g., one or more mutations described in Table 1 or Table 2) compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit up to 1000-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit up to 10000-fold greater inhibition of PI3Kα having a combination of mutations described herein compared to inhibition of wild-type PI3Kα.

[0161] In some embodiments, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit about 2-fold to about 10-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit about 10-fold to about 100-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit about 100-fold to about 1000-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, may exhibit about 1000-fold to about 10000-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα.

[0162] The compounds of formula (I), or pharma- ceutically acceptable salts thereof, are useful for treating PI3Kα-associated diseases and disorders, e.g., diseases and disorders that can be treated with PI3Kα inhibitors, such as proliferative disorders, e.g., cancer, including hematological cancers and solid tumors (e.g., progressive or metastatic solid tumors), including PIK3CA-associated overgrowth syndrome (PROS), and other cancers, including hematological cancers and solid tumors (e.g., progressive or metastatic solid tumors).

[0163] As used herein, the term "treat" or "treatment" refers to a therapeutic or preventative measure. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, attenuation of the extent of the disease, a stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or alleviation of a disease state (e.g., one or more symptoms of a disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment.

[0164] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0165] In some embodiments, the subject has been identified or diagnosed as having a cancer (PI3Kα-associated cancer) with dysregulation of the expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them (e.g., as determined using a regulatory approved, e.g., FDA approved, assay or kit). For example, the subject has a tumor that is positive for a mutation listed in Table 1 or Table 2. The subject may be a subject with a tumor(s) that is positive for dysregulation of the expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them (e.g., identified as positive using a regulatory approved, e.g., FDA approved, assay or kit). The subject may be one whose tumor has a dysregulated PIK3CA gene, PI3K alpha protein, or expression or activity or levels thereof (e.g., the tumor has been identified as such using a kit or assay approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject is suspected of having a PI3K alpha-associated cancer. In some embodiments, the subject has medical records indicating that the subject has a tumor with a dysregulated PIK3CA gene, PI3K alpha protein, or expression or activity or levels of any of them (and optionally, the medical records indicate that the subject should be treated with any of the compositions provided herein).

[0166] In some embodiments, the subject is a pediatric subject.

[0167] The term "pediatric subject" as used herein refers to a subject who is under 21 years old at the time of diagnosis or treatment. The term "child" can be further divided into various subpopulations, including neonates (birth to 1 month old), infants (1 month old to 2 years old); children (2 to 12 years old), and adolescents (12 to 21 years old (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 2 years of age, from 2 years of age to less than 12 years of age, or from 12 years of age to less than 21 years of age (up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 1 year of age, from 1 month of age to less than 4 months of age, from 3 months of age to less than 7 months of age, from 6 months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than 7 years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0168] In certain embodiments, the compounds of formula (I), or pharma- ceutically acceptable salts thereof, are useful for preventing diseases and disorders defined herein (e.g., PIK3CA-Associated Overgrowth Syndrome (PROS) and cancer). As used herein, the term "prevent" means to delay, in whole or in part, the onset, recurrence, or spread of a disease or condition described herein, or a symptom thereof.

[0169] The term "PI3K alpha-associated disease or disorder" as used herein refers to a disease or disorder associated with or having dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression or activity or level of the PIK3CA gene, or the PI3K alpha protein, or any of them described herein). Non-limiting examples of PI3K alpha-associated diseases or disorders include, for example, PIK3CA-associated overgrowth syndrome (PROS), brain disorders (e.g., as megalencephaly-capillary malformation syndrome (MCAP) and hemimegalencephaly), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibroadipose hyperplasia (FH), or cancer (e.g., PI3K alpha-associated cancer).

[0170] As used herein, the term "PI3K alpha associated cancer" refers to cancers associated with or having dysregulation of the PIK3CA gene, the PI3K alpha protein, or any of the expression or activity or levels thereof. Non-limiting examples of PI3K alpha associated cancers are described herein.

[0171] The phrase "dysregulated expression or activity or levels of the PIK3CA gene, the PI3K α protein, or any of them" refers to a genetic mutation (e.g., a mutation in the PIK3CA gene that results in expression of a PI3K α with at least one amino acid deletion compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in expression of a PI3K α with one or more point mutations compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in expression of a PI3K α with at least one inserted amino acid compared to wild-type PI3K α, a gene duplication that results in increased PI3K α levels in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in increased PI3K α levels in a cell), an alternatively spliced ​​version of PI3K α mRNA that results in a PI3K α with at least one amino acid deletion in PI3K α compared to wild-type PI3K α), or increased expression (e.g., increased levels) of wild-type PI3K α in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to a non-cancerous control cell). As another example, the dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them may be a mutation in the PIK3CA gene that encodes a PI3K alpha that is constitutively active or has increased activity compared to a protein encoded by a PIK3CA gene that does not contain a mutation. Non-limiting examples of PI3K alpha point mutations / substitutions / insertions / deletions are listed in Tables 1 and 2.

[0172] The term "activating mutation" in reference to PI3Kα describes a mutation in the PIK3CA gene that results in the expression of PI3Kα with increased kinase activity, e.g., compared to wild-type PI3Kα, when assayed under the same conditions. For example, an activating mutation can be a mutation in the PIK3CA gene that results in the expression of PI3Kα with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that have increased kinase activity, e.g., compared to wild-type PI3Kα, when assayed under the same conditions. In another example, an activating mutation can be a mutation in PIK3CA that results in the expression of PI3Kα with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid deletions, e.g., compared to wild-type PI3Kα, when assayed under the same conditions. In another example, an activating mutation can be a mutation in the PIK3CA gene that results in the expression of a PI3K alpha with at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid insertion compared to a wild-type PI3K alpha, e.g., an exemplary wild-type PI3K alpha described herein, when assayed under identical conditions. Additional examples of activating mutations are known in the art.

[0173] The term "wild type" or "wild-type" describes a nucleic acid (e.g., a PIK3CA gene or PI3Kα mRNA) or protein (e.g., a PI3Kα) sequence that is typically found in a subject that does not have a disease or disorder associated with the referenced nucleic acid or protein.

[0174] The term "wild type PI3K α" or "wild-type PI3K α" describes a normal PI3K α nucleic acid (e.g., PIK3CA or PI3K α mRNA) or protein found in a subject who does not have a PI3K α-related disease, e.g., a PI3K α-related cancer (and optionally, who does not have an increased risk of developing a PI3K α-related disease and / or is not suspected of having a PI3K α-related disease), or found in a cell or tissue from a subject who does not have a PI3K α-related disease, e.g., a PI3K α-related cancer (and optionally, who does not have an increased risk of developing a PI3K α-related disease and / or is not suspected of having a PI3K α-related disease).

[0175] Provided herein is a method for treating cancer (e.g., PI3K alpha-associated cancer) in a subject in need of cancer treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein is a method for treating PI3K alpha-associated cancer in a subject in need of cancer treatment, comprising a) detecting dysregulation of expression or activity or level of PIK3CA gene, PI3K alpha protein, or any of them in a sample from the subject, and b) administering a therapeutically effective amount of a compound of formula (I) or a pharma-ceutical acceptable salt thereof. In some embodiments, the dysregulation of expression or activity or level of PIK3CA gene, PI3K alpha protein, or any of them comprises one or more substitutions / point mutations / insertions of PI3K alpha protein. Non-limiting examples of substitutions / insertions / deletions of PI3K alpha protein are described in Table 1 and Table 2.

[0176] In some embodiments, the substitution / insertion / deletion in the PI3K alpha protein is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the substitution / insertion / deletion in the PI3K alpha protein is H1047X, where X is any amino acid.

[0177] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a PI3K alpha associated cancer) is selected from a hematological cancer and a solid tumor.

[0178] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Both breast cancers, ER + breast cancer, and triple-negative breast cancer), endometrial cancer, lung cancer (including adenocarcinoma of the lung and squamous cell lung carcinoma), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagogastric junction adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell carcinoma such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumors (pNETs), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0179] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Both breast cancers, ER +breast cancer, and triple-negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, squamous cell carcinoma of the head and neck (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), renal cancer, pancreatic neuroendocrine tumors (pNETs), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma of the lung and squamous cell carcinoma of the lung), and endometrial cancer.

[0180] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a PI3Kα-associated cancer) is selected from breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, gastroesophageal junction adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0181] In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is lung cancer.

[0182] In some embodiments of any of the methods or uses described herein, the PI3K alpha associated cancer is selected from the cancers listed in Tables 1 and 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

[0183] In some embodiments, dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K α protein, or any of them comprises a splice variation in the PI3K α mRNA that results in an expressed protein that is an alternative splice variant of PI3K α, in which at least one residue is deleted (compared to the wild-type PI3K α protein), thereby resulting in constitutive activity of the PI3K α protein domain.

[0184] In some embodiments, the dysregulation of the expression or activity or level of PIK3CA gene, PI3Kα protein, or any of them comprises at least one point mutation in PIK3CA gene, which results in the production of PI3Kα protein with one or more amino acid substitutions or insertions compared to wild-type PI3Kα protein, or a deletion in PIK3CA gene, which results in the production of PI3Kα protein with one or more amino acid insertions or deletions.In some cases, the resulting mutant PI3Kα protein has increased activity compared to wild-type PI3Kα protein or PI3Kα protein that does not contain the same mutation.In some embodiments, the compound described herein selectively inhibits the resulting mutant PI3Kα protein compared to wild-type PI3Kα protein or PI3Kα protein that does not contain the same mutation.

