Methods for treating cancer

Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, and compounds of Formula (II) and pharmaceutically acceptable salts thereof, which 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 disclosure also provides compositions containing them, as well as methods of using and making them. TIFF2025535066000159.tif54128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and the benefit to U.S. Provisional Patent Application No. 63 / 414,173, filed October 7, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically as an XML file entitled "50006-0102WO1_ST26_SL.XML". The XML file, created on October 3, 2023, is 2,935 bytes in size. The material in the XML file is incorporated herein by reference in its entirety.

[0003] FIELD OF THE INVENTION The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, and compounds of Formula (II) and pharmaceutically acceptable salts thereof, which 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 disclosure also provides compositions containing them, as well as methods of using and making them. [Background technology]

[0004] 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 demonstrated the role of PI3K / AKT signaling 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 tumor growth regression.

[0005] The PI3K pathway can be activated, for example, through point mutations in the PIK3CA gene or through 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, T. M. et al., Targeting PI3 kinase in cancer. Pharmacol. Ther. 2015, 146, 53–60.) PI3K consists of three subunits: the p85 regulatory subunit, the p55 regulatory subunit, and the p110 catalytic subunit. According to their distinct structures and specific substrates, PI3Ks are classified into three classes: class I, class II, and class III. Class I PI3Ks include class IA and class IB PI3Ks. Class IA PI3Ks, heterodimers of the p85 regulatory subunit and the p110 catalytic subunit, are the type most clearly implicated in human cancers. Class IA PI3Ks contain the p110α, p110β, and p110δ catalytic subunits, which are produced by distinct genes (PIK3CA, PIK3CB, and PIK3CD, respectively), whereas p110γ, produced by PIK3CG, represents the only catalytic subunit in class IB PI3Ks. The gene encoding the p110α subunit, PIK3CA, 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.)

[0006] However, the development of PI3K inhibitors has been problematic for several reasons, including (i) adaptive molecular mechanisms during therapeutic inhibition of PI3K, (ii) the inability to specifically inhibit signaling through PIK3CA mutations while sparing endogenous p110α, (iii) the limited use of these therapies in rational combinations, including those informed by strong mechanistic support, and (iv) dose-limiting toxicities that prevent sustained PI3K pathway suppression. (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.) For example, alpelisib is an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Kα. However, the therapeutic efficacy of alpelisib is limited by its inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities, including hyperglycemia.

[0007] Additionally, there are other factors and compensatory pathways from both clinical and in vitro laboratory studies that affect PI3K signaling, such as HRAS and KRAS mutations that reduce sensitivity to PI3K inhibitors (knockdown of which has been shown to improve sensitivity to PI3K inhibitors). (See Misrha, R.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci. 2021, 22, 3464.)

[0008] 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.) Therefore, targeting PI3Kα represents an approach for the treatment of proliferative disorders such as cancer. Summary of the Invention

[0009] Some embodiments include a compound of formula (I)

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 9-membered heteroaryl group, and Ring B is not 2-benzofuranyl or 2-indolyl; Each R 1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, a C3-C8 cycloalkyl, a 5- to 10-membered heteroaryl, or a 4- to 10-membered heterocyclyl; Each R 4 is, independently, (i) halogens, (ii) optionally one or two hydroxyls or -NR A R B C1-C6 alkyl substituted with (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) optionally one or two independently selected R G 3- to 9-membered heterocyclyl substituted with (xviii) optionally one or two independently selected R G C3-C6 cycloalkyl substituted with n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is, independently, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, or (ix) optionally hydroxyl, —C(═O)NR B2 R C2 , 5-6 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached, optionally represent hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H, or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments include a compound of formula (II)

[0012] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 9-membered heteroaryl group; Each R 1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, a C3-C8 cycloalkyl, a 5- to 10-membered heteroaryl, or a 4- to 10-membered heterocyclyl; Each R 4 is, independently, (i) halogens, (ii) optionally one or two hydroxyls or -NR A R B C1-C6 alkyl substituted with (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) optionally one or two independently selected R G 3- to 9-membered heterocyclyl substituted with (xviii) optionally one or two independently selected R G C3-C6 cycloalkyl substituted with n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is, independently, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, or (ix) optionally hydroxyl, —C(═O)NR B2 R C2 , 5-6 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and RD together with the nitrogen atom to which they are attached, optionally represent hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H; Provided are compounds of formula (II) or pharmaceutically acceptable salts thereof that are not compounds disclosed in PCT / US2022 / 033255, the entirety of which is incorporated herein by reference, for purposes of excluding compounds contained therein.

[0013] Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0014] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0015] 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 the expression or activity or level of either thereof; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0016] Also 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) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0017] The present disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising determining that 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0018] Also provided herein is a method for treating a PI3Kα-associated cancer 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) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0019] The present disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, the method comprising determining that the cancer in the subject is a PI3Kα-associated cancer, and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0020] Also provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject having clinical documentation 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.

[0021] The present disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Also provided herein are pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0023] 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0024] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: (a) determining that the cancer is associated with dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0025] Also provided herein is a method for treating a PI3Kα 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0026] The present disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising determining that 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0027] Also provided herein is a method for treating a PI3Kα-associated cancer 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 (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0028] The present disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, the method comprising determining that the cancer in the subject is a PI3Kα-associated cancer, and administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0029] Also provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject having clinical records indicating that the subject has dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them.

[0030] The present disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0031] Other embodiments include those described in the detailed description and / or claims.

[0032] Additional definitions To facilitate understanding of the disclosure set forth herein, some additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout this specification and the accompanying appendices is incorporated herein by reference in its entirety.

[0033] The term "about" when referring to a number or numerical range means that the referenced number or numerical range is an approximation, e.g., within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% of the stated number or numerical range.

[0034] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the overall health of the subject being treated.

[0035] The terms "inhibit" or "inhibition of" mean to reduce by a measurable amount or to prevent completely (eg, 100% inhibition).

[0036] "API" refers to active pharmaceutical ingredient.

[0037] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, 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, and 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 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.

[0038] The term "pharmaceutically 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 abrogate the compound's biological activity and properties. In certain examples, pharmaceutically acceptable salts are 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, or salicylic acid. In some examples, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine or lysine, or by other methods previously determined. There is no particular limitation on the pharmacologically acceptable salt, as long as it can be used in medicine. Examples of salts that the compounds described herein may form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts with basic amino acids such as lysine and ornithine, and ammonium salts. The salt may be an acid addition salt, specifically exemplified by 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.

[0039] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "pharmaceutically acceptable excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0040] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as primates (e.g., humans), 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 the disease or disorder being treated and / or prevented.

[0041] As used herein, the term "treat" or "treatment" refers to curative or palliative treatment. Beneficial or desirable 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, a reduction in the extent of the disease, a stable (i.e., not worsening) state of the disease, a delay or slowing of disease progression, an improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0042] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0043] 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.

[0044] The term "hydroxyl" refers to the --OH radical.

[0045] The term "cyano" refers to the -CN radical.

[0046] 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 1-10 indicates that the group may have 1 to 10 (inclusive) 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, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between the constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0047] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced with an independently selected halo.

[0048] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0049] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons, in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms in each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0050] The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and 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. Cycloalkyl groups may include 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. Cycloalkyls also include spirocycles (e.g., spiro bicycles in which two rings are joined 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.

[0051] The term "heteroaryl," as used herein, refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is aromatic (although not necessarily 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 vinyl analogs thereof, in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more pyridones (e.g.,

[0052] [ka] ), pyrimidones (e.g.

[0053] [ka] ), pyridazinones (e.g.

[0054] [ka] ), pyrazinones (e.g.

[0055] [ka] ), and imidazolone (e.g.

[0056] [ka] ), and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., an oxo group (i.e., "=O") herein is part of a heteroaryl ring).

[0057] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system) having 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, and 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems, wherein the heteroatoms are O, N, or S (e.g., carbon atoms and Heteroatoms are selected from 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, or S, respectively, and, if valences permit, one or more ring atoms may be substituted with 1 to 3 oxo (e.g., to form a lactam), one or more N or S atoms may be substituted with 1 to 2 oxides (e.g., to form an N-oxide, an S-oxide, or an S,S-dioxide), and 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. 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 [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 spirocycles (e.g., spiro bicycles in which 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. 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.

[0058] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0059] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms, in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0060] For the avoidance of doubt, and unless otherwise specified, for 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 defined as rings where the points of fusion are (i) adjacent ring atoms (e.g., [xxO] ring systems, where 0 is a zero atom bridge (e.g.,

[0061] [ka] )), (ii) a single ring atom (spiro-fused ring system) (e.g.,

[0062] [ka] ), or (iii) a contiguous sequence of ring atoms (bridged ring systems with all bridge lengths > 0) (e.g.

[0063] [ka] It is understood that the term "aryl" includes those having fused rings, including those located at positions (1) and (2).

[0064] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. As general examples, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include . 13 C and 14 Includes, but is not limited to, C.

[0065] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety:

[0066] [ka] A compound containing the moiety:

[0067] [ka] Similarly, a pyridinyl or pyrimidinyl moiety that is described as being optionally substituted with a hydroxyl includes the pyridone or pyrimidone tautomeric forms.

[0068] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic 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 named or depicted by a structure without specifying stereochemistry (e.g., a "flat" structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when a disclosed compound is named or depicted by a structure with specifying stereochemistry (e.g., a structure with "wedge" and / or "dashed" bonds) and has one or more chiral centers, it is understood to represent the depicted stereoisomer of the compound.

[0069] 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 INVENTION

[0070] The present disclosure provides compounds of Formula (I) and pharmaceutically 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 them, as well as methods of using and making them.

[0071] Compounds of formula (I) Some embodiments include a compound of formula (I)

[0072] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 9-membered heteroaryl group, and Ring B is not 2-benzofuranyl or 2-indolyl; Each R 1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, a C3-C8 cycloalkyl, a 5- to 10-membered heteroaryl, or a 4- to 10-membered heterocyclyl; Each R 4 is, independently, (i) halogens, (ii) optionally one or two hydroxyls or -NR A R B C1-C6 alkyl substituted with (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) optionally one or two independently selected R G 3- to 9-membered heterocyclyl substituted with (xviii) optionally one or two independently selected R G C3-C6 cycloalkyl substituted with n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R Fis, independently, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, or (ix) optionally hydroxyl, —C(═O)NR B2 R C2 , 5-6 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached, optionally represent hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1, —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H, or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0074] In some embodiments of Formula (I),

[0075] [ka] teeth,

[0076] [ka] In some embodiments, the compound is selected from the group consisting of:

[0077] [ka] teeth,

[0078] [ka] In some embodiments, the compound is selected from the group consisting of:

[0079] [ka] teeth,

[0080] [ka] In some embodiments, the compound is selected from the group consisting of:

[0081] [ka] teeth,

[0082] [ka] In some embodiments, the compound is selected from the group consisting of:

[0083] [ka] teeth,

[0084] [ka] is selected from the group consisting of:

[0085] In some embodiments,

[0086] [ka] teeth,

[0087] [ka] is selected from the group consisting of:

[0088] In some embodiments,

[0089] [ka] teeth,

[0090] [ka] In some embodiments, the compound is selected from the group consisting of:

[0091] [ka] teeth,

[0092] [ka] In some embodiments, the compound is selected from the group consisting of:

[0093] [ka] teeth,

[0094] [ka] is selected from.

[0095] In some embodiments,

[0096] [ka] teeth,

[0097] [ka] In some embodiments, the compound is selected from the group consisting of:

[0098] [ka] teeth,

[0099] [ka] In some embodiments, the compound is selected from the group consisting of:

[0100] [ka] teeth,

[0101] [ka] In some embodiments, the compound is selected from the group consisting of:

[0102] [ka] teeth,

[0103] [ka] In some embodiments, the compound is selected from the group consisting of:

[0104] [ka] teeth,

[0105] [ka] In some embodiments, the compound is selected from the group consisting of:

[0106] [ka] teeth,

[0107] [ka] In some embodiments, the compound is selected from the group consisting of:

[0108] [ka] teeth,

[0109] [ka] In some embodiments, the compound is selected from the group consisting of:

[0110] [ka] teeth,

[0111] [ka] In some embodiments, the compound is selected from the group consisting of:

[0112] [ka] teeth,

[0113] [ka] is selected from the group consisting of:

[0114] In some embodiments,

[0115] [ka] teeth,

[0116] [ka] is selected from the group consisting of:

[0117] In some embodiments,

[0118] [ka] teeth,

[0119] [ka] In some embodiments, the compound is selected from the group consisting of:

[0120] [ka] teeth,

[0121] [ka] In some embodiments,

[0122] [ka] teeth,

[0123] [ka] In some embodiments, the compound is selected from the group consisting of:

[0124] [ka] teeth,

[0125] [ka] and R 1A and R 1B is R 1 are independently selected from

[0126] In some embodiments,

[0127] [ka] teeth,

[0128] [ka] In some embodiments,

[0129] [ka] teeth,

[0130] [ka] In some embodiments, the compound is selected from the group consisting of:

[0131] [ka] teeth,

[0132] [ka] and R 1A and R 1B is R 1 are independently selected from

[0133] In some embodiments,

[0134] [ka] teeth,

[0135] [ka] In some embodiments,

[0136] [ka] teeth,

[0137] [ka] In some embodiments, the compound is selected from the group consisting of:

[0138] [ka] teeth,

[0139] [ka] and R 1A and R 1B is R 1 are independently selected from

[0140] In some embodiments, each R 1is an independently selected halogen. In some embodiments, each R 1 is independently selected from fluoro and chloro. In some embodiments, each R 1 is independently selected from fluoro and bromo. 1 is fluoro. In some embodiments, at least one R 1 are independently selected halogens. In some embodiments, at least one R 1 is independently selected from fluoro and chloro. In some embodiments, at least one R 1 is fluoro.

[0141] In some embodiments, at least one R 1 is cyano. In some embodiments, at least one R 1 is hydroxyl. In some embodiments, at least one R 1 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R 1 is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R 1 is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R 1 is hydroxymethyl. In some embodiments, at least one R 1 is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 1 is methyl. In some embodiments, at least one R 1 is C-C cycloalkyl. In some embodiments, at least one R 1 is cyclopropyl.

[0142] In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1is C1-C6 alkyl. In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 is C3-C6 cycloalkyl. In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 In some embodiments, m is 2 and one R 1 is a halogen, while R 1 In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 is fluoro.

[0143] In some embodiments, R 2 is hydroxyl. In some embodiments, R 2 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2 is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, R 2 is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R 2 is hydroxymethyl. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl. In some embodiments, R 2 is an unsubstituted C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0144] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.

[0145] In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro.

[0146] In some embodiments, R 2 is a C-C cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 2 is two fluoro-substituted C-C cycloalkyl. 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 fluoro. In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.

[0147] 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, t-butyl, or isopropyl. 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.

[0148] In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is difluoromethyl. In some embodiments, R 3 is trifluoromethyl.

[0149] In some embodiments, R 3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one fluoro at the C-C cycloalkyl position attached to the methine of formula (I). In some embodiments, R 3 is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R 3 is a C-C cycloalkyl substituted with one methyl. In some embodiments, R 3 is a C-C cycloalkyl substituted with one methyl at the C-C cycloalkyl position attached to the methine of formula (I). In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 3C-C cycloalkyl is cyclopropyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.

[0150] In some embodiments, ring A is a 6-10 membered aryl. In some embodiments, ring A is phenyl, naphthyl, or tetrahydronaphthyl. In some embodiments, ring A is phenyl.

[0151] In some embodiments, ring A is C3-C8 cycloalkyl. In some embodiments, ring A is C5-C6 cycloalkyl. In some embodiments, ring A is cyclohexyl.

[0152] In some embodiments, ring A is a 5-10 membered heteroaryl. In some embodiments, ring A is a 9-10 membered heteroaryl. In some embodiments, ring A is a 9 membered heteroaryl. In some embodiments, ring A is a 9 membered heteroaryl, and the point of attachment to the urea nitrogen atom in Formula (I) is on the 6 membered ring of ring A. In some embodiments, ring A is a 9 membered heteroaryl, and the point of attachment to the urea nitrogen atom in Formula (I) is on the 5 membered ring of ring A.

[0153] In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-6-yl, or imidazo[1,2-a]pyridinyl. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, or imidazo[1,2-a]pyridinyl. In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl,

[0154] [ka] In some embodiments, ring A is

[0155] [ka] wherein the formula is selected from the group consisting of: * " indicates the point of attachment to the urea nitrogen atom in formula (I).

[0156] In some embodiments, ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, ring A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. In some embodiments, ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A is

[0157] [ka] wherein the formula is selected from the group consisting of: * " indicates the point of attachment to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is 5-pyrimidinyl. In some embodiments, Ring A is

[0158] [ka] In the formula, * " indicates the point of attachment to the urea nitrogen atom in Formula (I). In some embodiments, ring A is a 4-10 membered heterocyclyl. In some embodiments, ring A is a 6-9 membered heterocyclyl. In some embodiments, ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopyranyl-1,1-dioxide.

[0159] In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl,

[0160] [ka] In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl,

[0161] [ka] is.

[0162] In some embodiments, Ring A is 3-piperidinyl,

[0163] [ka] is selected from.

[0164] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0165] In some embodiments, one R 4 is optionally 1 or 2 hydroxyl or -NR A R B In some embodiments, one R 4 is optionally 1 or 2 hydroxyl or -NR A R B In some embodiments, one R 4 is a C1-C6 alkyl substituted with 1 or 2 hydroxyl. In some embodiments, one R 4 is a C1-C6 alkyl substituted with one hydroxyl. In some embodiments, one R 4 is a C1-C6 alkyl substituted with two hydroxyls. In some embodiments, one R 4is a C1-C3 alkyl substituted with two hydroxyls. In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 -hydroxyl and -NR A R B In some embodiments, one R 4 is unsubstituted C1-C6 alkyl. In some embodiments, one R 4 is C1-C4 alkyl. In some embodiments, one R 4 is t-butyl. In some embodiments, one R 4 is methyl, ethyl, or isopropyl.

[0166] In some embodiments, one R 4 is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cycloalkyl. In some embodiments, one R 4 is a C1-C6 alkoxy substituted with hydroxyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with C3-C6 cycloalkyl. 4is C1-C6 alkoxy substituted with cyclopropyl. In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, one R 4 is methoxy.

[0167] In some embodiments, one R 4 is C1-C6 haloalkyl. In some embodiments, one R 4 is C1-C3 haloalkyl. In some embodiments, one R 4 is difluoromethyl. In some embodiments, one R 4 is trifluoromethyl.

[0168] In some embodiments, one R 4 is hydroxyl. In some embodiments, one R 4 is cyano. In some embodiments, one R 4 is —COH. In some embodiments, one R 4 is halogen. In some embodiments, one R 4 is fluoro. In some embodiments, one R 4 is chloro.

[0169] In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is =NR A2 is.

[0170] In some embodiments, R A and R B are each hydrogen. In some embodiments, R A and R B is hydrogen and R A and R B the other is optionally hydroxyl or —C(═O)NRB2 R C2 In some embodiments, R A and R B is hydrogen and R A and R B and the other is a C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NH2. In some embodiments, R A and R B is hydrogen and R A and R B and the other is —C(═O)O(C1-C6 alkyl). In some embodiments, R A and R B is hydrogen and R A and R B and the other is —C(═O)OCH. In some embodiments, R A and R B is hydrogen and R A and R B and the other is a 4- to 6-membered heterocyclyl (e.g., oxetanyl). A and R B is hydrogen and R A and R B and the other is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C6 alkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and RA and R B and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B is hydrogen and R A and R B and the other is propyl substituted with hydroxyl (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, or 1-hydroxy-2-propyl). In some embodiments, R A and R B is hydrogen and R A and R B and the other is butyl substituted with hydroxyl (e.g., 2-hydroxy-2-methyl-1-propyl). In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C3 alkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is methyl. In some embodiments, R A and R B are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of the groups is C1-C3 alkyl, and R A and R B and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B One of the groups is methyl, and R A and RB and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0171] In some embodiments, R B2 and R C2 are each hydrogen. In some embodiments, R B2 and R C2 is hydrogen and R B2 and R C2 and the other is C1-C6 alkyl. In some embodiments, R B2 and R C2 is hydrogen and R B2 and R C2 and the other is methyl. In some embodiments, R B2 and R C2 Both are methyl.

[0172] In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C6 haloalkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C3 haloalkyl. In some embodiments, R A and R B are each C1-C6 haloalkyl. In some embodiments, RA and R B are each C1-C3 haloalkyl.

[0173] In some embodiments, R A and R B one of the groups is C1-C6 alkyl, and R A and R B The other is C1-C6 haloalkyl.

[0174] In some embodiments, one R 4 is -C(=O)NR C R D is.

[0175] In some embodiments, R C and R D are each hydrogen. In some embodiments, R C and R D is hydrogen and R C and R D and the other is C1-C6 alkyl. In some embodiments, R C and R D is hydrogen and R C and R D and the other is C1-C3 alkyl. In some embodiments, R C and R D is hydrogen and R C and R D and the other is methyl. In some embodiments, R C and R D are each C1-C6 alkyl. In some embodiments, R C and R D are each C1-C3 alkyl. In some embodiments, R C and R D and each is methyl. In some embodiments, R C and R D one of the groups is C1-C6 alkyl, and R C and R D The other is a C1-C3 alkyl.

[0176] In some embodiments, R C and R D is hydrogen and R C and R D and the other is C1-C6 haloalkyl. In some embodiments, R C and R D is hydrogen and R C and R D and the other is C1-C3 haloalkyl. In some embodiments, R C and R D are each C1-C6 haloalkyl. In some embodiments, R C and R D one of the groups is C1-C6 alkyl, and R C and R D The other is C1-C6 haloalkyl.

[0177] In some embodiments, R C and R D together with the nitrogen atom to which they are attached, optionally represent hydroxyl, halogen, -C(=O)NR B1 R C1 , —SO2(C1-C6 alkyl), —CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy to form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from —SO2(C1-C6 alkyl), —CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. C and R D together with the nitrogen atom to which they are attached, form hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy to form a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0178] In some embodiments, R B1 and R C1 are each hydrogen. In some embodiments, RB1 and R C1 is hydrogen and R B1 and R C1 and the other is C1-C6 alkyl. In some embodiments, R B1 and R C1 is hydrogen and R B1 and R C1 and the other is methyl. In some embodiments, R B1 and R C1 are each independently selected C1-C6 alkyl. In some embodiments, R B1 and R C1 are each methyl.

[0179] In some embodiments, R C and R D taken together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0180] In some embodiments, one R 4 is -SO2(NR E R F In some embodiments, R E and R F are each hydrogen. In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C6 alkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C3 alkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is methyl. In some embodiments, R E and R Fare each C1-C6 alkyl. In some embodiments, R E and R F are each C1-C3 alkyl. In some embodiments, R E and R F are each methyl.

[0181] In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C6 haloalkyl. In some embodiments, R E and R F is hydrogen and R E and R F and the other is C1-C3 haloalkyl. In some embodiments, R E and R F are each C1-C6 haloalkyl. In some embodiments, R E and R F one of the groups is C1-C6 alkyl, and R E and R F The other is C1-C6 haloalkyl.

[0182] In some embodiments, one R 4 is —SO2(C1-C6 alkyl). In some embodiments, one R 4 is —SO2(C1-C3 alkyl). In some embodiments, one R 4 is -SO2Et. In some embodiments, one R 4 is -SO2Me.

[0183] In some embodiments, one R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, one R 4 is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, one R 4 is -S(=O)(=NH)Me.

[0184] In some embodiments, one R 4 is —C(═O)(C1-C6 alkyl). In some embodiments, one R 4 is —C(═O)(C1-C3 alkyl). In some embodiments, one R 4 is -C(=O)Me.

[0185] In some embodiments, one R 4 is —CO2(C1-C6 alkyl). In some embodiments, one R 4 is —CO2(C1-C3 alkyl). In some embodiments, one R 4 is -CO2Me.

[0186] In some embodiments, one R 4 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl. In some embodiments, one R 4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. 4 is tetrazolyl substituted with methyl. In some embodiments, one R 4 is pyrazolyl. In some embodiments, one R 4 is unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolyl.

[0187] In some embodiments, one R 4optionally one or two independently selected R G In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, R is a 7-9 membered heterocyclyl substituted with 4 The heterocyclyl is a spiro ring. In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one R G In some embodiments, one R 4 is two independently selected R G In some embodiments, one R 4 is an unsubstituted 3- to 6-membered heterocyclyl.

[0188] In some embodiments, one R 4 optionally one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R GIn some embodiments, one R 4 is one R G In some embodiments, one R 4 is two independently selected R G In some embodiments, one R 4 is an unsubstituted C3-C6 cycloalkyl.

[0189] In some embodiments, one or two independently selected R G is one R G In some embodiments, one or two independently selected R G is two independently selected R G In some embodiments, two R G When present, they are attached to the same atom if valence allows. G When present, they are attached to adjacent atoms if valence allows. In some embodiments, two R G If there are two R G are different. In some embodiments, two R G If there are two R G and are the same. 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 optionally substituted with hydroxyl. In some embodiments, one R G is 2-hydroxy-2-propyl. 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 Gis methyl. In some embodiments, one R G is ethyl.

[0190] 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.

[0191] In some embodiments, one R G is -NR A1 R B1 In some embodiments, R A1 and R B1 are each hydrogen. In some embodiments, R A1 and R B1 is hydrogen and R A1 and R B1 and the other is C1-C6 alkyl. In some embodiments, R A1 and R B1 is hydrogen and R A1 and R B1 and the other is C1-C3 alkyl. In some embodiments, R A1 and R B1 is hydrogen and R A1 and R B1 and the other is methyl. In some embodiments, R A1 and R B1 are each C1-C6 alkyl. In some embodiments, R A1 and R B1 are each methyl.

[0192] In some embodiments, R A1 and R B1 is hydrogen and R A1 and R B1 and the other is C1-C6 haloalkyl. In some embodiments, R A1 and R B1 is hydrogen and R A1 and R B1and the other is C1-C3 haloalkyl. In some embodiments, R A1 and R B1 are each C1-C6 haloalkyl. In some embodiments, R A1 and R B1 one of the groups is C1-C6 alkyl, and R A1 and R B1 The other is C1-C6 haloalkyl.

[0193] In some embodiments, one R G is =NR A2 In some embodiments, one R G is ═NH. In some embodiments, R A2 is hydrogen. In some embodiments, R A2 is C1-C6 alkyl. In some embodiments, R A2 is methyl.

[0194] In some embodiments, one R G is -C(=O)NR C1 R D1 In some embodiments, one R G is —CO 2 NH 2 . In some embodiments, one R G is —CO 2 NHCH 3 . In some embodiments, R C1 and R D1 are each hydrogen. In some embodiments, R C1 and R D1 is hydrogen and R C1 and R D1 and the other is C1-C6 alkyl. In some embodiments, R C1 and R D1 is hydrogen and R C1 and R D1 and the other is C1-C3 alkyl. In some embodiments, R C1 and R D1 is hydrogen and R C1 and R D1 and the other is methyl. In some embodiments, R C1 and RD1 are each C1-C6 alkyl. In some embodiments, R C1 and R D1 are each C1-C3 alkyl. In some embodiments, R C1 and R D1 are each methyl.

[0195] In some embodiments, R C1 and R D1 is hydrogen and R C1 and R D1 and the other is C1-C6 haloalkyl. In some embodiments, R C1 and R D1 is hydrogen and R C1 and R D1 and the other is C1-C3 haloalkyl. In some embodiments, R C1 and R D1 are each C1-C6 haloalkyl. In some embodiments, R C1 and R D1 one of the groups is C1-C6 alkyl, and R C1 and R D1 The other is C1-C6 haloalkyl.

[0196] In some embodiments, one R G is —CO2(C1-C6 alkyl). In some embodiments, one R G is —CO2CH3. In some embodiments, one R G is C1-C6 haloalkyl. In some embodiments, one R G is trifluoromethyl. In some embodiments, one R G is difluoromethyl. In some embodiments, one R G is C-C cycloalkyl. In some embodiments, one R G is cyclopropyl. In some embodiments, one R G is -CO2H.

[0197] In some embodiments, one R G is C1-C6 haloalkoxy. In some embodiments, one R G is C1-C3 haloalkoxy. In some embodiments, one R G is difluoromethoxy. In some embodiments, one R G is trifluoromethoxy.

[0198] In some embodiments, one R G is —SO2(C1-C6 alkyl). In some embodiments, one R G is -SO2CH3.