[0185] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO:1) [ka]

[0186] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is useful for treating cancers that have been identified as having one or more PI3Kα mutations.Accordingly, provided herein is a method for treating a subject diagnosed with (or identified as having) cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0187] Also provided herein is a method for treating a subject identified or diagnosed as having a PI3K alpha-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its pharma- ceutical acceptable salt, or a pharmaceutical composition thereof. In some embodiments, the subject identified or diagnosed as having a PI3K alpha-associated cancer through the use of a regulatory approved, e.g., FDA approved, test or assay for identifying dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them in the subject or in a biopsy sample from the subject, or by carrying out any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a PI3K alpha-associated cancer.

[0188] The term "regulatory authority" refers to a national authority for approval of the medical use of a drug in that country. For example, a non-limiting example of a regulatory authority is the United States Food and Drug Administration (FDA).

[0189] Also provided are methods for treating cancer in a subject in need thereof, comprising: (a) detecting a PI3K alpha-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is determined to have a PI3K alpha-associated cancer through the use of a regulatory approved, e.g., FDA approved, test or assay for identifying dysregulation of expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them in the subject or a biopsy sample from the subject, or by carrying out any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a PI3K alpha-associated cancer.

[0190] Also provided is a method of treating a subject, comprising performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them. Some embodiments of these methods further comprise administering another anti-cancer agent (e.g., immunotherapy) to the subject. In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, such as at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a PI3K alpha associated cancer, a subject exhibiting one or more symptoms of a PI3K alpha associated cancer, or a subject at high risk of developing a PI3K alpha associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory approved assay, such as an FDA approved kit. In some embodiments, the assay is liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0191] Also provided is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a PI3Kα-associated cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of the expression or activity or level of the PIK3CA gene, the PI3Kα protein, or any of them (wherein the presence of a dysregulation of the expression or activity or level of the PIK3CA gene, the PI3Kα protein, or any of them identifies the subject as having a PI3Kα-associated cancer). Also provided is the use of a compound of formula (I), or a medicament for treating a PI3Kα-associated cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer through performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulated expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them (wherein the presence of a dysregulated expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them identifies the subject as having a PI3Kα-associated cancer). Some embodiments of any of the methods or uses described herein further include recording in the subject's medical record (e.g., a computer-readable medium) that the subject is determined to have a dysregulated expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them through performing an assay, and should be administered a compound of formula (I), or a medicament for treating a PI3Kα-associated cancer in a subject. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory approved assay, e.g., an FDA approved kit, hi some embodiments, the assay is a liquid biopsy.

[0192] Also provided is a compound of formula (I), or a medicamentically acceptable salt thereof, for use in treating cancer in a subject in need of cancer treatment or a subject identified or diagnosed as having a PI3Kα-associated cancer. Also provided is the use of a compound of formula (I), or a medicamentically acceptable salt thereof, for the manufacture of a medicament for treating cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer. In some embodiments, a subject is identified or diagnosed as having a PI3Kα-associated cancer through the use of a kit approved by a regulatory agency, for example, approved by the FDA, for identifying dysregulation of the expression or activity or level of the PIK3CA gene, PI3Kα protein, or any of them in a subject or a biopsy sample from the subject. As defined herein, PI3Kα-associated cancer includes those described herein and known in the art.

[0193] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having cancer with dysregulation of PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may have a tumor(s) that is positive for dysregulation of PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having PI3K alpha-associated cancer. In some embodiments, provided herein is a method for treating PI3K alpha associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula (I), or a medicamentically acceptable salt thereof. In some embodiments, the dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them comprises one or more point mutations / insertions / deletions of the PI3K alpha protein. Non-limiting examples of point mutations / insertions / deletions of the PI3K alpha protein are listed in Table 1 and Table 2. In some embodiments, the point mutation / insertions / deletions of the PI3K alpha protein are H1047X, where X is any amino acid.In some embodiments, the point mutation / insertion / deletion of the PI3K alpha protein is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, the cancer with dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA. In some embodiments, the tumor with dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA.

[0194] In some embodiments of any of the methods or uses described herein, the subject has medical records indicating that the subject has a tumor having dysregulated expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them. Also provided is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject having medical records indicating that the subject has dysregulated expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them.

[0195] In some embodiments, the method provided herein comprises performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the expression or level of the PIK3CA gene, the PI3K alpha protein, or any of them. In some such embodiments, the method also comprises administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to the subject determined to have a dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them. In some embodiments, the method also comprises determining that the subject has a dysregulation of the expression or level of the PIK3CA gene, the PI3K alpha protein, or any of them, through an assay performed on a sample obtained from the subject. In such embodiments, the method also comprises administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to the subject. In some embodiments, the dysregulation in the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is one or more point mutations in the PIK3CA gene (e.g., any of one or more of the PI3K alpha point mutations described herein). One or more point mutations in the PIK3CA gene may result in the translation of a PI3K alpha protein having, for example, one or more of the following amino acid substitutions, deletions, and insertions: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. One or more mutations in the PIK3CA gene may result in the translation of a PI3K alpha protein having, for example, one or more of the following amino acids: 542, 545, 1043, and 1047, and 1049.In some embodiments, the dysregulation in the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is one or more PI3K alpha amino acid substitutions (e.g., any of the PI3K alpha amino acid substitutions described herein). Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., immunotherapy).

[0196] In some embodiments of any of the methods or uses described herein, the assay used to determine whether the subject has dysregulation of expression or activity or level of PIK3CA gene, or PI3K alpha protein, or any of them using a sample from the subject may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and real-time quantitative RT-PCR). As is well known in the art, the assay is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art for detecting dysregulation of expression or activity or level of PIK3CA gene, PI3K alpha protein, or any of them (see, for example, references cited herein). In some embodiments, the sample is a biological sample or biopsy sample (e.g., paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a PI3K alpha-associated cancer, a subject having one or more symptoms of a PI3K alpha-associated cancer, and / or a subject having an increased risk of developing a PI3K alpha-associated cancer.

[0197] In some embodiments, dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them may be identified using liquid biopsy (variously referred to as fluid biopsy or fluid-phase biopsy). See, for example, Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment", Ann.Transl.Med.,3(3):36,2016. Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them. Liquid biopsies can be performed on biological samples that are relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments, liquid biopsy can be used to detect the presence of dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them at an earlier stage than conventional methods. In some embodiments, the biological sample used in liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly sensitive detection techniques such as, but not limited to, next generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of the expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them.

[0198] Also provided is a method for inhibiting PI3K alpha activity in a cell, the method comprising contacting the cell with a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, the method comprising administering an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, to a subject having a cell with aberrant PI3K alpha activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer described herein. In some embodiments, the cancer cell is a PI3K alpha-associated cancer cell. As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" a PI3K alpha protein with a compound provided herein includes administering a compound provided herein to an individual or subject, such as a human, having a PI3K alpha protein, as well as introducing, for example, a compound provided herein into a sample containing a cell preparation or purified preparation containing a PI3K alpha protein.

[0199] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0200] Further provided herein is a method for increasing cell death in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) or its pharma- ceutically acceptable salt, or its pharmaceutical composition, as defined herein.Also provided herein is a method for increasing tumor cell death in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or its pharma- ceutically acceptable salt, in an amount effective to increase tumor cell death.

[0201] The phrase "therapeutically effective amount" refers to an amount of a compound sufficient to (i) treat a PI3Kα protein-related disease or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein, when administered to a subject in need of such treatment. The amount of a compound of formula (I), or a medicamentously acceptable salt thereof, that would correspond to such an amount will vary depending on factors such as the particular compound, the condition and its severity, the identity of the subject in need of treatment (e.g., body weight), and the like, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0202] When employed as pharmaceuticals, the compounds of formula (I) (including pharma- ceutically acceptable salts thereof) can be administered in the form of pharmaceutical compositions as described herein.

[0203] combination In the field of medical oncology, it is common practice to treat each subject with cancer using a combination of different forms of treatment. In medical oncology, such co-treatment or other component(s) of therapy in addition to the compositions provided herein can be, for example, surgery, radiation therapy, and chemotherapeutic agents such as other kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery can be open surgery or minimally invasive surgery. Thus, the compounds of formula (I), or a pharmacologic acceptable salt thereof, can also be useful as adjuncts to cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents acting by the same or different mechanism of action. In some embodiments, the compounds of formula (I), or a pharmacologic acceptable salt thereof, can be used prior to administration of the additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of the compounds of formula (I), or a pharmacologic acceptable salt thereof, for a period of time, and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, reduces the size of the tumor (e.g., tumor mass) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered one or more doses of a compound of formula (I), or a pharma-ceutically acceptable salt thereof, for a period of time, under one or more radiation therapies. In some embodiments, treatment with one or more doses of a compound of formula (I), or a pharma-ceutically acceptable salt thereof, reduces the size of the tumor (e.g., tumor mass) prior to one or more radiation therapies.

[0204] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a standard of care (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a previous treatment (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard of care. In some embodiments, the subject is PI3K alpha inhibitor naïve. For example, the subject is naïve to treatment with a selective PI3K alpha inhibitor. In some embodiments, the subject is not PI3K alpha inhibitor naïve. In some embodiments, the subject is kinase inhibitor naïve. In some embodiments, the subject is not kinase inhibitor naïve. In some embodiments, the subject has undergone a previous treatment.For example, a multikinase inhibitor (MKI) or another PI3K inhibitor, such as bupallisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolicib (PF-05212384, PKI-587 ), seravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK10 Treatment with 59615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, or GSK2636771.

[0205] In some embodiments of any of the methods described herein, the compound of Formula (I) (or a pharma- ceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic (e.g., chemotherapeutic) agents.