[0199] In some embodiments, R 4 The 3- to 9-membered heterocyclyl is a 3- to 6-membered heterocyclyl. 4 The 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4 The 3- to 6-membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. 4 The 3- to 6-membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. 4 3-9 membered heterocyclyl is

[0200] [ka] In some embodiments, R 4 3-9 membered heterocyclyl (e.g., R 4 3-6 membered heterocyclyl) is

[0201] [ka] wherein Q is a C1-C3 alkylene in which one or more carbons are optionally replaced by -C(=O)-, NH, O, or S. In some embodiments, Q is a C1-C3 alkylene in which one or more carbons are optionally replaced by -C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene in which one or more carbons are optionally replaced by -C(=O)- or NH. In some embodiments, R 4 3-9 membered heterocyclyl is

[0202] [ka] is selected from the group consisting of:

[0203] In some embodiments, one R 4 is an unsubstituted 3-6 membered heterocyclyl. In some embodiments, R 4 The 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4 is azetidinyl, morpholinyl, or tetrahydrofuranyl. 4 teeth,

[0204] [ka] is selected from the group consisting of:

[0205] In some embodiments,

[0206] [ka] teeth

[0207] [ka] wherein X is N and CR 4A2 Selected from R 4A1 and R 4A2 are independently hydrogen, optionally -NRA R B C1-C3 alkyl, methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), —SO2(C1-C6 alkyl), and optionally one or two independently selected R G and optionally one or two independently selected R G In some embodiments, X is selected from C3-C6 cycloalkyl substituted with CR 4A2 In some embodiments, R 4A1 and, if present, R 4A2 are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, —C(═O)NH, —C(═O)NHMe, —SONH, —SOMe, and azetidinyl optionally substituted with 1 to 2 independently selected fluoro, hydroxyl, or methyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, X is N and R 4A1 optionally one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0208] In some embodiments, X is N and R 4A1 is selected from amino, or azetidinyl optionally substituted with 1 to 2 independently selected fluoro, hydroxyl, or methyl.

[0209] In some embodiments,

[0210] [ka] teeth

[0211] [ka] where R 4B is -NR A R B and one nitrogen ring member, optionally 1 to 2 independently selected R G1 and R is selected from 4- to 6-membered heterocyclyl substituted with G1 is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl. G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0212] In some embodiments,

[0213] [ka] teeth

[0214] [ka] where R 4B is -NR A R B and one nitrogen ring member, optionally 1 to 2 independently selected R G1 wherein R is selected from 4- to 6-membered heterocyclyl substituted with G1 is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, —C(O)Me, —C(O)NH, ═NH, difluoromethoxy, —S(O)Me, —COH, C-C haloalkyl, and C-C alkyl. In some embodiments, R G1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, —C(O)Me, —C(O)NH, ═NH, difluoromethoxy, —S(O)Me, —COH, C-C haloalkyl, and C-C alkyl. G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0215] In some embodiments, R A and R B are each hydrogen. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C6 alkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R Bis hydrogen and R A and R B and the other is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B is hydrogen and R A and R B and the other is C1-C3 alkyl. In some embodiments, R A and R B is hydrogen and R A and R B and the other is methyl. In some embodiments, R A and R B are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of the groups is C1-C3 alkyl, and R A and R B and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B One of the groups is methyl, and R A. and R B and the other is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R A and R B One of the groups is methyl, and R A. and R B and the other is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0216] In some embodiments, R 4B is an amino group or a group having one nitrogen atom and optionally one to two independently selected R G 4- to 6-membered heterocyclyl substituted with R G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0217] In some embodiments, R 4B teeth,

[0218] [ka] wherein Ring C is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each optionally containing 1-2 =O, and each optionally containing 1-2 R independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. G In some embodiments, R 4B teeth,

[0219] [ka] wherein Ring C is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally containing 1 to 2 R independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, —COCH, and C-C alkyl. G In some embodiments, R 4B teeth,

[0220] [ka] wherein Ring C is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally containing 1 to 2 R independently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. G In some embodiments, R 4B teeth,

[0221] [ka] wherein Ring C is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally containing 1 to 2 R independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G In some embodiments, Ring C is azetidinyl.

[0222] In some embodiments, Ring C is unsubstituted.

[0223] In some embodiments, ring C is 1R G In some embodiments, R G is fluoro. In some embodiments, R G is cyano. In some embodiments, R G is an amino group, and in some embodiments, R G is hydroxyl. In some embodiments, R G is C1-C3 alkyl. In some embodiments, R G is methyl. In some embodiments, R G is ethyl. In some embodiments, R G is —CO2CH3. In some embodiments, R G is methoxy. In some embodiments, R G is methoxy.

[0224] In some embodiments, ring C is selected from two R G In some embodiments, each R Gis fluoro. In some embodiments, each R G is C1-C3 alkyl. In some embodiments, each R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is ethyl. In some embodiments, one R G is amino, and the other R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is cyclopropyl. In some embodiments, one R G is fluoro and the other R G1 is methyl. In some embodiments, one R G is hydroxyl, and the other R G is fluoro. In some embodiments, one R G is hydroxyl, and the other R G is trifluoromethyl. In some embodiments, each R G is attached to ring C in the para position relative to the nitrogen attached to ring A.

[0225] In some embodiments,

[0226] [ka] teeth

[0227] [ka] and one or two independently selected R G is attached to the 3-position of the azetidine.

[0228] [ka] teeth,

[0229] [ka] In some embodiments, the compound is selected from the group consisting of:

[0230] [ka] teeth,

[0231] [ka] In some embodiments, the compound is selected from the group consisting of:

[0232] [ka] teeth,

[0233] [ka] is selected from.

[0234] In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0235] In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 haloalkyl. In some embodiments, each R 1is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is trifluoromethyl.

[0236] In some embodiments, m is 2 and one R 4 is a halogen, and the other R 4 is —SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and the other R 4 is -SO2CH3.

[0237] In some embodiments, m is 2 and one R 4 is C1-C6 alkoxy, and the other R 4 is -C(=O)NR C R D is.

[0238] In some embodiments, m is 2 and one R 4 is methoxy, and the other R 4 is —C(O)NHCH 3 . In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, —CO2H, —NH2, —C(═O)NH2, —C(═O)NHMe, —SON2NH2, —SON2NHMe, —SO2Me, —S(═O)(═NH)Me, —C(═O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0239] In some embodiments, each R 1 is fluoro, m is 1 or 2; R 2 is a C1-C6 alkyl, R 3 is a C1-C6 alkyl, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0240] In some embodiments, each R 1 is fluoro, m is 1 or 2; R 2 is a C1-C6 alkyl, R 3 is a C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and optionally one or two independently selected R G 3- to 6-membered heterocyclyl substituted with n is 1 or 2.

[0241] In some embodiments, each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is a C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0242] In some embodiments, each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is a C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 independently, -NHR B and optionally 1 to 2 R G 4-6 membered heterocyclyl substituted with n is 1 or 2.

[0243] Non-limiting exemplary compounds In some embodiments, the compound is a compound selected from the group consisting of the compounds in Tables 1-7 (eg, compounds 1-11), or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound is a compound selected from the group consisting of the compounds depicted in Table A, or a pharmaceutically acceptable salt thereof.

[0245] Table A [Table 1-1]

[0246] (Continued from Table A) [Table 1-2]

[0247] Pharmaceutical Composition Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0248] Treatment method Indications Provided herein are methods for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα), encoded by the PIK3CA gene. For example, provided herein are inhibitors of PI3K alpha that are useful for treating or preventing diseases or disorders associated with dysregulation of the expression, activity, or levels of the PIK3CA gene, the PI3K alpha protein, or any of them (i.e., a PI3K alpha-associated disease or disorder), such as PIK3CA-related overgrowth syndrome (PROS; see, e.g., Venot, et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., macrocephalic capillary malformation (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., a PI3K alpha-associated cancer).

[0249] As used herein, a "PI3K alpha inhibitor" includes any compound that exhibits PI3K alpha inactivation activity (e.g., inhibits or reduces). In some embodiments, a PI3K alpha inhibitor may be selective for PI3K alphas with one or more mutations.

[0250] The ability of a test compound to act as an inhibitor of PI3Kα can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine kinase inhibition. Alternative in vitro assays quantitate the ability of an inhibitor to bind to a protein kinase and can be measured either by radiolabeling the compound prior to binding, isolating the compound / kinase complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which a new compound is incubated with a kinase bound to a known radioligand.

[0251] The efficacy of the PI3Kα inhibitors provided herein is measured by EC 50 A lower EC value when determined under substantially similar conditions may be determined by the 50 Compounds with higher EC 50 In some embodiments, the substantially similar conditions include determining the level of PI3K α-dependent phosphorylation 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 PI3K α, mutant PI3K α, or a fragment of either thereof).

[0252] The efficacy of the PI3Kα inhibitors provided herein is measured by IC 50 A lower IC value when determined under substantially similar conditions may also be determined by the IC 50 Compounds with higher IC 50In some embodiments, the substantially similar conditions include determining the PI3K alpha-dependent phosphorylation level in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3K alpha, mutant PI3K alpha, or a fragment of either 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).

[0253] Selectivity between wild-type PI3Kα and PI3Kα containing one or more 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.

[0254] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3K α. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3K α. In some embodiments, the compounds provided herein can exhibit nanomolar potency against PI3K α kinases containing one or more mutations, e.g., the mutations in Table 1 and Table 2.

[0255] In some embodiments, compounds provided herein may exhibit potent and selective inhibition of mutant PI3Kα. For example, compounds provided herein may bind to an allosteric site within the kinase domain. In some embodiments, 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 rash) that may affect quality of life and compliance. In some instances, inhibition of wild-type PI3Kα may result in dose-limiting toxicity. See, e.g., Hanker, et al., Cancer Disc. 2019, 9, 4, 482-491. Mutation-selective inhibitors may reduce the risk of such dose-limiting toxicities, including hyperglycemia, observed with inhibitors of wild-type PI3Kα.

[0256] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof can selectively target PI3K alpha, for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof can selectively target PI3K alpha over another kinase or non-kinase target.

[0257] In some embodiments, compound (I) or a pharmaceutically 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 the inhibition of wild-type PI3Kα. In some embodiments, compound (I) or a pharmaceutically 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 the inhibition of wild-type PI3Kα. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof may exhibit up to 1000-fold greater inhibition of PI3Kα containing one or more mutations described herein compared to the inhibition of wild-type PI3Kα. In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof may exhibit up to 10,000-fold greater inhibition of PI3Kα having a combination of mutations described herein compared to the inhibition of wild-type PI3Kα.

[0258] In some embodiments, Formula (I) or a pharmaceutically acceptable salt thereof may exhibit up to 2-fold to about 10-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, Formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 10-fold to about 100-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, Formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 100-fold to about 1000-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, Formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 1000-fold to about 10,000-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α.

[0259] Formula (I) or a pharmaceutically acceptable salt thereof is useful for treating PI3K alpha-associated diseases and disorders, e.g., diseases and disorders that can be treated with PI3K alpha inhibitors, such as PI3K alpha-associated hyperproliferative syndromes (PROS) and proliferative disorders such as cancer, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0260] In some embodiments, the subject has been identified or diagnosed with a cancer having dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them (a PI3K alpha-associated cancer) (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 dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha 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 such as those described in Table 1 or Table 2. The subject may be a subject having a tumor that is positive for dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha 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 a subject whose tumor has dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them (e.g., if the tumor is identified as such using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a PI3K alpha-associated cancer, hi some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the PIK3CA gene, the PI3K alpha protein, or either thereof (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0261] In some embodiments, the subject is a pediatric subject.

[0262] The term "pediatric subject" as used herein refers to a subject under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years (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 between birth and 28 days of age, between 29 days of age and under 2 years of age, between 2 years of age and under 12 years of age, or between 12 years of age and 21 years of age (up to but excluding the 22nd birthday). In some embodiments, the pediatric subject is between birth and 28 days of age, between 29 days of age and under 1 year of age, between 1 month of age and under 4 months of age, between 3 months of age and under 7 months of age, between 6 months of age and under 1 year of age, between 1 year of age and under 2 years of age, between 2 years of age and under 3 years of age, between 2 years of age and under 7 years of age, between 3 years of age and under 5 years of age, between 5 years of age and under 10 years of age, between 6 years of age and under 13 years of age, between 10 years of age and under 15 years of age, or between 15 years of age and under 22 years of age.

[0263] In certain embodiments, the compounds of Formula (I) or pharmaceutically 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 delaying the onset, recurrence, or spread of a disease or condition described herein, or a symptom thereof, in whole or in part.

[0264] As used herein, the term "PI3K alpha-associated disease or disorder" refers to a disease or disorder associated with or involving dysregulation of the expression, activity, or levels of the PIK3CA gene, the PI3K alpha protein, or any (e.g., one or more) of either. (E.g., any type of dysregulation of the expression, activity, or levels of the PIK3CA gene, or the PI3K alpha protein, or any of either.) Non-limiting examples of PI3K alpha-associated diseases or disorders include, for example, PIK3CA-associated hyperproliferative syndromes (PROS), encephalopathy (e.g., macrocephalic capillary malformation (MCAP) and hemimegalencephaly), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal abnormalities (e.g., Cloves syndrome) and fibrolipid hyperplasia (FH), or cancer (e.g., PI3K alpha-associated cancer).

[0265] As used herein, the term "PI3K alpha-associated cancer" refers to a cancer associated with or having dysregulated expression or activity or levels of the PIK3CA gene, the PI3K alpha protein, or any of them. Non-limiting examples of PI3K alpha-associated cancers are described herein.

[0266] The phrase "dysregulated expression, 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 the expression of PI3K α containing at least one amino acid deletion compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in the expression of PI3K α with one or more point mutations compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in the expression of PI3K α with at least one inserted amino acid compared to wild-type PI3K α, a gene duplication that results in an increased level of PI3K α in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3K α in a cell, an alternatively spliced ​​version of PI3K α mRNA that results in 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 dysregulation of autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the expression, activity, or levels of the PIK3CA gene, the PI3K alpha protein, or either thereof can be a mutation in the PIK3CA gene that encodes a PI3K alpha protein that is constitutively active or has increased activity compared to a protein encoded by a PIK3CA gene that does not contain the mutation. Non-limiting examples of PI3K alpha point mutations / substitutions / insertions / deletions are listed in Tables 1 and 2.

[0267] The term "activating mutation" with respect to PI3K α refers to a mutation in the PIK3CA gene that results in the expression of PI3K α with increased kinase activity, e.g., compared to wild-type PI3K α, 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 PI3K α 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 PI3K α, when assayed under the same conditions. In another example, an activating mutation can be a mutation in PIK3CA that results in the expression of PI3K α 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 PI3K α, when assayed under the same conditions. In another example, an activating mutation can be a mutation in the PIK3CA gene that results in expression of a PI3K α 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 wild-type PI3K α, such as the exemplary wild-type PI3K α described herein, when assayed, e.g., under identical conditions. Additional examples of activating mutations are known in the art.

[0268] The terms "wild type" or "wild-type" refer to 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 reference nucleic acid or protein.

[0269] The term "wildtype PI3K α" or "wild-type PI3K α" refers to 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, 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 cells or tissues from a subject who does not have a PI3K α-related disease, e.g., a PI3K α-related cancer (and, optionally, 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).

[0270] Provided herein are methods for treating cancer (e.g., PI3K α-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3K α-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K α 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 pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the PIK3CA gene, the PI3K α protein, or any of them comprises one or more substitutions / point mutations / insertions in the PI3K α protein. Non-limiting examples of substitutions / insertions / deletions in the PI3K α protein are listed in Tables 1 and 2.

[0271] In some embodiments, the substitution / insertion / deletion in the ΡΙ3Κ α 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 ΡΙ3Κ α protein is H1047X, where X is any amino acid.

[0272] In some embodiments of any of the methods or uses described herein, the cancer (eg, a PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor.

[0273] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is breast cancer (e.g., HER2 + and HER2 - Both breast cancer and ER + breast cancer, and triple-negative breast cancer), endometrial cancer, lung cancer (including lung adenocarcinoma and squamous cell carcinoma), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagogastric adenocarcinoma, gastric cancer, 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), prostate cancer, kidney cancer, pancreatic neuroendocrine tumor (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0274] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is breast cancer (e.g., HER2 + and HER2 - Both breast cancer and ER +breast cancer, including triple-negative breast cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumor (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including lung adenocarcinoma and squamous cell carcinoma), and endometrial cancer.

[0275] 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, esophagogastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0276] 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.

[0277] 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.

[0278] Table 1. Amino acid substitutions / insertions / deletions in PI3Kα protein A [Table 2-1] TIFF2025535066000105.tif86169

[0279] (Continued from Table 1) [Table 2-2] TIFF2025535066000107.tif92169

[0280] (Continued from Table 1) [Table 2-3]

[0281] (Continued from Table 1) [Table 2-4] TIFF2025535066000110.tif49169

[0282] (Continued from Table 1) [Table 2-5] TIFF2025535066000112.tif77169

[0283] (Continued from Table 1) [Table 2-6] TIFF2025535066000114.tif166169

[0284] (Continued from Table 1) [Table 2-7]

[0285] (Continued from Table 1) [Table 2-8]

[0286] (Continued from Table 1) [Table 2-9] TIFF2025535066000118.tif83169

[0287] (Continued from Table 1) [Table 2-10] TIFF2025535066000120.tif50169

[0288] (Continued from Table 1) [Table 2-11] TIFF2025535066000122.tif55169

[0289] (Continued from Table 1) [Table 2-12]

[0290] (Continued from Table 1) [Table 2-13] TIFF2025535066000125.tif66169 A Unless otherwise stated, the mutations in Table 1 are found in the cBioPortal database, derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2;401, and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer.Eur J Cancer.2005 Jul;41(11):1649-54.doi:10.1016 / j.ejca.2005.04.022.PMID:15994075.

[0291] Table 2. Amino acid substitutions / insertions / deletions in additional PI3Kα proteins A [Table 3-1] TIFF2025535066000127.tif185169

[0292] (Continued from Table 2) [Table 3-2] A Unless otherwise stated, the mutations in Table 2 are found in the cBioPortal database, derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2;401, and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer.Eur J Cancer.2005 Jul;41(11):1649-54.doi:10.1016 / j.ejca.2005.04.022.PMID:15994075.

[0293] In some embodiments, the dysregulation of the PIK3CA gene, the PI3K α protein, or the expression, activity, or levels of either thereof comprises a splice variation in the PI3K α mRNA that results in the expressed protein being an alternatively spliced ​​variant of PI3K α, with at least one residue deleted (compared to the wild-type PI3K α protein), resulting in constitutive activity of the PI3K α protein domain.

[0294] In some embodiments, the dysregulation of the PIK3CA gene, the PI3K α protein, or the expression, activity, or level of either thereof comprises at least one point mutation in the PIK3CA gene that results in the production of a PI3K α protein having one or more amino acid substitutions, insertions, or deletions in the PIK3CA gene, resulting in the production of a PI3K α protein in which one or more amino acids are inserted or deleted compared to the wild-type PI3K α protein. In some cases, the resulting mutant PI3K α protein has increased activity compared to the wild-type PI3K α protein or a PI3K α protein that does not contain the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3K α protein compared to the wild-type PI3K α protein or a PI3K α protein that does not contain the same mutation.

[0295] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0296] In some embodiments, compounds of Formula (I) or a pharmaceutically acceptable salt thereof are useful for treating cancers identified as having one or more PI3K alpha mutations. Accordingly, provided herein are methods 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 pharmaceutically acceptable salt thereof.

[0297] Also provided herein are methods for treating a subject identified or diagnosed with a PI3K alpha-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has been identified or diagnosed with a PI3K alpha-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay, or by performing any of the non-limiting examples of assays described herein, to identify dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression, activity, or levels of either in the subject or in a biopsy sample from the subject. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a PI3K alpha-associated cancer.

[0298] The term "regulatory authority" refers to a national agency that approves the medical use of pharmaceuticals in each country. For example, a non-limiting example of a regulatory authority is the US Food and Drug Administration (FDA).

[0299] Also provided are methods for treating cancer in a subject in need thereof, the methods 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 pharmaceutically 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 tumor resection or radiation therapy. In some embodiments, the subject is determined to have a PI3K alpha-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay, or by performing any of the non-limiting examples of assays described herein, to identify dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression, activity, or levels of either in the subject or in a biopsy sample from the subject. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a PI3K alpha-associated cancer.

[0300] Also provided are methods of treating a subject, comprising performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or either of them; and then administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or either of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is 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, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0301] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a PI3K alpha-associated cancer in a subject identified or diagnosed as having the cancer via performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulation of the expression, activity or level of the PIK3CA gene, the PI3K alpha protein, or either of them, wherein in the assay, the presence of dysregulation of the expression, activity or level of the PIK3CA gene, the PI3K alpha protein, or either of them identifies the subject as having the PI3K alpha-associated cancer. Also provided is use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a PI3K α-associated cancer in a subject identified or diagnosed with the cancer via performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the PIK3CA gene, the PI3K α protein, or any of them, wherein the presence of dysregulated expression, activity, or level of the PIK3CA gene, the PI3K α protein, or any of them identifies the subject as having a PI3K α-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the patient's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the PIK3CA gene, the PI3K α protein, or any of them via performance of the assay, and that the subject should be administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 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. In some embodiments, the assay is a liquid biopsy.

[0302] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need of cancer treatment or a subject identified or diagnosed with a PI3K alpha-associated cancer. Also provided is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in a subject identified or diagnosed with a PI3K alpha-associated cancer. In some embodiments, the subject has been identified or diagnosed with a PI3K alpha-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression, activity, or levels of either thereof in the subject or in a biopsy sample from the subject. As provided herein, PI3K alpha-associated cancers include those described herein and those known in the art.

[0303] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulated expression, activity, or levels of the 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 dysregulated expression, activity, or levels of the 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 is positive for dysregulated expression, activity, or levels of the 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 dysregulated expression, activity, or levels of the 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 a PI3K alpha-associated cancer. In some embodiments, provided herein are methods for treating a PI3K alpha-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, 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 pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them comprises one or more point mutations / insertions / deletions in the PI3K alpha protein. Non-limiting examples of point mutations / insertions / deletions in the PI3K alpha protein are listed in Tables 1 and 2. In some embodiments, the point mutation / insertion / deletion in the PI3K alpha protein is H1047X, where X is any amino acid.In some embodiments, the point mutation / 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, and G1049R. In some embodiments, cancers associated with dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them are determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, tumors associated with dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them are determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

[0304] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor having a 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 pharmaceutically acceptable salt thereof to a subject having clinical records indicating that the subject has a tumor having a dysregulated expression or activity or level of the PIK3CA gene, PI3K alpha protein, or any of them.

[0305] In some embodiments, the methods described herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulated expression or level of the PIK3CA gene, PI3K α protein, or any of them. In some such embodiments, the method also includes administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to have a dysregulated expression, activity, or level of the PIK3CA gene, PI3K α protein, or any of them. In some embodiments, the method includes determining that the subject has a dysregulated expression or level of the PIK3CA gene, PI3K α protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the dysregulation in the expression, activity, or level of the PIK3CA gene, PI3K α protein, or any of them is one or more point mutations in the PIK3CA gene (e.g., any one or more of the PI3K α point mutations described herein). One or more point mutations in the PIK3CA gene can 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 can result in the translation of a PI3K alpha protein having, for example, one or more of the following amino acids: 542, 545, 1043, 1047, and 1049. In some embodiments, the dysregulation in the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of either thereof 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 (eg, immunotherapy).

[0306] In some embodiments of any of the methods or uses described herein, assays used to determine whether a subject has dysregulated expression, activity, or levels of the PIK3CA gene, or PI3K α protein, or either thereof, 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 quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assays can utilize other detection methods known in the art for detecting dysregulated expression, activity, or levels of the PIK3CA gene, PI3K α protein, or either thereof (see, for example, the references cited herein). In some embodiments, the sample is a biological sample or biopsy sample (e.g., a 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 with one or more symptoms of a PI3K alpha-associated cancer, and / or a subject at increased risk of developing a PI3K alpha-associated cancer.

[0307] In some embodiments, dysregulation of the expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid-phase biopsy). See, e.g., 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, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of the expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them at an earlier stage than traditional methods. In some embodiments, biological samples used in liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, 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 levels of PIK3CA, PI3K alpha protein, or any of them.

[0308] Also provided herein 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 pharmaceutically 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 and the method comprises administering to a subject having abnormal PI3K alpha activity an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 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 system or an 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, for example, introducing a compound provided herein into a sample containing cells or a purified preparation containing a PI3K alpha protein.

[0309] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0310] Also provided herein are methods for inhibiting cell proliferation in vitro or in vivo, comprising contacting a subject with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof described herein. Also provided herein are methods for increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount effective to increase tumor cell death.

[0311] The phrase "therapeutically effective amount" means an amount of a compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Kα protein-associated disease or disorder, (ii) attenuate, 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. The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof corresponding to such an amount may vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., body weight) of the subject requiring treatment, and the like, but may nevertheless be routinely determined by one of ordinary skill in the art.

[0312] When employed as pharmaceuticals, the compounds of formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions described herein.

[0313] combination In the field of medical oncology, it is common to use a combination of different treatment modalities to treat each subject with cancer. In medical oncology, in addition to the compositions provided herein, other components of such combined treatment or therapy may be surgery, radiation therapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery may be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be useful as adjuvants in cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, such as chemotherapeutic agents acting by the same or different mechanisms of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof may be used before the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the compounds of formula (I) or pharmaceutically acceptable salts thereof for a certain period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time and under one or more radiation therapy regimens. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) prior to one or more radiation therapy regimens.

[0314] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (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 therapy (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 therapy. In some embodiments, the subject is PI3K alpha inhibitor naive. For example, the subject is naive to treatment with a selective PI3K alpha inhibitor. In some embodiments, the subject is not PI3K alpha inhibitor naive. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive. In some embodiments, the subject has received previous therapy.For example, a multi-kinase inhibitor (MKI) or another PI3K inhibitor, such as buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolicib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, A SN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), ceravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG Treatment with 511, CH5132799, GSK1059615, 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.

[0315] In some embodiments of any of the methods described herein, the compound of Formula (I) (or a pharmaceutically 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 therapies or treatments (e.g., chemotherapeutic) agents.

[0316] Non-limiting examples of additional therapeutic agents include other PI3Kα targeted therapeutic agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (including the mTOR inhibitors described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutic agents (e.g., Trk inhibitors or multikinase inhibitors)), farnesyltransferase inhibitors, signal transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SELMs / SELDs), checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax), cytotoxic chemotherapeutic agents, angiogenesis targeted therapies, immune targeted agents including immunotherapies, and radiation therapy.

[0317] In some embodiments, the EGFR inhibitor is selected from the group consisting of osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKER B (registered trademark), panitumumab (ABX-EGF, VECTIBIX (registered trademark), vandetanib (CAPRELSA (registered trademark), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), nacotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuximab (humanized mAb 806, ABT-806), depatuximab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacryl-shikonin, and acetyl-alkannin), 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, barlitinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, disluptin, CL-387785, EGFRBi-armed 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.

[0318] 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®), and dacomiti These include nibs (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, pozotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1, and AEE-788.

[0319] As used herein, a "RAS pathway-targeted therapeutic" 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 the 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 may be selective for a protein in the RAS pathway, e.g., the RAS pathway modulator may be selective for RAS (also referred to as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway-targeted therapeutic 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 may be selective for a protein in the RAS pathway, e.g., the KRAS pathway modulator may be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0320] Non-limiting examples of KRAS-targeted therapeutics (e.g., KRAS inhibitors) include BI 1701963, AMG510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0321] Further non-limiting examples of RAS-targeted therapeutics 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.

[0322] 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.

[0323] 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 a combination thereof.

[0324] 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 buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN00 3. Pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), ceravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), 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.

[0325] 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, M K-2206, edelfosine, miltefosine, perifosine, erucylphosphocholine, elfosine, 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, BAY 1125976, 3-oxo-tirucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0326] 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.

[0327] Non-limiting examples of farnesyltransferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0328] In some embodiments, the chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based drug, mitomycin, gemcitabine, eribulin (HALAVEN™), or a combination thereof.

[0329] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0330] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0331] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedoplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0332] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0333] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0334] Non-limiting examples of selective estrogen receptor modulators or degraders (SERM / SERD) include tamoxifen, fulvestrant, brilanellastine, elasant, zildetran, amsenestrant (SAR439859), AZD9833, lintodetran, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0335] 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 a combination thereof. In some embodiments, the PD-L1 inhibitor is chosen 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).

[0336] 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, buparlisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG 479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, amsenestrant, and combinations thereof.