[0206] Non-limiting examples of additional therapeutic agents include other PI3K alpha targeted therapies (i.e., other PI3K alpha inhibitors), EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapies (including mTOR inhibitors described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapies (e.g., Trk inhibitors or multikinase inhibitors)), farnesyltransferase inhibitors, signal transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERM / SERD), checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapeutic agents, angiogenesis targeted therapies, immune targeted agents including immunotherapies, and radiation therapy.

[0207] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), bandeline (BMP, BRAFIX®), rivaroxaban (RIV ... Tanib (CAPRELSA®), Rociletinib (CO-1686), Olmutinib (OLITATM, HM61713, BI-1482694), Naquotinib (ASP8273), Nazartinib (EGF816, NVS-816), PF-06747775, Icotinib (BPI-2009H), Afatinib (BIBW2992, GILOTRIF®), Dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), Avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-Dimethylacryl-shikonin and acetyl-alkanenin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlitinib (ASLAN001, ARRY -334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, abatinib, Disruptin, CL-387785, EGFRBi-arm autologous T cells, and EGFR CAR-T therapy. In some embodiments, the EGFR targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0208] Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), HER2 inhibitors (e.g., HER2 inhibitors ... (R), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-222611, and AEE-788.

[0209] As used herein, "RAS pathway targeting therapeutic agent" includes any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, the RAS pathway modulator can be selective for proteins in the RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also known as RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeting therapeutic agent is a "KRAS pathway modulator". KRAS pathway modulators include any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors described herein), AKT, and mTOR. In some embodiments, the KRAS pathway modulator can be selective for proteins in the RAS pathway, for example, the KRAS pathway modulator can be selective for KRAS (also known as KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0210] Non-limiting examples of KRAS targeted therapeutics (e.g., KRAS inhibitors) include BI1701963, AMG510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0211] Further non-limiting examples of RAS targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

[0212] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0213] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947 , KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or combinations thereof.

[0214] In some embodiments, the other PI3K inhibitor is another PI3K alpha inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is bupallisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-86 6), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), piralalisib (XL147, SAR245408), gedatolicib (PF-05212384, PKI-587), seravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK1059615, GDC-0084 (RG76 66), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

[0215] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphosphocholine, erufosine e), SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (triciribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY1125976, 3-oxo-tirucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0216] In some embodiments, the mTOR inhibitor is selected from MLN0128, bistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

[0217] Non-limiting examples of farnesyltransferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0218] In some embodiments, the chemotherapeutic agents include anthracyclines, cyclophosphamide, taxanes, platinum-based agents, mitomycin, gemcitabine, eribulin (HALAVEN™), or combinations thereof.

[0219] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0220] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0221] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0222] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0223] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0224] Non-limiting examples of selective estrogen receptor modulators or degraders (SERM / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amsenestrant (SAR439859), AZD9833, lindestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0225] Non-limiting examples of immunotherapies include immune checkpoint therapy, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapy include inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or a combination thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, e.g., Marin-Acevedo, et al., J Hematol Oncol. 11:39 (2018).

[0226] In some embodiments, the additional therapy or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab-paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, bupallisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, amsenestrant, and combinations thereof.

[0227] In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of certain anti-cancer therapies and / or as palliative therapy (e.g., opioids and corticosteroids). In some embodiments, the additional therapy or agent described herein is selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, metformin, and combinations thereof.

[0228] Non-limiting examples of GLP-1 receptor agonists include liraglutide (VICTOZA®, NN2211), dulaglutide (LY2189265, TRULICITY®), exenatide (BYETTA®, BYDUREON®, exendin-4), taspoglutide, lixisenatide (LYXUMIA®), albiglutide (TANZEUM®), semaglutide (OZEMPIC®), ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0229] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, serfliflozin, licofliglozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin.

[0230] Non-limiting examples of DPP-4 inhibitors include sitagliptin (JANUVIA®), vildagliptin, saxagliptin (ONGLYZA®), linagliptin (TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (NESINA®), omarigliptin, evogliptin, and dutogliptin.

[0231] In some embodiments, the subject is also instructed to maintain a particular diet and / or exercise regimen to control blood glucose levels.

[0232] Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer comprising (a) a compound of Formula (I), or a pharma- ceutical acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharma- ceutical acceptable carrier, for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharma- ceutical acceptable salt thereof, and the additional therapeutic agent are together effective to treat cancer.

[0233] In some embodiments, the additional therapeutic agent(s) include any one of the therapies or therapeutic agents listed above that are standard of care in cancer, where the cancer has dysregulation of the expression or activity or levels of the PIK3CA gene, the PI3K alpha protein, or any of them.

[0234] These additional therapeutic agents may be administered as part of the same or a separate dosage form, via the same or a different route of administration, and / or on the same or a different dosing schedule, together with one or more doses of a compound of formula (I) or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition thereof, in accordance with standard pharmaceutical practice known to those of skill in the art.

[0235] Also provided herein are (i) pharmaceutical combinations for treating cancer in a subject in need thereof, comprising (a) a compound of formula (I), or a pharma- ceutical acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharma- ceutical acceptable carrier, wherein the amounts of the compound of formula (I), or a pharma- ceutical acceptable salt thereof, and the additional therapeutic agent are effective in treating cancer together, for simultaneous, separate, or sequential use, (ii) pharmaceutical compositions comprising such combinations, (iii) uses of such combinations for the preparation of medicaments for the treatment of cancer, and (iv) commercial packages or articles of manufacture comprising such combinations as combined preparations for simultaneous, separate, or sequential use, and methods of treating cancer in a subject in need thereof. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0236] The term "pharmaceutical combination" as used herein refers to a drug therapy resulting from the mixing or combination of multiple active ingredients, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are both administered to a subject simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages so that they can be administered to a subject in need thereof simultaneously, in parallel, or sequentially with variable intervening time limits, such administration resulting in effective levels of the two or more compounds in the subject's body. These also apply to cocktail therapy, for example, administration of three or more active ingredients.

[0237] Thus, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer, comprising (a) a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and (b) an additional therapeutic agent, for simultaneous, separate, or sequential use for the treatment of cancer, wherein the compound of formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, and the amounts of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are jointly effective for treating cancer. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially in any order as separate dosages, for example, in a daily dosage or intermittent dosages, in a jointly therapeutically effective amount. In some embodiments, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[0238] Embodiment Embodiment 1: A compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is a C-C cycloalkyl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; X 1 , X 2 , X 3 , and X 4 each independently represents N, CH, or CR 4 where X 1 , X 2 , X 3 , and X 4 up to two of may be N; Each R 4 are independently halogen, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), phenyl, 5- to 6-membered heteroaryl, and each of the R G and selected from the group consisting of 3-6 membered heterocyclyl or 3-6 membered cycloalkyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, R G C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), or -SO2(C1-C6 alkyl), optionally substituted with R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and -CO2H, or a pharma- ceutical acceptable salt thereof.

[0239] Embodiment 2: The compound of embodiment 1, wherein m is 1.

[0240] Embodiment 3: The compound of embodiment 1, wherein m is 2.

[0241] Embodiment 4: [ka] but, [ka] 3. The compound of embodiment 1 or 2, wherein

[0242] Embodiment 5: [ka] but, [ka] 3. The compound of embodiment 1 or 2, wherein

[0243] Embodiment 6: [ka] but, [ka] 4. The compound of embodiment 1 or 3, wherein

[0244] Embodiment 7: Each R 1 The compound of any one of embodiments 1-6, wherein is independently selected from fluoro and chloro.

[0245] Embodiment 8: Each R 1 The compound of any one of embodiments 1-7, wherein is fluoro.

[0246] Embodiment 9: The compound of embodiment 1, wherein m is 0.

[0247] Embodiment 10: X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 is N or CH.

[0248] Embodiment 11: X 1 , X 2 , X 3 , and X 4 Two of the CRs are selected independently. 4 and the other two X 1 , X 2 , X 3 , and X 4 is N or CH.

[0249] Embodiment 12: X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 The compound of any one of embodiments 1-9, wherein is CH.

[0250] Embodiment 13: X 1 , X 2 , X 3 , and X 4 Two of the CRs are selected independently. 4 and the other two X 1 , X 2 , X 3 , and X 4 The compound of any one of embodiments 1-9, wherein is CH.

[0251] Embodiment 14: X 1 , X 2 , X 3 , and X 4 One of them is CR 4 And the other three X 1 , X 2 , X 3 , and X 4 is N.

[0252] Embodiment 15:X 1 , X2 , X 3 , and X 4 Two of the CRs are selected independently. 4 and the other two X 1 , X 2 , X 3 , and X 4 is N.

[0253] Embodiment 16:X 1 , X 2 , X 3 , and X 4 But X 1 and X 4 The compound according to any one of embodiments 1-9, wherein together with the adjacent carbon atom, forms a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl ring.

[0254] Embodiment 17: Structure of formula (Ia): [ka] wherein R 1A is a halogen, R 1B is a halogen or is absent, X 2 and X 4 is each independently N or CH, or a pharma- ceutically acceptable salt thereof.

[0255] Embodiment 18: Structure of Formula (Ib): [ka] 18. The compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, having the following structure:

[0256] Embodiment 19: Structure of formula (Ic): [ka] 18. The compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, having the following structure:

[0257] Embodiment 20: Structure of formula (Id): [ka] 18. The compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, having the following structure:

[0258] Embodiment 21: Structure of formula (Ie): [ka] 18. The compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, having the following structure:

[0259] Embodiment 22: R 1A and R 1B The compound of any one of embodiments 17-21, wherein each is an independently selected halogen.

[0260] Embodiment 23: R 1A and R 1B The compound of any one of embodiments 17-21, wherein each is fluoro.

[0261] Embodiment 24: R 1A is fluoro and R 1B The compound of any one of embodiments 17-21, wherein

[0262] Embodiment 25: R 1A is fluoro and R 1B The compound of any one of embodiments 17-21, wherein is chloro.

[0263] Embodiment 26:R 2 The compound of any one of embodiments 1-25, wherein is C1-C6 alkyl.

[0264] Embodiment 27: R 2 The compound of any one of embodiments 1-26, wherein is methyl.

[0265] Embodiment 28: R 2 The compound of any one of embodiments 1-25, wherein is C1-C6 haloalkyl.

[0266] Embodiment 29:R 2 The compound of any one of embodiments 1-25 and 28, wherein is difluoromethyl or trifluoromethyl.

[0267] Embodiment 30: R 2 The compound of any one of embodiments 1-25, wherein is halogen.

[0268] Embodiment 31: R 2 The compound of any one of embodiments 1-25 and 30, wherein is chloro.

[0269] Embodiment 32: R 2 The compound according to any one of embodiments 1-25, wherein is a C3-C6 cycloalkyl optionally substituted with one or two fluoro.

[0270] Embodiment 33: R 2 The compound according to any one of embodiments 1-25 and 32, wherein is C3-C6 cycloalkyl substituted with 1 or 2 fluoro.

[0271] Embodiment 34: R 2 The compound according to any one of embodiments 1-25 and 32, wherein is unsubstituted C3-C6 cycloalkyl.

[0272] Embodiment 35: R 2 is cyclopropyl.

[0273] Embodiment 36: R 3The compound of any one of embodiments 1-35, wherein is C1-C6 alkyl.

[0274] Embodiment 37: R 3 The compound of any one of embodiments 1-36, wherein is C1-C3 alkyl.

[0275] Embodiment 38: R 3 The compound of any one of embodiments 1-37, wherein is methyl, ethyl, or isopropyl.

[0276] Embodiment 39: R 3 The compound of any one of embodiments 1-38, wherein is methyl.

[0277] Embodiment 40:R 3 The compound of any one of embodiments 1-38, wherein is ethyl.

[0278] Embodiment 41:R 3 The compound of any one of embodiments 1-38, wherein is isopropyl.

[0279] Embodiment 42:R 3 The compound of any one of embodiments 1-35, wherein is C1-C6 haloalkyl.

[0280] Embodiment 43: R 3 The compound of any one of embodiments 1-35 and 42, wherein is trifluoromethyl.

[0281] Embodiment 44: R 3 The compound according to any one of embodiments 1-35, wherein is a C3-C6 cycloalkyl optionally substituted with one or two fluoro.

[0282] Embodiment 45:R 3 The compound according to any one of embodiments 1-35 and 44, wherein is a C3-C6 cycloalkyl substituted with one or two fluoro.

[0283] Embodiment 46:R 3 The compound of any one of embodiments 1-35 and 44, wherein is unsubstituted C3-C6 cycloalkyl.

[0284] Embodiment 47:R 3 The compound according to any one of embodiments 1-35 and 44-46, wherein is cyclopropyl.

[0285] Embodiment 48:R 4 The compound of any one of embodiments 1-47, wherein is halogen.

[0286] Embodiment 49:R 4 The compound of any one of embodiments 1-47, wherein is C1-C6 alkyl.

[0287] Embodiment 50: R 4 The compound of any one of embodiments 1-47 and 49, wherein is methyl.

[0288] Embodiment 51: R 4 The compound of any one of embodiments 1-47, wherein is C1-C6 alkoxy.

[0289] Embodiment 52: R 4 The compound of any one of embodiments 1-47 and 51, wherein is methoxy.

[0290] Embodiment 53: R 4 The compound of any one of embodiments 1-47, wherein is C1-C6 haloalkyl.

[0291] Embodiment 54: R 4 The compound of any one of embodiments 1-47 and 53, wherein is trifluoromethyl.

[0292] Embodiment 55: R 4 The compound of any one of embodiments 1-47, wherein is hydroxyl.

[0293] Embodiment 56: R 4 The compound of any one of embodiments 1-47, wherein is cyano or -CO2H.

[0294] Embodiment 57: R 4 But -NR A R B The compound of any one of embodiments 1-47, wherein

[0295] Embodiment 58: R A and R B The compound of any one of embodiments 1-47 and 57, wherein each is hydrogen.

[0296] Embodiment 59: R A and R B is hydrogen, and R A and R B The other of R G The compound according to any one of embodiments 1-47 and 57, wherein R is C1-C6 alkyl optionally substituted with:

[0297] Embodiment 60: R A and R B is hydrogen, and R A and R B The other of R G The compound according to any one of embodiments 1-47 and 57, wherein R is C1-C3 alkyl substituted with R.

[0298] Embodiment 61: R A and R B is hydrogen, and R A and R B the other of which is fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 R selected from the group consisting of -COH G The compound according to any one of embodiments 1-47 and 60, wherein R is C1-C3 alkyl, substituted with R.

[0299] Embodiment 62: R A and R B is hydrogen, and R A and R B The compound of any one of embodiments 1-47 and 57, wherein the other of is methyl.

[0300] Embodiment 63: R A and R B The compound of any one of embodiments 1-47 and 57, wherein each is C1-C6 alkyl.

[0301] Embodiment 64: R A and R B The compound of any one of embodiments 1-47, 57, and 63, wherein each is methyl.

[0302] Embodiment 65: R A and R B is hydrogen, and R A and R B The compound of any one of embodiments 1-47 and 57, wherein the other of is C1-C6 haloalkyl.

[0303] Embodiment 66: R A and R B The compound of any one of embodiments 1-47 and 57, wherein each is C1-C6 haloalkyl.

[0304] Embodiment 67: R A and R B one of them is C1-C6 alkyl, and R A and R B The compound of any one of embodiments 1-47 and 57, wherein one of the other is C1-C6 haloalkyl.

[0305] Embodiment 68: One R 4 But -C(=O)NR C R D The compound of any one of embodiments 1-47, wherein

[0306] Embodiment 69: R C and R D The compound of any one of embodiments 1-47 and 68, wherein each is hydrogen.

[0307] Embodiment 70:R C and R D is hydrogen, and R C and R D The compound of any one of embodiments 1-47 and 68, wherein the other of is C1-C6 alkyl.

[0308] Embodiment 71:R C and R D is hydrogen, and R C and R D The compound of any one of embodiments 1-47 and 68, wherein the other of is methyl.

[0309] Embodiment 72:R C and R D The compound of any one of embodiments 1-47 and 68, wherein each is C1-C6 alkyl.

[0310] Embodiment 73:R C and R D The compound of any one of embodiments 1-47, and 68, wherein each is methyl.

[0311] Embodiment 74: R C and R D is hydrogen, and R C and R D The compound of any one of embodiments 1-47 and 68, wherein the other of is C1-C6 haloalkyl.

[0312] Embodiment 75:R C and R D The compound of any one of embodiments 1-47 and 68, wherein each is C1-C6 haloalkyl.

[0313] Embodiment 76:R C and R D one of them is C1-C6 alkyl, and R C and R D The compound of any one of embodiments 1-47 and 68, wherein the other of is C1-C6 haloalkyl.

[0314] Embodiment 77: One R 4 But -SO2(NR E R F ). The compound of any one of embodiments 1-47, wherein

[0315] Embodiment 78:R E and R F The compound of any one of embodiments 1-47 and 77, wherein each is hydrogen.

[0316] Embodiment 79: R E and R F is hydrogen, and R E and R F The compound of any one of embodiments 1-47 and 77, wherein the other of is C1-C6 alkyl.

[0317] Embodiment 80:R E and R F is hydrogen, and R E and R F The compound of any one of embodiments 1-47, 77, and 79, wherein the other of is methyl.

[0318] Embodiment 81: R E and R F The compound of any one of embodiments 1-47 and 77, wherein each is C1-C6 alkyl.

[0319] Embodiment 82:R E and R F The compound of any one of embodiments 1-47 and 77, wherein each is methyl.

[0320] Embodiment 83: RE and R F is hydrogen, and R E and R F The compound according to any one of embodiments 1-47 and 77, wherein the other of is C1-C6 haloalkyl.

[0321] Embodiment 84:R E and R F The compound of any one of embodiments 1-47 and 77, wherein each is C1-C6 haloalkyl.

[0322] Embodiment 85:R E and R F one of them is C1-C6 alkyl, and R E and R F The compound according to any one of embodiments 1-47 and 77, wherein the other of is C1-C6 haloalkyl.

[0323] Embodiment 86:R 4 The compound according to any one of embodiments 1-47, wherein is -SO2(C1-C6 alkyl).

[0324] Embodiment 87:R 4 The compound according to any one of embodiments 1-47 and 86, wherein is -SO2Me.

[0325] Embodiment 88:R 4 The compound according to any one of embodiments 1-47 and 86, wherein is -SO2Et.

[0326] Embodiment 89:R 4 The compound of any one of embodiments 1-47, wherein is -S(=O)(=NH)(C1-C6 alkyl).

[0327] Embodiment 90:R 4 The compound of any one of embodiments 1-47 and 89, wherein is -S(=O)(=NH)Me.

[0328] Embodiment 91:R 4The compound of any one of embodiments 1-47, wherein is -C(=O)(C1-C6 alkyl).

[0329] Embodiment 92:R 4 The compound of any one of embodiments 1-47 and 91, wherein is -C(=O)Me.

[0330] Embodiment 93:R 4 The compound of any one of embodiments 1-47, wherein is -CO2(C1-C6 alkyl).

[0331] Embodiment 94:R 4 The compound of any one of embodiments 1-47 and 93, wherein is -CO2Me.