[0337] In some embodiments, additional therapeutic agents, such as opioids and corticosteroids, may be administered to treat potential side effects of certain anti-cancer therapies and / or as palliative therapy. In some embodiments, the additional therapy or therapeutic 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.

[0338] 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.

[0339] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (e.g., STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, cefliflozin, licofriglozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin.

[0340] 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.

[0341] In some embodiments, the subject is also instructed to maintain a particular diet and / or exercise regimen to control blood glucose levels.

[0342] 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 pharmaceutically acceptable salt thereof; (b) an additional therapeutic agent; and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for treating cancer, wherein the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together are effective to treat cancer.

[0343] In some embodiments, the additional therapeutic agent comprises any one of the therapies or therapeutic agents listed above that are standard of care for cancer, wherein the cancer has dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or levels of either thereof.

[0344] These additional therapeutic agents may be administered together with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as part of the same or separate dosage form, via the same or different route of administration, and / or on the same or different dosing schedule, in accordance with standard pharmaceutical practice known to those skilled in the art.

[0345] 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 pharmaceutically 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 pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are together effective to treat cancer; (ii) pharmaceutical compositions comprising such combinations; (iii) use 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 a combined preparation for simultaneous, separate, or sequential use, as well as methods of treating cancer in a subject in need thereof. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0346] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical therapy resulting from the mixing or combination of two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are administered to a subject simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or dosages that can be administered to a subject in need thereof simultaneously, concurrently, or sequentially, with a limited time interval between each administration, such that each administration results in effective levels of the two or more compounds in the subject's body. This also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0347] Thus, also provided herein are methods for 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 pharmaceutically acceptable salt thereof; and (b) an additional therapeutic agent, wherein the compound of Formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, and wherein the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are together effective to treat cancer. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially in any order as separate dosages in jointly therapeutically effective amounts, for example, daily or intermittent dosages. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as combined dosages.

[0348] Embodiment Embodiment 1: Compound of Formula (I)

[0349] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 9-membered heteroaryl group, and Ring B is not 2-benzofuranyl or 2-indolyl; Each R 1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, a C3-C8 cycloalkyl, a 5- to 10-membered heteroaryl, or a 4- to 10-membered heterocyclyl; Each R 4 But independently, (i) halogens, (ii) optionally one or two hydroxyls or -NR A R B C1-C6 alkyl substituted with (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) optionally one or two independently selected R G 3- to 9-membered heterocyclyl substituted with (xviii) optionally one or two independently selected R G C3-C6 cycloalkyl substituted with n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F But independently, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, or (ix) optionally hydroxyl, —C(═O)NR B2 R C2, 5-6 membered heteroaryl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached, optionally hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 2:

[0351] [ka] but,

[0352] [ka] 2. The compound of embodiment 1, wherein

[0353] Embodiment 3:

[0354] [ka] but,

[0355] [ka] 3. The compound of embodiment 2, wherein

[0356] Embodiment 4:

[0357] [ka] but,

[0358] [ka] 3. The compound of embodiment 2, wherein

[0359] Embodiment 5:

[0360] [ka] but,

[0361] [ka] 3. The compound of embodiment 2, wherein

[0362] Embodiment 6:

[0363] [ka] but,

[0364] [ka] 3. The compound of embodiment 2, wherein

[0365] Embodiment 7: The compound of any one of embodiments 1 to 6, wherein m is 1.

[0366] Embodiment 8: The compound of any one of embodiments 1-6, wherein m is 2.

[0367] Embodiment 9: Each R 1 The compound of any one of embodiments 1-8, wherein is halogen.

[0368] Embodiment 10: Each R 1 The compound of any one of embodiments 1-9, wherein is selected from fluoro and chloro.

[0369] Embodiment 11: Each R 1 The compound of any one of embodiments 1-10, wherein is fluoro.

[0370] Embodiment 12: Each R 1 The compound of any one of embodiments 1-8, wherein is hydroxyl.

[0371] Embodiment 13: One R 1 The compound of any one of embodiments 1-8, wherein is cyano.

[0372] Embodiment 14: One R 1 The compound of any one of embodiments 1-8, wherein is C1-C6 alkyl optionally substituted with hydroxyl.

[0373] Embodiment 15: 1 R 1 The compound of any one of embodiments 1-8, wherein is C3-C6 cycloalkyl.

[0374] Embodiment 16: The compound of any one of embodiments 1 to 6, wherein m is 0.

[0375] Embodiment 17:R 2The compound of any one of embodiments 1-16, wherein is C1-C6 alkyl optionally substituted with hydroxyl.

[0376] Embodiment 18:R 2 The compound of any one of embodiments 1-17, wherein is unsubstituted C1-C6 alkyl.

[0377] Embodiment 19:R 2 is methyl.

[0378] Embodiment 20:R 2 The compound of any one of embodiments 1-16, wherein is C1-C6 haloalkyl.

[0379] Embodiment 21:R 2 is difluoromethyl.

[0380] Embodiment 22:R 2 The compound of embodiment 20, wherein is trifluoromethyl.

[0381] Embodiment 23:R 2 The compound of any one of embodiments 1-16, wherein is halogen.

[0382] Embodiment 24:R 2 The compound of any one of embodiments 1-16, wherein is hydroxyl.

[0383] Embodiment 25:R 2 The compound of any one of embodiments 1-16, wherein is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro.

[0384] Embodiment 26:R 3 The compound of any one of embodiments 1-25, wherein is C1-C6 haloalkyl.

[0385] Embodiment 27:R 3The compound of any one of embodiments 1-26, wherein is difluoromethyl.

[0386] Embodiment 28:R 3 The compound of any one of embodiments 1-26, wherein is trifluoromethyl.

[0387] Embodiment 29:R 3 The compound of any one of embodiments 1-25, wherein is C1-C6 alkyl.

[0388] Embodiment 30:R 3 The compound of any one of embodiments 1-25 and 29, wherein is Me, Et, or iPr.

[0389] Embodiment 31:R 3 The compound of any one of embodiments 1-25, wherein is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl.

[0390] Embodiment 32: A compound of any one of embodiments 1 to 31, wherein ring A is a 5-10 membered heteroaryl.

[0391] Embodiment 33: A compound of any one of embodiments 1 to 32, wherein Ring A is a 5- to 6-membered heteroaryl.

[0392] Embodiment 34: A compound of any one of embodiments 1 to 33, wherein Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl.

[0393] Embodiment 35: A compound of any one of embodiments 1 to 34, wherein Ring A is pyrimidinyl.

[0394] Embodiment 36: A compound of any one of embodiments 1 to 34, wherein Ring A is pyridyl.

[0395] Embodiment 37: A compound of any one of embodiments 1 to 34, wherein Ring A is thiazolyl.

[0396] Embodiment 38: The compound of any one of embodiments 1 to 34, wherein Ring A is thiophenyl.

[0397] Embodiment 39: A compound of any one of embodiments 1 to 34, wherein Ring A is pyrazolyl.

[0398] Embodiment 40: A compound of any one of embodiments 1 to 32, wherein ring A is a 9-10 membered heteroaryl.

[0399] Embodiment 41: The compound of any one of embodiments 1-32 and 40, wherein Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, or imidazo[1,2-a]pyridinyl.

[0400] Embodiment 42: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is benzimidazolyl.

[0401] Embodiment 43: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is indazolyl.

[0402] Embodiment 44: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is indolyl.

[0403] Embodiment 45: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is a quinazolone.

[0404] Embodiment 46: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is isobenzofuranonyl.

[0405] Embodiment 47: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is isoindolinonyl.

[0406] Embodiment 48: The compound of any one of embodiments 1-32 and 40-41, wherein Ring A is imidazo[1,2-a]pyridinyl.

[0407] Embodiment 49: A compound of any one of embodiments 1 to 31, wherein ring A is a 6- to 10-membered aryl.

[0408] Embodiment 50: The compound of any one of embodiments 1 to 31 and 49, wherein Ring A is phenyl.

[0409] Embodiment 51: A compound of any one of embodiments 1 to 31, wherein Ring A is C3-C8 cycloalkyl.

[0410] Embodiment 52: A compound of any one of embodiments 1 to 31, wherein ring A is a 4- to 10-membered heterocyclyl.

[0411] Embodiment 53: The compound of any one of embodiments 1 to 31 and 52, wherein ring A is a 4- to 6-membered heterocyclyl.

[0412] Embodiment 54: The compound of any one of embodiments 1 to 53, wherein n is 1.

[0413] Embodiment 55: The compound of any one of embodiments 1 to 53, wherein n is 2.

[0414] Embodiment 56: One R 4 is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[0415] Embodiment 57: One R 4 The compound of any one of embodiments 1-55, wherein is C1-C6 haloalkyl.

[0416] Embodiment 58: One R4 is hydroxyl, cyano, —COH, halogen, or optionally 1 to 2 hydroxyl or —NR A R B The compound of any one of embodiments 1-55, wherein R is C1-C6 alkyl substituted with R.

[0417] Embodiment 59: One R 4 But, -NR A R B , =NR A2 , -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), or —CO2(C1-C6 alkyl).

[0418] Embodiment 60: One R 4 The compound of any one of embodiments 1-55, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0419] Embodiment 61: One R 4 optionally one or two independently selected R G The compound of any one of embodiments 1-55, wherein the compound is 3-9 membered heterocyclyl substituted with

[0420] Embodiment 62: One R 4 optionally one or two independently selected R G The compound of any one of embodiments 1-55, wherein the compound is C3-C6 cycloalkyl substituted with

[0421] Embodiment 63: The compound of any one of embodiments 1 to 53, wherein n is 0.

[0422] Embodiment 64: A compound selected from the group consisting of the compounds of Table A, or a pharmaceutically acceptable salt thereof.

[0423] Embodiment 65: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 64 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0424] Embodiment 66: A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 65.

[0425] Embodiment 67: 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 the expression or activity or level of any of them; and (b) administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 65.

[0426] Embodiment 68: 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 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 65.

[0427] Embodiment 69: A method for modulating PI3K alpha in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of any one of embodiments 1 to 64 or a pharmaceutically acceptable salt thereof. [Example]

[0428] Preparation of compounds The compounds disclosed herein can be prepared in a variety of ways by employing standard synthetic methods and procedures that are either known to those skilled in the art or will become apparent to those skilled in the art in light of the teachings herein, using commercially available starting materials, compounds known in the literature, or readily prepared intermediates. Synthesis of the compounds disclosed herein can generally be accomplished by following the schemes provided herein, with modifications for specific desired substituents.

[0429] 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. Without being limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & 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 texts on organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are intended to illustrate, but not limit, general procedures for preparing compounds of the present disclosure.

[0430] The synthetic processes disclosed herein can tolerate a wide variety of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the completion of the overall process, in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0431] Example 1: Preparation of Compound 1

[0432] [ka]

[0433] Step 1 A solution of 6-fluoro-1H-indole-2-carboxylic acid (1-a; 2.00 g, 11.16 mmol, 1.00 equiv.) in DMF (14 mL) was treated with KCO (4.63 g, 33.49 mmol, 3.00 equiv.) under a nitrogen atmosphere at 0 °C for 1 minute, followed by the dropwise addition of CHI (2.78 mL, 44.66 mmol, 4.00 equiv.) at 0 °C. The solution was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction was quenched with saturated NHCl (aq.) at 0 °C. The precipitated solid was collected by filtration and washed with water (1 × 200 mL) to give methyl 6-fluoro-1-methylindole-2-carboxylate (1-b; 2 g, 87%) as an off-white solid. MS (ESI): C 11 H 10 Calculated mass of FNO2: 207.07, measured m / z: 208.05 [M+H] + .

[0434] Step 2 To a stirred solution of methyl 6-fluoro-1-methylindole-2-carboxylate (1-b; 1.00 g, 4.83 mmol, 1.00 equiv.) in THF (4 mL) was added dropwise a solution of LiAlH4 (5.79 mL, 5.79 mmol, 1.20 equiv.) in THF at 0°C under a nitrogen atmosphere. The solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with sodium sulfate decahydrate at 0°C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1 x 100 mL). The filtrate was concentrated under reduced pressure to give (6-fluoro-1-methylindol-2-yl)methanol (1-c; 875 mg) as a brown solid. The crude product was used directly in the next step without further purification. MS (ESI): C 10 H 10 Calculated mass of FNO: 179.07, measured m / z: 180.05 [M+H] + .

[0435] Step 3 To a stirred solution of (6-fluoro-1-methylindol-2-yl)methanol (1-c; 775 mg, 4.32 mmol, 1.00 equiv.) in DCM (8 mL) was added manganese dioxide (3.76 g, 43.25 mmol, 10.00 equiv.). The solution was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1×100 mL). The filtrate was concentrated under reduced pressure to give 6-fluoro-1-methylindole-2-carbaldehyde (1-d; 754 mg) as a yellow solid. The crude product was used directly in the next step without further purification. MS (ESI): C 10 Calculated mass of H8FNO: 177.06, measured m / z: 178.05 [M+H] + .

[0436] Step 4 To a stirred solution of 6-fluoro-1-methylindole-2-carbaldehyde (1-d; 650 mg, 3.67 mmol, 1.00 equiv.) and K2CO3 (1.52 g, 11.00 mmol, 3.00 equiv.) in DMF (7 mL) was added TMSCF3 (1.04 g, 7.34 mmol, 2.00 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanol (1-e; 743 mg, 82%) as a brown solid. MS (ESI): C 11 Calculated mass of H9F4NO: 247.06, measured m / z: 248.05 [M+H] + .

[0437] Step 5 To a stirred solution of 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanol (1-e; 600 mg, 2.43 mmol, 1.00 equiv.) in EA (6 mL) was added IBX (1.36 g, 4.85 mmol, 2.00 equiv.) portionwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was filtered, and the filter cake was washed with PE (1×60 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE, to give 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanone (1-f; 560 mg, 94%) as a white solid. MS MS (ESI): C 11 Calculated mass of H7F4NO: 245.05, measured m / z: 245.90 [M+H] + .

[0438] Step 6 A solution of 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanone 1-f (560 mg, 2.28 mmol, 1.00 equiv) in EtOH (6 mL) was treated with AcONa (937 mg, 11.42 mmol, 5.00 equiv) under a nitrogen atmosphere at 0 °C for 1 minute, followed by the addition of NH OH.HCl (794 mg, 11.42 mmol, 5.00 equiv) in portions at 0 °C. The resulting solution was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (£)-N-[2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethylidene]hydroxylamine (1-g; 460 mg, 77%) as a white solid. MS (ESI): C 11 Calculated mass of H8F4N2O: 260.06; measured m / z: 258.90 [MH] - .