[0332] Embodiment 95:R 4 is one to two independently selected R G The compound according to any one of embodiments 1-47, wherein R is phenyl optionally substituted with:

[0333] Embodiment 96:R 4 is one to two independently selected R G The compound according to any one of embodiments 1-47, wherein R is 5-6 membered heteroaryl optionally substituted by:

[0334] Embodiment 97:R 4 is one or two independently selected R G The compound according to any one of embodiments 1-47, wherein R is 3-6 membered heterocyclyl optionally substituted by:

[0335] Embodiment 98:R 4 is one or two independently selected R G The compound according to any one of embodiments 1-47 and 97, wherein the compound is 3-6 membered heterocyclyl substituted with

[0336] Embodiment 99:R 4 But one R GThe compound according to any one of embodiments 1-47 and 97-98, wherein R is 3-6 membered heterocyclyl substituted with

[0337] Embodiment 100:R 4 are two independently selected R G The compound according to any one of embodiments 1-47 and 97-98, wherein R is 3-6 membered heterocyclyl substituted with

[0338] Embodiment 101:R 4 is one or two independently selected R G The compound according to any one of the preceding embodiments, wherein R is a 3-6 membered cycloalkyl optionally substituted with:

[0339] Embodiment 102: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is fluoro.

[0340] Embodiment 103: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is hydroxyl.

[0341] Embodiment 104: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is cyano.

[0342] Embodiment 105: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is C1-C6 alkyl.

[0343] Embodiment 106: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is methyl.

[0344] Embodiment 107: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is C1-C6 alkoxy.

[0345] Embodiment 108: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is methoxy.

[0346] Embodiment 109: One R G The compound according to any one of embodiments 1-47 and 97-101, wherein is -CO2H.

[0347] Embodiment 110: One R G But -NR A1 R B1 The compound according to any one of embodiments 1-47 and 97-101, wherein

[0348] Embodiment 111:R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein each is hydrogen.

[0349] Embodiment 112:R A1 and R B1 is hydrogen, and R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein the other of is C1-C6 alkyl.

[0350] Embodiment 113:R A1 and R B1 is hydrogen, and R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein the other of is methyl.

[0351] Embodiment 114:R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein each is C1-C6 alkyl.

[0352] Embodiment 115:R A1 and R B1The compound of any one of embodiments 1-47, 97-101, and 110, wherein each is methyl.

[0353] Embodiment 116:R A1 and R B1 is hydrogen, and R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein the other of is C1-C6 haloalkyl.

[0354] Embodiment 117:R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein each is C1-C6 haloalkyl.

[0355] Embodiment 118:R A1 and R B1 one of them is C1-C6 alkyl, and R A1 and R B1 The compound of any one of embodiments 1-47, 97-101, and 110, wherein the other of is C1-C6 haloalkyl.

[0356] Embodiment 119: One R G But -C(=O)NR C1 R D1 The compound according to any one of embodiments 1-47 and 97-101, wherein

[0357] Embodiment 120:R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein each is hydrogen.

[0358] Embodiment 121:R C1 and R D1 is hydrogen, and R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein the other of is C1-C6 alkyl.

[0359] Embodiment 122:R C1 and R D1 is hydrogen, and R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein the other of is methyl.

[0360] Embodiment 123:R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein each is C1-C6 alkyl.

[0361] Embodiment 124:R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein each is methyl.

[0362] Embodiment 125:R C1 and R D1 is hydrogen, and R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein the other of is C1-C6 haloalkyl.

[0363] Embodiment 126:R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein each is C1-C6 haloalkyl.

[0364] Embodiment 127:R C1 and R D1 one of them is C1-C6 alkyl, and R C1 and R D1 The compound of any one of embodiments 1-47, 97-101, and 119, wherein the other of is C1-C6 haloalkyl.

[0365] Embodiment 128:R 4 The compound according to any one of embodiments 1-47 and 97, wherein is unsubstituted 3-6 membered heterocyclyl.

[0366] Embodiment 129:R 4 is one or two independently selected R G The compound according to any one of embodiments 1-47 and 98, wherein R is 4-6 membered heterocyclyl optionally substituted by:

[0367] Embodiment 130:R 4 The compound according to any one of embodiments 1-47 and 129, wherein is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or tetrahydropyranyl.

[0368] Embodiment 131:R 4 The compound according to any one of embodiments 1-47 and 129-130, wherein is 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0369] Embodiment 132:R 4 but, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, and has one to two R, each independently selected from fluoro, hydroxyl, cyano, -CONH, or -COH. G The compound of embodiment 129, optionally substituted with:

[0370] Embodiment 133: A compound of embodiment 132, wherein Ring B is azetidinyl.

[0371] Embodiment 134: A compound of embodiment 132, wherein Ring B is pyrrolidinyl.

[0372] Embodiment 135: A compound of embodiment 132, wherein Ring B is piperidinyl.

[0373] Embodiment 136: A compound of embodiment 132, wherein Ring B is unsubstituted.

[0374] Embodiment 137: Ring B is one R G The compound according to embodiment 132, wherein the compound is substituted with

[0375] Embodiment 138:R G The compound of embodiment 137, wherein is fluoro.

[0376] Embodiment 139:R G is hydroxyl.

[0377] Embodiment 140:R G is cyano.

[0378] Embodiment 141:R G The compound of embodiment 137, wherein is -CONH2.

[0379] Embodiment 142:R G The compound of embodiment 137, wherein is -CO2H.

[0380] Embodiment 143: Ring B is selected from two independently selected R G The compound according to embodiment 132, wherein the compound is substituted with

[0381] Embodiment 144: One R G The compound of embodiment 143, wherein is fluoro.

[0382] Embodiment 145: One R G is hydroxyl.

[0383] Embodiment 146: One R G is cyano.

[0384] Embodiment 147: One R GThe compound of embodiment 143, wherein is -CONH2.

[0385] Embodiment 148: One R G is -CO2H.

[0386] Embodiment 149: Each R G is attached at a position on ring B distal to said nitrogen.

[0387] Embodiment 150: A compound according to any one of embodiments 1 to 149, wherein Z is O.

[0388] Embodiment 151: Z is NR x The compound of any one of embodiments 1-149, wherein

[0389] Embodiment 152: The compound of embodiment 1, wherein the compound of formula (I), or the pharma- ceutically acceptable salt thereof, is selected from the compounds in Table A, Table B, or Table C, or a pharma- ceutically acceptable salt of any of the foregoing.

[0390] Embodiment 153: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 152, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0391] Embodiment 154: A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 152 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 153.

[0392] Embodiment 155: A method for treating cancer in a subject in need of such treatment, comprising: (a) determining that the cancer is associated with dysregulation of the PIK3CA gene, the PI3K alpha protein, or any of their expression or activity or levels; and (b) administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 152 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described in embodiment 153.

[0393] Embodiment 156: A method for treating a PI3K alpha-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3K alpha-associated cancer a therapeutically effective amount of a compound described in any one of embodiments 1 to 152 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described in embodiment 153.

[0394] Embodiment 157: A method of treating a PI3K alpha associated cancer in a subject, comprising: (a) determining that the cancer in the subject is a PI3Kα-associated cancer; (b) administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 152 or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to embodiment 153.

[0395] Embodiment 158: A method of treating a subject, comprising administering a therapeutically effective amount of a compound described in any one of embodiments 1 to 152 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 153, to a subject having medical records indicating that the subject has a dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them.

[0396] Embodiment 159: The method of any one of embodiments 155 and 157, wherein the step of determining that the cancer in the subject is a PI3K alpha associated cancer comprises performing an assay to detect dysregulation in the PIK3CA gene, PI3K alpha protein, or the expression or activity or level of any of them in a sample from the subject.

[0397] Embodiment 160: The method of embodiment 159, further comprising obtaining a sample from the subject.

[0398] Embodiment 161: The method of embodiment 160, wherein the sample is a biopsy sample.

[0399] Embodiment 162: The method according to any one of embodiments 159 to 161, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0400] Embodiment 163: The method of embodiment 162, wherein said FISH is a break-apart FISH assay.

[0401] Embodiment 164: The method of embodiment 162, wherein said sequencing is pyrosequencing or next-generation sequencing.

[0402] Embodiment 165: The method of any one of embodiments 155, 158, and 159, wherein the dysregulation in the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is one or more point mutations in the PIK3CA gene.

[0403] Embodiment 166: The method of embodiment 165, wherein said one or more point mutations in the PIK3CA gene result in translation of a PI3K alpha protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1:

[0404] Embodiment 167: The method of embodiment 166, wherein said one or more point mutations in the PIK3CA gene are selected from the mutations in Table 2.

[0405] Embodiment 168: The method of embodiment 166, wherein said one or more point mutations in the PIK3CA gene comprise a substitution at amino acid position 1047 of the human PI3K alpha protein.

[0406] Embodiment 169: The method of embodiment 168, wherein the substitution is H1047R.

[0407] Embodiment 170: The method of any one of embodiments 156, 157, and 159 to 169, wherein the PI3Kα-associated cancer is selected from the group consisting of breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, gastroesophageal junction adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0408] Embodiment 171: The method of any one of embodiments 156, 157, and 159 to 170, wherein the PI3K alpha associated cancer is breast cancer, colorectal cancer, lung cancer, or endometrial cancer.

[0409] Embodiment 172: The method of any one of embodiments 154 to 171, further comprising administering an additional therapy or therapeutic agent to the subject.

[0410] Embodiment 173: The method of embodiment 172, wherein the additional therapy or therapeutic agent is selected from radiation therapy, cytotoxic chemotherapy agents, kinase targeted therapeutic agents, apoptosis modulators, signal transduction inhibitors, immune targeted therapy, and angiogenesis targeted therapy.