[0439] Step 7 A solution of (E)-N-[2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethylidene]hydroxylamine (1-g; 250 mg, 0.96 mmol, 1.00 equiv.), Zn powder (628 mg, 9.61 mmol, 10.00 equiv.), and NH4Cl (514 mg, 9.61 mmol, 10.00 equiv.) in EtOH (2 mL) and HO (0.4 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was extracted with EtOAc (1 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanamine (1-h; 143 mg, 60%) as a brown solid. MS (ESI): C 11 H10 Calculated mass of F4N2: 246.08, measured m / z: 230.05 [M-NH3+H] + .

[0440] Step 8 To a stirred solution of 2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethanamine (1-h; 140 mg, 0.57 mmol, 1.00 equiv.) in pyridine (1 mL) was added phenyl N-(2-aminopyrimidin-5-yl)carbamate (157 mg, 0.68 mmol, 1.20 equiv.). The resulting solution was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give 1-(2-aminopyrimidin-5-yl)-3-[2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethyl]urea (170 mg) as a pale yellow solid. The crude product (170 mg) was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NHHCO) in water, 10% to 50% gradient in 30 min; detector, UV 254 nm) to give 1-(2-aminopyrimidin-5-yl)-3-[2,2,2-trifluoro-1-(6-fluoro-1-methylindol-2-yl)ethyl]urea (Compound 1; 60 mg, 28%) as a pale yellow solid. MS (ESI): C 16 H 14 Calculated mass of F4N6O: 382.12, measured m / z: 383.15 [M+H] +. 1H NMR(400MHz,DMSO-d6)δ 8.22(s,2H),8.07(s,1H),7.60(dd,J=8.7,5.5Hz,1H),7.53(d,J=9.3Hz,1H),7.41-7.37 (m,1H),6.96-6.91(m,1H),6.66(s,1H),6.40(s,2H),5.99(p,J=8.0Hz,1H),3.73(s,3H).

[0441] Example 2: Preparation of Compound 2

[0442] [ka]

[0443] Step 1 To a stirred solution of 6-fluoro-1-methylindole-2-carbaldehyde (1-d; 790 mg, 4.46 mmol, 1.00 equiv) in THF (16 mL) was added isopropylmagnesium bromide, a 1 M solution in THF (22 mL, 22.30 mmol, 5.00 equiv) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was quenched with saturated NH4Cl (aq) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 1-(6-fluoro-1-methylindol-2-yl)-2-methylpropan-1-ol (2-a; 580 mg, 59%) as a green solid. MS (ESI): C 13 H 16 Calculated mass of FNO: 221.12, measured m / z: 222.20 [M+H] + .

[0444] Step 2 To a stirred solution of 1-(6-fluoro-1-methylindol-2-yl)-2-methylpropan-1-ol (2-a; 300 mg, 1.36 mmol, 1.00 equiv.) and phthalimide (219 mg, 1.49 mmol, 1.10 equiv.) in THF (3 mL) was added PPh3 (533 mg, 2.03 mmol, 1.50 equiv.) and DEAD (354 mg, 2.03 mmol, 1.50 equiv.) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give 2-[1-(6-fluoro-1-methylindol-2-yl)-2-methylpropyl]isoindole-1,3-dione (2-b; 330 mg, 69%) as a yellow oil. MS (ESI): C 21 H 19 Calculated mass of FN2O2: 350.14, measured m / z: 351.10 [M+H] + .

[0445] Step 3 To a stirred solution of 2-[1-(6-fluoro-1-methylindol-2-yl)-2-methylpropyl]isoindole-1,3-dione (2-b; 280 mg, 0.80 mmol, 1.00 equiv.) in EtOH (5 mL) was added NH2NH2.HO (400 mg, 7.99 mmol, 10.00 equiv.). The resulting mixture was stirred at 80 °C under air for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with 1 M NaOH (1 × 20 mL), water (1 × 20 mL), brine (1 × 20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give 1-(6-fluoro-1-methylindol-2-yl)-2-methylpropan-1-amine (2-c; 170 mg, 96%) as a yellow oil. MS (ESI): C13 H 17 Calculated mass of FN2: 220.14, measured m / z: 221.15 [M+H] + .

[0446] Step 4 A solution of 1-(6-fluoro-1-methylindol-2-yl)-2-methylpropan-1-amine (2-c; 100 mg, 0.45 mmol, 1.00 equiv.) and phenyl N-(2-aminopyrimidin-5-yl)carbamate (125 mg, 0.54 mmol, 1.20 equiv.) in pyridine (2 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with 1 M HCl (1×20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 60% gradient in 30 min; detector, UV 254 nm to give 1-(2-aminopyrimidin-5-yl)-3-[1-(6-fluoro-1-methylindol-2-yl)-2-methylpropyl]urea (compound 2; 54.3 mg, 34%) as a pale yellow solid. MS (ESI): C 18 H 21 Calculated mass of FN6O: 356.18; measured m / z: 357.05 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.20(s,2H),8.09(s,1H),7.47(dd,J=8.6,5.5Hz,1H),7.30-7.27(m,1H),6.87-6.81(m,1H),6.73(d,J=9.0Hz,1H),6.3 6(s,1H),6.26(s,2H),4.79-4.75(m,1H),3.70(s,3H),2.16-2.08(m,1H),0.97(d,J=6.6Hz,3H),0.93(d,J=6.6Hz,3H).

[0447] Example 3: Preparation of Compound 3

[0448] [ka]

[0449] Step 1 A solution of (2,4-difluorophenyl)hydrazine (3-a; 1.8 g, 12.49 mmol, 1 equiv.) and dimethylpyruvic acid (1.89 g, 16.28 mmol, 1.30 equiv.) in EtOH (60 mL) was stirred at room temperature for 3 h. After the reaction was completed, the solvent was evaporated to give methyl (2Z)-2-[2-(2,4-difluorophenyl)hydrazin-1-ylidene]butanoate (3-b; 2.43 g, 80.33%) as a yellow semi-solid product.

[0450] Step 2 A solution of methyl (2Z)-2-[2-(2,4-difluorophenyl)hydrazin-1-ylidene]butanoate (3-b; 2.43 g, 10.00 mmol, 1 equiv.) and ZnCl (50.6 g, 371.6 mmol, 5 equiv.) in AcOH was stirred at 120 °C for 1 h. After the reaction was completed, the pH of the solution was adjusted to 8 with NaHCO, and the reaction mixture was then extracted with EA, washed with brine, and dried over anhydrous NaSO to give methyl 5,7-difluoro-3-methyl-1H-indole-2-carboxylate (3-c; 5 g, 30%) as a yellow solid.

[0451] Step 3 A solution of methyl 5,7-difluoro-3-methyl-1H-indole-2-carboxylate (3-c; 1.55 g, 6.88 mmol, 1 equiv.), CHI (4.88 g, 34.38 mmol, 5.00 equiv.), and CsCO (5.61 g, 17.21 mmol, 2.5 equiv.) in DMF (50 mL) was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water, extracted with EA, washed with brine, and dried over anhydrous NaSO to give the crude product. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 10 min; detector, UV 254 nm to give methyl 5,7-difluoro-1,3-dimethylindole-2-carboxylate (3-d; 1.325 g, 80%) as a yellow solid. MS(ESI):C 12 H 11 Calculated mass of F2NO2: 239.2, measured m / z: 240.0 [M+H] + .

[0452] Step 4 Methyl 5,7-difluoro-1,3-dimethylindole-2-carboxylate (3-d; 1.3 g, 5.43 mmol, 1 equiv.) and LiAlH (412.46 mg, 10.87 mmol, 2 equiv.) in THF (15 mL) were stirred at 0 °C to room temperature for 2 h. After the reaction was complete, the solution was quenched with NH Cl, extracted with ethyl acetate, washed with brine, and dried over anhydrous Na SO to give (5,7-difluoro-1,3-dimethylindol-2-yl)methanol (3-f; 1.1 g, 96%) as a yellow solid.

[0453] Step 5 A solution of (5,7-difluoro-1,3-dimethylindol-2-yl)methanol (3-f; 1.05 g, 4.97 mmol, 1 equiv.) and Dess-Martin periodinane (DMP; 3.16 g, 7.46 mmol, 1.5 equiv.) in DCM (50 mL) was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 (aq.) and filtered. The filtrate was extracted with DCM and then dried over anhydrous Na2SO4 to give the crude product, which was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 10 min; detector, UV 254 nm to give 5,7-difluoro-1,3-dimethylindole-2-carbaldehyde (3-g; 600 mg, 58%) as a yellow solid. MS (ESI): C 11 Calculated mass of H9F2NO: 209.2, measured m / z: 210.1 [M+H] + .

[0454] Step 6 A solution of 5,7-difluoro-1,3-dimethylindole-2-carbaldehyde (3-g; 607 mg, 2.90 mmol, 1 equiv.), KCO (802.03 mg, 5.80 mmol, 2 equiv.), and TMSCF (825.19 mg, 5.80 mmol, 2 equiv.) in DMF (10 mL) was stirred at room temperature overnight. After the reaction was complete, the reaction mixture was quenched with water, extracted with water, washed with brine, and diluted with anhydrous NaSO. 4, The mixture was dried at 40°C for 1 hour and concentrated under reduced pressure to give 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanol (3-h; 580 mg, 71.59%) as a pale yellow solid. MS (ESI): C 12 H 10 Calculated mass of F5NO: 279.2, measured m / z: 280.15 [M+H] + .

[0455] Step 7 A solution of 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanol (3-h; 2.1 g, 7.52 mmol, 1 equiv.) and DMP (4.79 g, 11.28 mmol, 1.5 equiv.) in DCM (70 mL) was stirred at room temperature for 4 hours. After the reaction was complete, the solution was quenched with saturated NaHCO (aq.) and filtered. The filtrate was extracted with DCM and dried over anhydrous NaSO to give the crude product, which was purified by reverse-phase flash chromatography to give 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanone (3-i; 1.8 g, 86%) as a yellow solid.

[0456] Step 8 A solution of 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanone (3-i; 831 mg, 3.00 mmol, 1 equiv.), NHOH.HCl (1041.62 mg, 14.99 mmol, 5 equiv.), and NaOAc (1229.65 mg, 14.99 mmol, 5 equiv.) in EtOH (30 mL) was stirred at 80 °C overnight. After the reaction was complete, the reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 254 nm to give (Z)-N-[1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine (3-j; 720 mg, 82%) as a yellow solid. MS(ESI):C 12 Calculated mass of H9F5N2O: 292.2; measured m / z: 293.0 [M+H] + .

[0457] Step 9 A solution of (Z)-N-[1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine (3-j; 643.3 mg, 2.20 mmol, 1 equiv.), Zn powder (1439.34 mg, 22.02 mmol, 10 equiv.), and NHCl (588.79 mg, 11.01 mmol, 5 equiv.) in EtOH (30 mL) and HO (10 mL) was stirred at 80 °C overnight. After the reaction was complete, the reaction mixture was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 10 min; detector, UV 254 nm to give 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanamine (3-k; 252 mg, 41%), a yellow solid. MS (ESI): C 12 H 11 Calculated mass of F5N2: 278.2, measured m / z: 262.05 [M-NH3+H] + .

[0458] Step 10 A solution of 1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethanamine (3-k; 132 mg, 0.47 mmol, 1 equiv.) in phenyl N-(2-aminopyrimidin-5-yl)carbamate (3 mL) was stirred overnight at 80° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and then purified by reverse-phase flash chromatography to give the crude product, which was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30 * Purification on a 150 mm 5 μm column (n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 47% B, 47% B in 8 min; wavelength: 254; 220 nm; RT1 (min): 7.65; injection volume: 1.5 mL) gave 35 mg of racemic product.

[0459] Step 11 The racemic product mixture from step 10 was purified by preparative chiral HPLC (column: (R,R)-WHELK-O1-Kromasi, 5* Purification by HPLC (25 cm, 5 μm column; mobile phase A: Hex (0.5% 2M NH3-MeOH) HPLC, mobile phase B: EtOH HPLC; flow rate: 20 mL / min; gradient: 40% B to 40% B in 13 min; wavelength: 220 / 254 nm; RT1 (min): 5.45; RT2 (min): 11.55; sample solvent: EtOH HPLC; injection volume: 2.65 mL; run number: 1) afforded 1-(2-aminopyrimidin-5-yl)-3-[(1R)-1-(5,7-difluoro-1,3-dimethylindol-2-yl)-2,2,2-trifluoroethyl]urea (compound 3; 19.8 mg, 10%) as an off-white solid. MS (ESI): C 17 H 15 Calculated mass of F5N6O: 414.3, measured m / z: 415.2 [M+H] + . 1 H NMR(400MHz,DMSO)δ 8.35(s,1H),8.22(s,1H),7.63(d,J=8.8Hz,1H),7.24(dd,J=2.4,8.2Hz,1H),7 .09-7.03(m,1H),6.39(s,2H),6.06(d,J=8.8Hz,1H),3.96(s,3H),2.33(s,3H).

[0460] Example 4: Preparation of Compound 4 and Compound 5

[0461] [ka]

[0462] Step 1 A solution of ethyl 3-methylpyrazolo[1,5-a]pyridine-2-carboxylate (4-a; 500 mg, 2.448 mmol, 1 equiv.) and LiAlH (92.91 mg, 2.448 mmol, 1 equiv.) in THF (10 mL, 61.714 mmol) was stirred at 0 °C for 30 min under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The reaction was quenched by adding sodium sulfate decahydrate (2 g) at 0 °C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 1 mL). The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (4 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1). The resulting mixture was concentrated under reduced pressure to give {3-methylpyrazolo[1,5-a]pyridin-2-yl}methanol (4-b; 260 mg, 65%) as a pale yellow solid. MS (ESI): CH 10 Calculated mass of NO: 162.1, measured m / z: 163.3 [M+H] + .

[0463] Step 2 A solution of {3-methylpyrazolo[1,5-a]pyridin-2-yl}methanol (4-b; 200 mg, 1.233 mmol, 1 equiv.) and DMP (1046.03 mg, 2.466 mmol, 2 equiv.) in DCM (10 mL) was stirred at room temperature for 3 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give 3-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (4-c; 160 mg, 81%) as a pale yellow solid. MS (ESI): mass calculated for CHNO 161.1, m / z found 161.2 [M+H]. + .