[0411] Embodiment 174: The method of embodiment 173, wherein the additional therapeutic agent is selected from one or more kinase targeted therapeutic agents.

[0412] Embodiment 175: The method of embodiment 174, wherein the additional therapeutic agent is a tyrosine kinase inhibitor.

[0413] Embodiment 176: The method of embodiment 174, wherein the additional therapeutic agent is an mTOR inhibitor.

[0414] Embodiment 177: The method of embodiment 173, wherein the additional therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab-paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, bupallisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, amsenestrant, and combinations thereof.

[0415] Embodiment 178: The method of embodiment 173, wherein the additional therapeutic agent is selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, metformin, and combinations thereof.

[0416] Embodiment 179: The method according to any one of embodiments 172 to 178, wherein the compound according to any one of embodiments 1 to 152 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 153, and the additional therapeutic agent are administered simultaneously as separate dosages.

[0417] Embodiment 180: The method according to any one of embodiments 172 to 178, wherein the compound according to any one of embodiments 1 to 152 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 153, and the additional therapeutic agent are administered sequentially in any order as separate dosages.

[0418] Embodiment 181: A method for modulating PI3K alpha in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound according to any one of embodiments 1 to 152, or a pharma- ceutically acceptable salt thereof.

[0419] Embodiment 182: The method of embodiment 181, wherein said contacting occurs in vivo.

[0420] Embodiment 183: The method of embodiment 181, wherein said contacting occurs in vitro.

[0421] Embodiment 184: The method of any one of embodiments 181 to 183, wherein the mammalian cell is a mammalian cancer cell.

[0422] Embodiment 185: The method of embodiment 184, wherein the mammalian cancer cells are mammalian PI3K alpha-associated cancer cells.

[0423] Embodiment 186: The method of any one of embodiments 181 to 185, wherein the cell has a dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them.

[0424] Embodiment 187: The method of embodiment 186, wherein said dysregulation in the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is one or more point mutations in said PIK3CA gene.

[0425] Embodiment 188: The method of embodiment 187, wherein said one or more point mutations in the PIK3CA gene result in translation of a PI3K alpha protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1:

[0426] Embodiment 189: The method of embodiment 188, wherein said one or more point mutations in the PIK3CA gene are selected from the mutations in Table 2.

[0427] Embodiment 190: The method of embodiment 189, wherein said one or more point mutations in the PIK3CA gene comprise a substitution at amino acid position 1047 of the human PI3K alpha protein.

[0428] Embodiment 191: The method of embodiment 190, wherein the substitution is H1047R. EXAMPLES

[0429] Preparation of compounds The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein. The synthesis of the compounds disclosed herein can be accomplished generally by following the schemes provided herein, with modifications for specific desired substituents.

[0430] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Exemplary textbooks, without being limited to any one or several sources, include R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001, and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks for organic synthesis known in the art. The following descriptions of synthetic methods are intended to illustrate, but not limit, general procedures for the preparation of compounds of the present disclosure.

[0431] The synthetic processes disclosed herein can tolerate a wide variety of functional groups, and therefore can employ a variety of substituted starting materials. Although the processes generally provide the desired final compound at or near the end of the overall process, in certain instances it may be desirable to further convert the compound to its pharma- ceutical acceptable salt.

[0432] Example 1: Synthesis of Compounds 1 and 2 [ka] Step 1 To a mixture of (S)-1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropan-1-amine (1.0 g, 4.52 mmol) and NaHCO3 (saturated aqueous solution, 4 mL) in DCM (10 mL) was added thiophosgene (1.04 g, 9.05 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 4 h. After completion, the resulting mixture was diluted with water (40 mL) and extracted with DCM (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (S)-5-fluoro-2-(1-isothiocyanato-2-methylpropyl)-3-methylbenzofuran (1.1 g, 93%) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, J = 9.0, 4.1 Hz, 1H), 7.45 (dd, J = 8.7, 2.6 Hz, 1H), 7.21 - 7.15 (m, 1H), 5.24 (d, J = 7.9 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.23 (s, 3H), 1.10 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H).

[0433] Step 2 A mixture of (S)-5-fluoro-2-(1-isothiocyanato-2-methylpropyl)-3-methylbenzofuran (200 mg, 0.76 mmol) and 3,4-diaminobenzonitrile (112 mg, 0.84 mmol) in MeCN (5 mL) was stirred at 70° C. for 8 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-1-(2-amino-5-cyanophenyl)-3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thiourea (260 mg, 86%) as a yellow solid. MS (ESI): C 21 H 21 Calculated mass for FN4OS, 396.14, observed m / z 397.1 [M+H] + .

[0434] Step 3 (S)-1-(2-amino-5-cyanophenyl)-3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thiourea (260 mg, 0.66 mmol), phenyl-λ in MeCN (5 mL). 3 A solution of 1-iodanediyl diacetate (318.8 mg, 0.99 mmol) and DIPEA (425.7 mg, 3.3 mmol) was stirred at room temperature for 3 h. After completion, the resulting mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-2-((1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)amino)-1H-benzo[d]imidazole-6-carbonitrile (1, 144 mg, 58.9%) as an orange solid. MS (ESI): C 21 H 19 Calculated mass for FNO, 362.15, observed m / z 363.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (d, J = 37.8 Hz, 1H), 7.76 (m, 1H), 7.59 - 7.42 (m, 2H), 7.39 - 7.19 (m, 3H), 7.08 (m, 1H), 4.94 (q, J = 8.9 Hz, 1H), 2.35 - 2.28 (m, 1H), 2.27 (s, 3H), 1.07 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H).

[0435] Step 4 A solution of (S)-2-((1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)amino)-1H-benzo[d]imidazole-6-carbonitrile (50 mg, 0.14 mmol), K2CO3 (38.6 mg, 0.28 mmol) and H2O2 (0.2 mL, 30% (aq)) in DMSO (2 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH 1 to 8%) to give (S)-2-((1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)amino)-1H-benzo[d]imidazole-6-carboxamide (2, 30 mg, 56%) as a white solid. MS (ESI):C 21 H 21 Calculated mass for FN4O2, 380.16, observed m / z 381.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.68 (d, J = 13.1 Hz, 2H), 7.51 - 7.33 (m, 4H), 7.14 - 6.97 (m, 3H), 4.93 (q, J = 8.7 Hz, 1H), 2.34 - 2.31 (m, 1H), 2.28 (s, 3H), 1.08 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H).

[0436] Example 2: Synthesis of Compound 3 [ka] Step 1 A mixture of (S)-5-fluoro-2-(1-isothiocyanato-2-methylpropyl)-3-methylbenzofuran (200 mg, 0.76 mmol) and 3,4-diaminobenzenesulfonamide (157 mg, 0.84 mmol) in MeCN (5 mL) was stirred at 70° C. for 8 h. After completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-4-amino-3-(3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thioureido)benzenesulfonamide (270 mg, 79%) as a white solid. MS (ESI): C 20 H 23 Calculated mass for FN4O3S2, 450.12, observed m / z 451.0 [M+H] + .

[0437] Step 2 (S)-4-Amino-3-(3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thioureido)benzenesulfonamide (170 mg, 0.38 mmol), phenyl-λ in MeCN (3 mL). 3 A solution of -iodanediyl diacetate (183.5 mg, 0.57 mmol) and DIPEA (245 mg, 1.9 mmol) was stirred at room temperature for 3 h. After completion, the resulting mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-2-((1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)amino)-1H-benzo[d]imidazole-6-sulfonamide (3, 50 mg, 32%) as a yellow solid. MS (ESI): C 20 H 21 Calculated mass for FN4O3S, 416.13, observed m / z 417.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (d, J = 21.0 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.58 - 7.48 (m, 2H), 7.41 - 7.32 (m, 2H), 7.22 - 7.19 (m, 1H), 7.10 - 7.03 (m, 3H), 4.93 (q, J = 9.1 Hz, 1H), 2.34 - 2.30 (m, 1H), 2.28 (d, J = 4.9 Hz, 3H), 1.10 - 1.07 (m, 3H), 0.84 (d, J = 6.7Hz, 3H).

[0438] Example 3: Synthesis of Compound 4 [ka] Step 1 A mixture of (S)-5-fluoro-2-(1-isothiocyanato-2-methylpropyl)-3-methylbenzofuran (220 mg, 0.84 mmol) and 4-(methylsulfonyl)benzene-1,2-diamine (171.9 mg, 0.92 mmol) in MeCN (5 mL) was stirred at 70° C. for 8 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-1-(2-amino-5-(methylsulfonyl)phenyl)-3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thiourea (240 mg, 64%) as a white solid. MS (ESI): C 21 H 24 Calculated mass for FN3O3S2, 449.12, observed m / z 450.1 [M+H] + .

[0439] Step 2 (S)-1-(2-amino-5-(methylsulfonyl)phenyl)-3-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)thiourea (120 mg, 0.27 mmol), phenyl-λ in MeCN (3 mL). 3A solution of -iodanediyl diacetate (128.8 mg, 0.4 mmol) and DIPEA (172.9 mg, 1.34 mmol) was stirred at room temperature for 3 h. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH 1 to 5%) to give (S)-N-(1-(5-fluoro-3-methylbenzofuran-2-yl)-2-methylpropyl)-6-(methylsulfonyl)-1H-benzo[d]imidazol-2-amine (4, 60 mg, 54%) as a yellow solid. MS (ESI): C 21 H 22 Calculated mass for FN3O3S, 415.14, observed m / z 416.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 - 10.81 (m, 1H), 7.85 - 7.58 (m, 2H), 7.50 (m, 1H), 7.46 - 7.23 (m, 3H), 7.08 (m, 1H), 5.01 - 4.88 (m, 1H), 3.09 (d, J = 5.4 Hz, 3H), 2.36 - 2.31 (m, 1H), 2.28 (d, J = 4.6 Hz, 3H), 1.13 - 1.03 (m, 3H), 0.85 (d, J = 6.6 Hz, 3H).

[0440] Example 3: Synthesis of Compounds 5a and 5b [ka] Step 1 To a solution of 5-bromopyridine-2,3-diamine (1.6 g, 8.38 mmol) in DMSO (20 mL) was added (1S,2S)-1-N,2-N-dimethylcyclohexane-1,2-diamine (596 mg, 4.19 mmol), sodium methanesulfinate (1.71 g, 16.7 mmol), trifluoromethanesulfonate copper(I) benzene complex (2 g) and the reaction was stirred at 130° C. for 13 h. The reaction was diluted with water and extracted with EA. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography on silica gel (EA) to give 5-(methylsulfonyl)pyridine-2,3-diamine (200 mg, 13%). MS (ESI): mass calculated for C6H9N3O2S, 187.04, m / z found 188.0 [M+H] + .

[0441] Step 2 To a solution of 2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethan-1-amine (260 mg, 1.05 mmol) in DCM and saturated NaHCO3 was added thiophosgene (240 mg, 2.1 mmol) at 0° C. The reaction was stirred for 10 min, the DCM was collected and dried to give the crude product, which was purified by column chromatography on silica gel (PE) to give 5-fluoro-3-methyl-2-(2,2,2-trifluoro-1-isothiocyanatoethyl)benzofuran (200 mg, 69%) as an oil.

[0442] Step 3 To a solution of 5-fluoro-3-methyl-2-(2,2,2-trifluoro-1-isothiocyanatoethyl)benzofuran (200 mg, 0.69 mmol) in ACN (5 mL) was added 5-(methylsulfonyl)pyridine-2,3-diamine (200 mg, 1.06 mmol) and the mixture was stirred at 20° C. for 3 h. The solvent was removed to give the crude product, which was purified by column on silica gel (PE:EA=1:1) to give 1-(2-amino-5-(methylsulfonyl)pyridin-3-yl)-3-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)thiourea (100 mg, 30%). MS (ESI): C 18 H 16 Calculated mass for F4N4O3S2, 476.06, observed m / z 477.0 [M+H] + .

[0443] Step 4 To a solution of 1-(2-amino-5-(methylsulfonyl)pyridin-3-yl)-3-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)thiourea (100 mg, 0.20 mmol) in ACN (5 mL) was added DIEA (200 mg, 1.55 mmol) and phenyl-13-iodanediyl diacetate (674 mg, 2.1 mmol) and the reaction was stirred at 20° C. for 16 h. The mixture was concentrated to give the crude product, which was purified by preparative HPLC to give 6-(methylsulfonyl)-N-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine (25 mg, 26%). MS (ESI):C 18 H 14 Calculated mass for F4N4O3S, 442.07, measured m / z 443.1 [M+H] + . HPLC conditions: Column: WELCH Xtimate C18 21.2 x 250 mm 10 um Conditions: A (water, 0.1% FA) B (acetonitrile) 45 to 75% B in 9 minutes, hold B at 100% for 1 minute, return B to 45% in 1.5 minutes, stop at 15 minutes. Flow rate: 25mL / min Detectors: 214

[0444] Step 5 25 mg of 6-(methylsulfonyl)-N-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine was subjected to SFC to give (R)-6-(methylsulfonyl)-N-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine (5a, 7.1 mg) and (S)-6-(methylsulfonyl)-N-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine (5b, 6.5 mg). Separation conditions: Equipment: SFC 150 Column: Daicel CHIRALCEL IF, 250 mm x 30 mm inner diameter, 10 μm Mobile phase: CO2 / MeOH [0.2% NH3 (7M solution in MeOH)] = 75 / 25 Flow rate: 80g / min Wavelength: UV214nm Temperature: 35℃ compound 5a MS(ESI):C 18 H 14 Calculated mass for F4N4O3S, 442.07, measured m / z 443.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.99 (s, 1H), 7.50 (dd, J = 8.0, 4.0 Hz, 1H), 7.34 (dd, J = 8.0, 4.0 Hz, 1H), 7.14 (td, J = 8.0, 4.0 Hz, 1H), 6.35 - 6.29 (m, 1 H), 3.18 (s, 3 H), 2.40 (s, 3 H). Compound 5b MS (ESI): C 18 H 14 Calculated mass for C14H14N4O3S, 442.07, found m / z 443.1 [M+H]+ + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.99 (s, 1H), 7.50 (dd, J = 8.0, 4.0 Hz, 1H), 7.22 (dd, J = 8.0, 4.0 Hz, 1H), 6.99 (td, J = 8.0, 4.0 Hz, 1H), 6.23 - 6.17 (m, 1 H), 3.03 (s, 3 H), 2.28 (s, 3 H).

[0445] Example 4: Synthesis of Compounds 6a and 6b

Chemical Structure

[0446] Step 2 To a solution of 5-fluoro-3-methyl-2-(2,2,2-trifluoro-1-isothiocyanatoethyl)benzofuran (240 mg, 0.83 mmol) in ACN (10 mL) was added 4-methanesulfonylbenzene-1,2-diamine (154 mg, 0.83 mmol). The mixture was stirred at 25° C. for 2 h, then TEA (419 mg, 4.15 mmol) and ((diacetoxyiodo)benzene (1.1 g, 3.32 mmol) were added. The mixture was stirred at 25° C. for 2 h, then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA 5 / 1 to 2 / 1) to give 5-(methylsulfonyl)-N-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-1H-benzo[d]imidazol-2-amine (260 mg, 71%) as a white solid. MS (ESI): C 19 H 15 Calculated mass for F4N3O3S, 441.1, measured m / z 442.1 [M+H] + .

[0447] Step 3 260 mg of the racemate was separated by SFC to give (6a, 81.9 mg) as a white solid and (6b, 87.0 mg) as a white solid. Chiral separation conditions: Equipment: SFC 80 Column: Daicel CHIRALCEL OD, 250mm x 30mm ID, 10μm Mobile phase: CO2 / MeOH [0.2% NH3 (7M solution in MeOH)] = 80 / 20 Flow rate: 70g / min Wavelength: UV214nm Temperature: 35℃ compound 6a MS(ESI):C 19 H 15 Calculated mass for F4N3O3S, 441.1, observed m / z 442.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.80 - 8.67 (m, 1H), 7.81 - 7.68 (m, 1H), 7.63 (dd, J = 8.8, 4.0 Hz, 1H), 7.51 (dd, J = 8.8, 2.8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.23 (td, J = 9.2, 2.8 Hz, 1H), 6.32 (s, 1H), 3.12 (s, 3H), 2.34 (s, 3H). compound 6b MS(ESI):C 19 H 15 Calculated mass for F4N3O3S, 441.1, measured m / z 442.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 0.47 H), 11.05 (s, 0.53 H), 8.74 (d, J = 9.2 Hz, 0.54 H), 8.66 (d, J = 9.6 Hz, 0.46 H), 7.77 (d, J = 1.6 Hz, 0.54 H), 7.73 (d, J = 1.2 Hz, 0.46 H), 7.68 - 7.59 (m, 1 H), 7.55 - 7.47 (m, 2 H), 7.43 (d, J = 0.4 Hz, 0.60 H), 7.41 (d, J = 0.8 Hz, 0.36 H), 7.30 - 7.18 (m, 1 H), 6.40 - 6.24 (m, 1 H), 3.13 (s, 1.45 H), 3.12 (s, 1.53 H), 2.35 (s, 1.41H), 2.34 (s, 1.62 H).

[0448] Example 5: Synthesis of Compounds 7a and 7b [ka] Step 1 To a mixture of 2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethan-1-amine (320 mg, 1.3 mmol) and NaHCO3 (saturated aqueous solution, 1.2 mL) in DCM (5 mL) was added thiophosgene (299 mg, 2.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h, and the resulting mixture was diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 5-fluoro-3-methyl-2-(2,2,2-trifluoro-1-isothiocyanatoethyl)benzofuran (300 mg, 80%) as a colorless oil, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.45 (m, 2H), 7.29 - 7.18 (m, 1H), 6.82 - 6.76 (m, 1H), 2.34 - 2.25 (m, 3H).

[0449] Step 2 A mixture of 5-fluoro-3-methyl-2-(2,2,2-trifluoro-1-isothiocyanatoethyl)benzofuran (200 mg, 0.69 mmol) and pyrimidine-2,4,5-triamine (95 mg, 0.76 mmol) in MeCN (5 mL) was stirred at 70° C. for 8 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM / MeOH 1 to 5%) to give 1-(2,5-diaminopyrimidin-4-yl)-3-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)thiourea (180 mg, 63%) as a white solid. MS (ESI): C 16 H 14 Calculated mass for F4N6OS, 414.09, observed m / z 415.1 [M+H] + .

[0450] Step 3 1-(2,5-diaminopyrimidin-4-yl)-3-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)thiourea (180 mg, 0.43 mmol), phenyl-λ in MeCN (5 mL) 3 A solution of -iodanediyl diacetate (209 mg, 0.65 mmol) and DIPEA (277 mg, 2.15 mmol) was stirred at room temperature for 3 h. After completion, the resulting mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM / MeOH 1 to 5%) to give N 8-(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-7H-purine-2,8-diamine (106 mg, 65%) was obtained as a yellow solid. MS (ESI): C 16 H 12 Calculated mass for F4N6O, 380.1, measured m / z 381.1 [M+H] + .