[0464] Step 3 To a 40 mL vial, 3-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (4-c; 400 mg, 2.497 mmol, 1 equiv.), trifluoromethyltrimethylsilane (1065.30 mg, 7.491 mmol, 3 equiv.), and THF (10 mL) were added at room temperature. The mixture was cooled to 0 °C, and TBAF (652.94 mg, 2.497 mmol, 1 equiv.) was added with stirring at 0 °C. The resulting mixture was stirred at room temperature for another 12 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3:1) to give 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanol) (4-d; 444 mg, 77%) as a pale yellow solid. MS (ESI): C 10 Calculated mass of H9F3N2O: 230.1, measured m / z: 231.2 [M+H] + .

[0465] Step 4 A solution of 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanol (4-d; 420 mg, 1.825 mmol, 1 equiv.) and DMP (1547.77 mg, 3.650 mmol, 2 equiv.) in DCM (10 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanone (4-e; 416 mg, 100%) as a yellow solid. MS (ESI): C 10 Calculated mass of H7F3N2O: 228.2, measured m / z: 247.2 [M+H+H2O] + .

[0466] Step 5 To a stirred solution of 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanone (4-e; 300 mg, 1.446 mmol, 1 equiv.) and NH2OH.HCl (502.50 mg, 7.230 mmol, 5 equiv.) in EtOH (20 mL) was added NaOAc (593.21 mg, 7.23 mmol, 5 equiv.) at room temperature under an air atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (4 × 1 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give (Z)-N-(2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethylidene)hydroxylamine (4-e; 180 mg, 56%) as a white solid. MS (ESI): C 10 Calculated mass of H8F3N3O: 243.2, measured m / z: 244.2 [M+H] + .

[0467] Step 6 To a stirred solution of (Z)-N-(2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethylidene)hydroxylamine (4-e; 150 mg, 0.617 mmol, 1 equiv.) and Zn powder (403.27 mg, 6.170 mmol, 10 equiv.) in EtOH (3 mL), NHCl (329.93 mg, 6.170 mmol, 10 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (4 × 1 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanamine (4-f; 80 mg, 57%) as a white solid. MS (ESI): C 10 H 10Calculated mass of F3N3: 229.2; measured m / z: 230.2 [M+H] + .

[0468] Step 7 A solution of 2,2,2-trifluoro-1-{3-methylpyrazolo[1,5-a]pyridin-2-yl}ethanamine (4-f; 100 mg, 0.436 mmol, 1 equiv.) and phenyl N-(2-aminopyrimidin-5-yl)carbamate (100.45 mg, 0.436 mmol, 1 equiv.) in pyridine (3 mL) was stirred at 80 °C under a nitrogen atmosphere for 4 hours. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (4 × 1, 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeCN (1 mL). The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 1, 1 mL). The filtrate was concentrated under reduced pressure to give the crude product (4-g, 50 mg) as an off-white solid. MS(ESI):C 15 H 14 Calculated mass of F3N7O: 365.1, measured m / z: 366.2 [M+H] + .

[0469] Step 8 50 mg of racemic 4-g was purified by chiral SFC to give compound 4 (9 mg as a white solid) and compound 5 (5 mg as a white solid). Chiral separation conditions: Equipment: SFC 80 Column: DZ-CHIRALPAK IG-3, 4.6 * 50mm, 3.0μm Mobile phase A: Hex (0.2% DEA): (EtOH:DCM = 1:1) = 70:30 Flow rate: 1mL / min Gradient: 0%B~0%B Injection volume: 5ul mL

[0470] Compound 4:MS(ESI):C 15 H 14Calculated mass of F3N7O: 365.1, measured m / z: 366.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.63(dt,J=7.0,1.1Hz,1H),8.43(s,1H),8.22(s,2H),7.70(dt,J=8.9,1.2Hz,1H),7.40(d,J=9.2Hz,1H),7. 24(ddd,J=9.0,6.7,1.0Hz,1H),6.94(td,J=6.9,1.4Hz,1H),6.37(s,2H),5.85(p,J=8.3Hz,1H),2.30(s,3H).

[0471] Compound 5:MS(ESI):C 15 H 14 Calculated mass of F3N7O: 365.1, measured m / z: 366.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.63(d,J=7.0Hz,1H),8.43(s,1H),8.22(s,2H),7.70(dd,J=9.0,1.3Hz,1H),7.40(d,J=9.2Hz,1H),7. 24(dd,J=9.0,6.7Hz,1H),6.94(td,J=6.8,1.4Hz,1H),6.37(s,2H),5.85(p,J=8.2Hz,1H),2.30(s,3H).

[0472] Example 5: Preparation of Compound 6 and Compound 7

[0473]

change

[0474] ステップ1 To a stirred solution of 1,3,5-trifluoro-2-nitrobenzene (6-a; 1.00 g, 5.65 mmol, 1.00 equiv.) and DIEA (2.19 g, 16.94 mmol, 3.00 equiv.) in THF (10 mL) was added methylamine hydrochloride (570 mg, 8.47 mmol, 1.50 equiv.) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 3,5-difluoro-N-methyl-2-nitroaniline (6-b; 1.05 g, 99%) as a yellow solid. MS (ESI): calculated mass for C7H6F2N2O2 188.04, found m / z 189.00 [M+H]. + .

[0475] Step 2 A mixture of 3,5-difluoro-N-methyl-2-nitroaniline (6-b; 1.05 g, 5.59 mmol, 1.00 equiv.), Fe powder (1.56 g, 27.95 mmol, 5.00 equiv.), and NHCl (1.50 g, 27.95 mmol, 5.00 equiv.) in EtOH (10 mL) and HO (2 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 3,5-difluoro-N1-methylbenzene-1,2-diamine (6-c; 890 mg, 88%) as a brown oil. MS (ESI): calculated mass for C7H8F2N2: 158.07, observed m / z: 159.05 [M+H] + .

[0476] Step 3 To an aqueous solution of HCl (10 mL) (4 M) and glycolic acid (481 mg, 6.32 mmol, 1.00 equiv.) was added 3,5-difluoro-N1-methylbenzene-1,2-diamine 6-c (1.00 g, 6.32 mmol, 1.00 equiv.), and the reaction mixture was refluxed overnight. The reaction mixture was cooled to 0 °C and then alkalized to pH = 8 with approximately 40% aqueous NaOH. The precipitated solid was collected by filtration and washed with water (3 × 30 mL) to give (4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)methanol (6-d; 1 g, 80%) as a gray solid. MS (ESI): calculated mass for CHFNO 198.06, found m / z 199.00 [M+H]. + .

[0477] Step 4 A mixture of (4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)methanol (6-d; 1.00 g, 5.05 mmol, 1.00 equiv.) and MnO (4.39 g, 50.46 mmol, 10.00 equiv.) in DCM (15 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give 4,6-difluoro-1-methyl-1,3-benzodiazol-2-carbaldehyde (6-e; 480 mg, 48%) as a yellow solid. MS (ESI): mass calculated for CHFNO 196.04, m / z found 197.00 [M+H]. + .

[0478] Step 5 To a solution of 4,6-difluoro-1-methyl-1,3-benzodiazole-2-carbaldehyde (6-e; 200 mg, 1.02 mmol, 1.00 equiv) in DCM (2 mL) was added CsCO (339 mg, 1.04 mmol, 1.02 equiv) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes, and then tert-butanesulfinamide (140 mg, 1.15 mmol, 1.13 equiv) was added. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE / EA (3:1) to give N-[(1E)-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)methylidene]-2-methylpropane-2-sulfinamide (6-f; 250 mg, 82%) as a pale yellow solid. MS (ESI): C 13 H 15 Calculated mass of F2N3OS: 299.09; measured m / z: 300.00 [M+H] + .

[0479] Step 6 To a solution of N-[(1E)-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)methylidene]-2-methylpropane-2-sulfinamide (6-f; 200 mg, 0.67 mmol, 1.00 equiv.) in THF (5 mL) was added difluorotriphenylsilanuide, tetrabutylammonium (361 mg, 0.67 mmol, 1.00 equiv.), and TMSCF (380 mg, 2.67 mmol, 4.000 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous NH Cl at 0 °C and then extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The crude N-[1-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide (6-g; 300 mg) was used directly in the next step without further purification as a yellow oil. MS (ESI): C 14 H 16Calculated mass of F5N3OS: 369.09; measured m / z: 370.10 [M+H] + .

[0480] Step 7 To a solution of N-[1-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide (6-g; 300 mg, 0.81 mmol, 1.00 equiv.) in EA (4 mL) was added HCl (2 mL) (4 M in EA) at 0° C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by silica gel column chromatography eluting with PE / EA (1:1) to give 1-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)-2,2,2-trifluoroethanamine (6-h; 60 mg, 28%) as a pale yellow solid. MS (ESI): C 10 Calculated mass of H8F5N3: 265.06, measured m / z: 266.05 [M+H] + .

[0481] Step 8 A solution of 1-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)-2,2,2-trifluoroethanamine (6-h; 60 mg, 0.23 mmol, 1.00 equiv) and phenyl N-(2-aminopyrimidin-5-yl)carbamate (53 mg, 0.23 mmol, 1.00 equiv) in pyridine (1.5 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to give 1-(2-aminopyrimidin-5-yl)-3-[1-(4,6-difluoro-1-methyl-1,3-benzodiazol-2-yl)-2,2,2-trifluoroethyl]urea (6-i; 60 mg, 66%) as a pale yellow solid. MS (ESI): C 15 H 12 Calculated mass of F5N7O: 401.10, measured m / z: 402.10 [M+H]+ .

[0482] ステップ9 60 mg of the compound 6-iをキラルHPLC was separated and the compound 6 (white solid 22.8 mg) and compound 7 (white solid 18.0 mg) were obtained. Korra separation conditions: Device: fractionation HPLC-037 カラム:CHIRALPAK IG、2 * 25cm, 5μm Mobile phase: Mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile phase B: EtOH: DCM = 1:1-HPLC Flow rate: 20mL / min Wavelength: UV220 / 254nm Temperature: 25℃

[0483] Compound 6:MS(ESI):C 15 H 12 The calculated mass value of F5N7O is 401.10, and the measured m / z value is 402.10[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 8.41(s,1H),8.22(s,2H),7.71(d,J=9.1Hz,1H),7.50(dd,J=8.9,2.3Hz,1H) ,7.18(td,J=10.6,2.3Hz,1H),6.39(s,2H),6.27-6.13(m,1H),3.89(s,3H).

[0484] Compound 7:MS(ESI):C 15 H 12 The calculated mass value of F5N7O is 401.10, and the measured m / z value is 402.10[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 8.42(s,1H),8.22(s,2H),7.71(d,J=9.1Hz,1H),7.50(dd,J=9.0,2.2Hz,1H), 7.18(td,J=10.6,2.2Hz,1H),6.40(s,2H),6.21(p,J=7.2Hz,1H),3.89(s,3H).

[0485] Example 6: Preparation of Compound 8 and Compound 9

[0486] [ka]

[0487] Step 1 To a stirred solution of 4,6-difluoro-1H-indole-2-carboxylic acid (8-a; 2.00 g, 10.15 mmol, 1.00 equiv.) and KCO (4.21 g, 30.44 mmol, 3.00 equiv.) in DMF (20 mL) was added CHCl (2.53 mL, 40.58 mmol, 4.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The solution was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with saturated NHCl (aq.) at 0° C. The precipitated solid was collected by filtration and washed with water (1×50 mL). The resulting methyl 4,6-difluoro-1-methylindole-2-carboxylate (8-b; 2.1 g, 92%) was obtained as a white solid. MS (ESI): C 11 Calculated mass of H9F2NO2: 225.06, measured m / z: 226.15 [M+H] + .

[0488] Step 2 To a stirred solution of methyl 4,6-difluoro-1-methylindole-2-carboxylate (8-b; 1.00 g, 4.44 mmol, 1.00 equiv.) in THF (5 mL) was added LiAlH (solution in THF; 5.33 mL, 5.33 mmol, 1.20 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The solution was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched with sodium sulfate decahydrate at 0° C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1×100 mL). The filtrate was concentrated under reduced pressure to give (4,6-difluoro-1-methylindol-2-yl)methanol (8-c; 895 mg) as a white solid. The crude product was used directly in the next step without further purification. MS (ESI): C 10 Calculated mass of H9F2NO: 197.07, measured m / z: 198.15 [M+H]+ .

[0489] Step 3 To a stirred solution of (4,6-difluoro-1-methylindol-2-yl)methanol (8-c; 850 mg, 4.31 mmol, 1.00 equiv.) in DCM (10 mL) was added MnO (7.50 g, 86.22 mmol, 2.00 equiv.) portionwise under a nitrogen atmosphere at 0° C. The solution was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1×100 mL). The filtrate was concentrated under reduced pressure to give 4,6-difluoro-1-methylindole-2-carbaldehyde (8-d; 880 mg) as a white solid. The crude product was used directly in the next step without further purification. MS (ESI): C 10 Calculated mass of H7F2NO: 195.05, measured m / z: 196.00 [M+H] + .

[0490] Step 4 To a stirred solution of 4,6-difluoro-1-methylindole-2-carbaldehyde (8-d; 895 mg, 4.59 mmol, 1.00 equiv.) and K2CO3 (1.90 g, 13.76 mmol, 3.00 equiv.) in DMF (10 mL) was added TMSCF3 (1.30 g, 9.17 mmol, 5 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The solution was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with TBAF at 0 °C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanol (8-e; 1.02 g, 84%) as a yellow oil. MS (ESI): C 11 Calculated mass of H8F5NO: 265.05, measured m / z: 266.00 [M+H] + .

[0491] Step 5 To a stirred solution of 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanol (8-e; 1.02 g, 3.85 mmol, 1.00 equiv) in EA (10 mL) was added IBX (2.15 g, 7.69 mmol, 2.00 equiv) portionwise at 0 °C under a nitrogen atmosphere. The solution was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by TLC. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE, to give 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanone (8-f; 910 mg, 90%) as a white solid.

[0492] Step 6 To a stirred solution of 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanone (8-f; 850 mg, 3.23 mmol, 1.00 equiv.) and AcONa (1.32 g, 16.15 mmol, 5.00 equiv.) in EtOH (8 mL), NH2OH.HCl (1.12 g, 16.15 mmol, 5.00 equiv.) was added portionwise at 0 °C under a nitrogen atmosphere. The solution was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 5:1) to give (E)-N-[1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine (8-g; 890 mg, 99%) as a yellow solid. MS (ESI): C 11 Calculated mass of H7F5N2O: 278.05; measured m / z: 277.00 [M+H] + .