[0451] Step 4 Compound 7 (106 mg) was separated by SFC 80 (Daicel CHIRALCEL OX, 250×30 mm ID, 10 μm, 75 / 25 CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)], 70 g / min, 120 bar, 35° C.) into two enantiomers: (R)-N 8 -(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-7H-purine-2,8-diamine (7a, 30 mg, 28%) as a pale yellow solid and (S)-N 8 -(2,2,2-trifluoro-1-(5-fluoro-3-methylbenzofuran-2-yl)ethyl)-7H-purine-2,8-diamine (7b, 35.2 mg, 33%) was obtained as a pale yellow solid. Compound 7a: MS(ESI):C 16 H 12 Calculated mass for F4N6O, 380.1, measured m / z 381.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.15 - 10.46 (m, 1H), 8.81 (d, J = 9.4 Hz, 1H), 7.94 (s, 1H), 7. 64 - 7.61 (m, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.22 (t, J = 9.2 Hz, 1H), 6.34 - 6.13 (m, 1H), 5.94 - 5.71 (m, 2H), 2.32 (s, 3H). Compound 7b: MS(ESI):C 16 H12 Calculated mass for F4N6O, 380.1, measured m / z 381.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.16 - 10.47 (m, 1H), 8.82 - 8.11 (m, 1H), 8.12 - 7.82 (m, 1H), 7. 64 - 7.61 (m, 1H), 7. 51 - 7.49 (m, 1H), 7. 25 - 7.20 (m, 1H), 6.27 (s, 1H), 5.94 - 5.74 (m, 2H), 2.32 (s, 3H).

[0452] Homogeneous time-resolved fluorescence (HTRF) assay-pAKT-T47D Compounds were assayed using homogeneous time resolved fluorescence (HTRF), see Table 3.

[0453] Materials, reagents, and equipment Gibco RPMI 1640 medium, phenol red free; Gibco RPMI 1640 medium; Gibco trypsin-EDTA (0.5%), phenol red free; Gibco DPBS; trypan blue solution 0.4% (Corning); Avantor Seradigm premium grade fetal bovine serum (FBS); Greiner 784080-384 well TC treated white plates; pAKT (Ser473) HTRF; Gibco insulin, human recombinant, zinc solution; Gibco Recovery cell culture freezing medium; Countess II FL automated cell counter (ThermoFisher); Countess II slides (ThermoFisher); microscope; and PHERAstar FSX microplate reader (BMG LABTECH, Inc.).

[0454] procedure Scinamic cell line ID is T47D.1, HTRF detection is pAKT(S473), PI3Kα H1047R mutation is present, seeding density was 5000, time point was 1 hour, media used was RPMI+10% FBS (phenol red free)+0.2 units / ml bovine insulin.

[0455] Cell culture maintenance: ● Cell density was not allowed to reach 100% confluence. Cells were split 1:5 when they reached approximately 80% confluence. Cells were split twice a week (Monday and Friday). Cells older than passage 18 were not used (maintained for approximately 2 months). No antibiotics were used in tissue culture maintenance or assays.

[0456] Regarding freezing cells: 1. Trypsinized cells were harvested and counted. Cells were pelleted at 1000 rpm for 5 minutes and the supernatant was aspirated. 2. Gently resuspend the pelleted cells at 3e6 cells / 1mL freezing medium (Gibco Freezing Medium). For example, if there are 9e6 total cells, resuspend the cell pellet in 3mL of freezing medium. 3. Weighed out a 1 mL aliquot of resuspended cells / cryovial. Cells were frozen at -80°C in an appropriate cell freezing container (i.e. Mr. Frosty or Corning CoolCell freezing system). 4. The cells were transferred to a liquid nitrogen cryotank for long-term storage.

[0457] Thawing cells: 1. Cells were removed from the liquid nitrogen tank. The cryovial was thawed in a 37°C water bath until a small "ice pellet" remained. This was then sprayed with 70% ethanol before being moved to a TC / BSC hood. 2. 9 mL of fresh medium was added to a 15 mL conical tube. 10 mL of fresh medium was added to a T75 TC treated flask. 3. 1 mL of cells in freezing medium was gently transferred from the cryovial to the 15 mL conical tube containing medium. 4. Cells were pelleted by centrifugation at 1000 rpm for 5 minutes. 5. Media / freezing media was aspirated. 6. The cell pellet was gently resuspended in 5 mL of fresh medium and transferred to a T75 flask containing 10 mL of fresh medium. The flask was placed in a 37° C. incubator (5% CO2).

[0458] protocol Day 1 The procedure was as follows: 1. ARP was prepared: a. 12.5nL was stamped from the 10mM source plate to the destination plate using an Echo. Plates were immediately sealed and frozen at -20°C if not used the same day. b. If using frozen ARP, thaw plate and spin at 1000 rpm x 1 minute. 2. Preparation of cells (adherent): a. Media was aspirated from cells. Cells were washed with sterile 1x PBS. PBS was aspirated and an appropriate amount of trypsin was added. b. Once the cells were completely trypsinized, the appropriate medium was added to resuspend the cells. The cells were transferred to a 15 mL or 50 mL conical tube. c. Cells were counted using a Countess II cell counter. 3. Cell seeding: a. Cells were prepared at the appropriate seeding density. Using a Multidrop Combi, 12uL of diluted cells were dispensed per well into columns 1-23 of a Greiner 7840 80-384 well TC treated white plate. 12uL of the appropriate phenol free medium was added to column 24 only. b. Plates were placed in a 37° C. tissue culture incubator for the appropriate treatment time (see "Assay" table). 4. HTRF Lysis Buffer Prepared Calculate the amount of HTRF Lysis Buffer Master Mix needed to perform the desired experiment plus any extra dead volume needed for dispensing (4 μL required per well). Dilute Blocking Reagent in 4x Lysis Buffer at a 1:25 ratio (i.e. 0.1 mL of Blocking Reagent solution + 2.4 mL of 4x Lysis Buffer). b. Add 4 uL of Lysis Buffer Master Mix to all wells containing samples or DMSO. Centrifuge plate at 1000 rpm for 1 minute. c. Incubate at room temperature for 30 minutes. 5. HTRF antibodies were prepared a. Calculate the amount of HTRF antibody master mix needed to perform the desired experiment plus any extra dead volume needed for dispensing (4mL required per well). Eu Cryptate and d2 antibodies were added to detection buffer in a 1:40 ratio each (i.e. 100μL Eu Cryptate + 100μL d2 Cryptate + 3800μL detection buffer). b. 4 μL of antibody master mix was added to each well, including column 24 which was media only. c. The plate was centrifuged at 1000 rpm for 1 minute. A "humidity chamber" was created by closing the lid and placing the plate in a Ziploc bag with a damp paper towel or something similar and incubating overnight at room temperature, protected from light. Day 2 6. Measured on a PHERAstar / Envision using the HTRF protocol. When reading the plate, all wells were read.

[0459] The biological activity of certain compounds using the above-mentioned assays is shown in Table 2. IC of T47D pAKT 50 (nM) D The ranges are as follows: A represents <200 nM, B represents 200 nM ≤ IC 50<500 nM and C represents ≧500 nM. ND indicates that a value was not determined in that assay for the specified compound. [Table 3]

Claims

1. The structure of formula (I-a): 【Chemical 1】 having, wherein R １Ａ is a halogen, and R １Ｂ is halogen or absent, X ２ and X ４ are each independently N or CH, R ２ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by one or two fluorines, R ３ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by one or two fluorines, R ４ is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO Ａ R Ｂ optionally substituted by, -NR ２ H, -NR Ａ R Ｂ , -C(=O)NR Ｃ R Ｄ , -SO ２ (NR Ｅ R Ｆ ), -SO ２ (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO ２ (C1-C6 alkyl), phenyl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl or 3-6 cycloalkyl each optionally substituted by one or two independently selected R Ｇ and is selected from the group consisting of Each R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ , and R Ｆ is independently hydrogen, C1-C6 alkyl optionally substituted by R Ｇ , C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), or -SO ２ (C1-C6 alkyl), or R Ｃ and R Ｄ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, Each R Ｇ is independently selected from the group consisting of fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR Ａ１ R Ｂ１ , -C(=O)NR Ｃ１ R Ｄ１ , and -CO ２ H, Each R Ａ１ , R Ｂ１ , R Ｃ１ , and R Ｄ１ are independently hydrogen, C1-C6 alkyl optionally substituted by R Ｇ , C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), or -SO ２ (C1-C6 alkyl), a compound, or a pharmaceutically acceptable salt thereof.

2. R １Ａ and R １Ｂ are each fluorine or R １Ａ is fluoro and R １Ｂ is absent or R １Ａ is fluoro and R １Ｂ is chloro, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 alkyl.

4. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

5. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 alkyl.

6. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 haloalkyl.

7. R ３ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R is trifluoromethyl.

8. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a halogen.

9. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 alkyl.

10. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 alkoxy.

11. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is C1-C6 haloalkyl.

12. R ４ is hydroxyl, cyano, or -CO ２ H, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. R ４ is -NR Ａ R Ｂ , -C(=O)NR Ｃ R Ｄ , -C(=O)(C1-C6 alkyl), or -CO ２ (C1-C6 alkyl), the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. R ４ is -SO ２ (NR Ｅ R Ｆ )、-SO ２ (C1-C6 alkyl), or -S(=O)(=NH)(C1-C6 alkyl), the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. R ４ is cyano, -NH ２ , -C(=O)NH ２ , -SO ２ NH ２ , or -SO ２ CH ３ and the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the compounds in Table A, Table B, or Table C, or pharmaceutically acceptable salts of any of the foregoing. Table A 【Table 1】 Table B 【Table 2】 Table C 【Table 3】

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

18. A therapeutic agent for cancer comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

19. A therapeutic agent for PI3Kα-related cancer comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

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