[0493] Step 7 To a stirred solution of (E)-N-[1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethylidene]hydroxylamine (8-g; 850 mg, 3.06 mmol, 1.00 equiv.) and NH4Cl (1.63 g, 30.56 mmol, 10.00 equiv.) in EtOH (7 mL) and HO (1.4 mL), Zn powder (1.99 g, 30.56 mmol, 10.00 equiv.) was added portionwise at 0 °C under a nitrogen atmosphere. The solution was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (1 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanamine (8-h; 610 mg, 75.56%) as a brown solid. MS (ESI): C 11 Calculated mass of H9F5N2: 264.07, measured m / z: 248.00 [M-NH4+H] + .

[0494] Step 8 To a stirred solution of 1-(4,6-difluoro-1-methylindol-2-yl)-2,2,2-trifluoroethanamine (8-h; 400 mg, 1.51 mmol, 1.00 equiv) in pyridine (4 mL) was added phenyl N-(2-aminopyrimidin-5-yl)carbamate (523 mg, 2.27 mmol, 1.50 equiv) in portions at 0° C. under a nitrogen atmosphere. The solution was stirred at 80° C. under a nitrogen atmosphere for 1 day. The reaction was monitored by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, 10% to 50% gradient in 20 min; detector: UV 254 nm) to give 1-(2-aminopyrimidin-5-yl)-3-[1-(4,6-difluoro-1-methylindol-2-yl)]-2,2,2-trifluoroethyl]urea (8-i; 350 mg, 58%) as a white solid. MS (ESI): C 16 H 13 Calculated mass of F5N6O: 400.11, measured m / z: 401.05 [M+H]+ .

[0495] Step 9 Racemic 8-i (350 mg) was separated by chiral HPLC to give compound 8 (114.4 mg as a white solid) and compound 9 (105.7 mg as a white solid). Column: CHIRALPAK IG, 2 * 25 cm, 5 μm; Mobile phase A: Hex (0.2% TEA)-HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; Flow rate: 20mL / min; Gradient: 30%B to 30%B in 11 min; Wavelength: 220 / 254nm; RT1(min):5.64;RT2(min):8.04; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.65mL; Number of runs: 20

[0496] Compound 8:MS(ESI):C 16 H 13 Calculated mass of F5N6O: 400.11, measured m / z: 401.05 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.22(s,2H),8.07(s,1H),7.62(d,J=9.3Hz,1H),7.36-7.31(m,1H),6.93- 6.92(m,1H),6.69(s,1H),6.40(s,2H),6.02(p,J=7.9Hz,1H),3.76(s,3H).

[0497] Compound 9:MS(ESI):C 16 H 13 Calculated mass of F5N6O: 400.11, measured m / z: 401.10 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.22(s,2H),8.07(s,1H),7.62(d,J=9.3Hz,1H),7.36-7.31(m,1H),6.93- 6.92(m,1H),6.69(s,1H),6.40(s,2H),6.02(p,J=8.0Hz,1H),3.76(s,3H).

[0498] Example 7: Preparation of Compound 10 and Compound 11

[0499] [ka]

[0500] Step 1 A solution of 5-fluoropyridin-2-amine (10-a; 10 g, 89.200 mmol, 1 equiv.) and methyl 3-bromo-2-oxobutanoate (16.70 g, 85.632 mmol, 0.96 equiv.) in DME was stirred overnight at room temperature under air. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with DME (3 × 5 mL). This gave methyl 3-(5-fluoro-2-iminopyridin-1-yl)-2-oxobutanoate (10-b; (19 g, 94%)) as an off-white solid. MS (ESI): C 10 H 11 Calculated mass of FN2O3: 226.1, measured m / z: 227.1 [M+H] + .

[0501] Step 2 A solution of methyl 3-(5-fluoro-2-iminopyridin-1-yl)-2-oxobutanoate 10-b (19 g) in MeOH (20 mL) was stirred at 75° C. for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (10-c) was used directly in the next step without further purification. MS (ESI): C 10 Calculated mass of H9FN2O2: 208.1, measured m / z: 209.1 [M+H] + .

[0502] Step 3 To a stirred mixture of methyl 6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (10-c; 16.4 g, 78.773 mmol, 1 equiv.) in THF was added LiBH (59.1 mL, 118.162 mmol, 1.5 equiv.) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give {6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}methanol (10-d; 13 g). The crude product was used directly in the next step without further purification. MS (ESI): mass calculated for C9H9FN2O 180.1, m / z found 181.1 [M+H] + .

[0503] Step 4 A solution of 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanol (10-d; 3 g, 12.086 mmol, 1 equiv.) and DMP (7.687 g, 18.134 mmol, 1.5 equiv.) in DCM was stirred at room temperature under air for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 100 mL). The filtrate was concentrated under reduced pressure to give 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanone (10-e; 1.8 g) as a brown solid, which was used crude in the next step. MS (ESI): mass calculated for CHFNO 178.1, m / z found 179.1 [M+H]. + .

[0504] Step 5 6-Fluoro-3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (10-e; 1.13 g, 6.342 mmol, 1 equiv.) in DMF was treated with KCO (876.55 mg, 6.342 mmol, 1 equiv.) under a nitrogen atmosphere at 0 °C, followed by the portionwise addition of TMSCF (1.80 g, 12.684 mmol, 2 equiv.). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanol (10-f; 720 mg, 46%) as a brown solid. MS (ESI): C 10 Calculated mass of H8F4N2O: 248.1, measured m / z: 249.1 [M+H] + .

[0505] Step 6 A solution of 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanol (10-f; 250 mg, 1.007 mmol, 1 equiv.) and DMP (854.50 mg, 2.014 mmol, 2 equiv.) in DCM was stirred at room temperature under air for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeCN (1 × 50 mL). The filtrate was concentrated under reduced pressure. This afforded 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanone (10-g; 250 mg, 100%) as a brown solid. MS (ESI): C 10 Calculated mass of H6F4N2O: 246.0, measured m / z: 247.0 [M+H] + .

[0506] Step 7 To a stirred mixture of (3-chlorophenyl)[1-(trifluoromethyl)cyclopropyl]methanone (10-g; 650 mg, 2.614 mmol, 1 equiv.) and hydroxylamine hydrochloride (908.35 mg, 13.070 mmol, 5 equiv.) in EtOH was added AcONa (1072.32 mg, 13.070 mmol, 5 equiv.) portionwise at 100° C. under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 4 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This afforded (E)-N-(2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethylidene)hydroxylamine (10-h; 150 mg, 100.98%) as a brown solid. MS (ESI): C 10 Calculated mass of H7F4N3O: 261.1, measured m / z: 262.1 [M+H] + .

[0507] Step 8 A solution of (E)-N-(2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethylidene)hydroxylamine (10-h; 500 mg, 1.91 mmol, 1 equiv.) and NH4Cl (1024.01 mg, 19.140 mmol, 10 equiv.) and Zn (1251.63 mg, 19.14 mmol, 10 equiv.) in EtOH was stirred overnight at 80 °C under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, gradient from 0% to 100% in 30 min; detector, UV 254 nm. This gave 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanamine (10-i; 200 mg, 42%) as a brown oil. MS (ESI): C 10 Calculated mass of H9F4N3: 247.1; measured m / z: 248.1 [M+H] + .

[0508] Step 9 A solution of 2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethanamine (10-i; 150 mg, 0.607 mmol, 1 equiv.) and phenyl N-(2-aminopyrimidin-5-yl)carbamate (139.70 mg, 0.607 mmol, 1 equiv.) in pyridine was stirred overnight at 80 °C under air atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CHCl / MeOH 15:1) to give 1-(2-aminopyrimidin-5-yl)-3-(2,2,2-trifluoro-1-{6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl}ethyl)urea (10-j; 15 mg, 6.45%) as an off-white solid. MS(ESI):C 15 H 13 Calculated mass of F4N7O: 383.1, measured m / z: 384.1 [M+H] + .

[0509] Step 10 Racemic 10-j (20 mg) was purified by chiral SFC to give compound 10 (5.5 mg as an off-white solid) and compound 11 (5.5 mg as a white solid). Chiral separation conditions: Column: DZ-CHIRALPAK IG-3, 4.6 * 50mm, 3.0μm Mobile phase A: Hex (0.2% DEA):EtOH = 50:50 Flow rate: 1mL / min Injection volume: 5ul mL

[0510] Compound 10:MS(ESI):C 15 H 13 Calculated mass of F4N7O: 383.1, measured m / z: 384.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.28 (s, 2H), 7.86 (s, 2H), 7.52 (s, 1H), 7.20 (s, 2H), 5.89 (s, 2H), 5.05 (s, 1H), 2.54 (s, 3H).

[0511] Compound 11:MS(ESI):C 15 H 13 Calculated mass of F4N7O: 383.1, measured m / z: 384.1 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 8.28(s,2H),7.85(s,2H),7.50(dd,J=9.4,4.9Hz,1H),7.20(d,J=9.7Hz,2H),5.87(q,J=7.8Hz,2H),5.04(s,1H),2.53(s,3H).

[0512] Assay ADP-Glo Compounds were plated on the Echo 655T using acoustic liquid dispensing by transferring 50 nL / well of compound DMSO solution from the Echo source plate to a 384-well assay plate to generate a 10-point dose-response curve with a maximum final concentration of 10 μM and 1:3 serial downward dilutions. The same volume of DMSO was dispensed into wells designated as positive and negative controls. On the day of the assay, a 2× enzyme solution was prepared in assay buffer (50 mM Tris, 150 mM NaCl, 0.01% Brij35, 15 mM MgCl2, 0.05% Tween-20, and 1 mM DTT). The enzyme concentrations used were 20 nM for wild-type, 2 nM for H1047R and H1047L, and 10 nM for H1047Y protein. 2.5 μL / well of 2x enzyme solution was dispensed into the assay plate, and the enzyme was incubated with the test compound for 1 hour at room temperature. An equal volume of assay buffer without enzyme was dispensed into wells designated as positive controls. At the end of the incubation, the ATPase reaction was initiated by dispensing 2.5 μL / well of 2x ATP solution in assay buffer and incubated for 100 minutes at room temperature. The reaction was terminated, and ADP production was measured using the ADP-Glo ​​kit according to the manufacturer's instructions. See Table 3.

[0513] The biological activity of certain compounds using the above assays is shown in Table 3. IC50 The ranges (nM) are as follows: A indicates <200 nM, B indicates 200 nM ≤ IC 50 indicates <500 nM, C indicates ≥ 500 nM. ND indicates a value not determined in that assay for a particular compound.

[0514] [Table 4]

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 9-membered heteroaryl group, and Ring B is not 2-benzofuranyl or 2-indolyl; Each R １ is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R ２ is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R ３ is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R ４ But independently, (i) halogen, (ii) optionally one or two hydroxyl or -NR Ａ R Ｂ C1-C6 alkyl substituted with (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii)-CO ２ H、 ())) Ａ ( Ｂ 、 (i8)=NR Ａ２ 、 (x)-C(=O)NR Ｃ R Ｄ 、 (xi)-SO ２ (NR Ｅ R Ｆ )、 (xii) -SO ２ (C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) —CO ２ (C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) optionally one or two independently selected R Ｇ 3- to 9-membered heterocyclyl substituted with (xviii) optionally one or two independently selected R Ｇ C3-C6 cycloalkyl substituted with n is 0, 1, or 2; Each R Ａ , R Ａ１ , R Ｂ , R Ｂ１ , R Ｃ , R Ｃ１ , R Ｄ , R Ｄ１ , R Ｅ , and R Ｆ But independently, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO ２ (C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, or (ix) optionally hydroxyl, —C(═O)NR Ｂ２ R Ｃ２ , 5-6 membered heteroaryl, C3-C6 cycloalkyl, —SO ２ (C1-C6 alkyl), —CO ２ H, and -SO ２ (NH ２ or C1-C6 alkyl substituted with 1-2 substituents independently selected from R Ｃ and R Ｄ together with the nitrogen atom to which they are attached, optionally hydroxyl, halogen, —C(═O)NR Ｂ１ R Ｃ１ , -SO ２ (C1-C6 alkyl), —CO ２ forming a 4-10 membered heterocyclyl substituted by 1-2 substituents independently selected from H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R Ａ２ , R Ｂ２ , and R Ｃ２ are independently hydrogen or C1-C6 alkyl; Each R Ｇ are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, —NR Ａ１ R Ｂ１ , =NR Ａ２ , —C(═O)NR Ｃ１ R Ｄ１ , -CO ２ (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO ２ (C1-C6 alkyl), and —CO ２ H or a pharmaceutically acceptable salt thereof. 【Request 2】 【Chemical 2】 but, 【Chemistry 3】 2. The compound of claim 1, wherein: 【Request 3】 【Chemical 4】 but, 【Chemistry 5】 3. The compound of claim 2, wherein: 【Request 4】 【Chemical 6】 but, 【Chemistry 7】 3. The compound of claim 2, wherein:

5. 【Chemical 8】 but, 【Chemistry 9】 3. The compound of claim 2, wherein:

6.

10. but, 【Chemistry 11】 3. The compound of claim 2, wherein:

7. The compound according to any one of claims 1 to 6, wherein m is 1.

8. The compound according to any one of claims 1 to 6, wherein m is 2.

9. Each R １ The compound according to any one of claims 1 to 8, wherein is halogen.

10. Each R １ A compound according to any one of claims 1 to 9, wherein is selected from fluoro and chloro.

11. Each R １ The compound of any one of claims 1 to 10, wherein is fluoro.

12. Each R １ The compound of any one of claims 1 to 8, wherein is hydroxyl.

13. 1 R １ The compound of any one of claims 1 to 8, wherein is cyano.

14. 1 R １ The compound of any one of claims 1 to 8, wherein is C1-C6 alkyl optionally substituted with hydroxyl.

15. 1 R １ The compound according to any one of claims 1 to 8, wherein is C3-C6 cycloalkyl.

16. The compound according to any one of claims 1 to 6, wherein m is 0.

17. R ２ The compound of any one of claims 1 to 16, wherein is C1-C6 alkyl optionally substituted with hydroxyl.

18. R ２ The compound of any one of claims 1 to 17, wherein is unsubstituted C1-C6 alkyl.

19. R ２ 19. The compound of claim 18, wherein is methyl.

20. R ２ The compound of any one of claims 1 to 16, wherein is C1-C6 haloalkyl.

21. R ２ 21. The compound of claim 20, wherein is difluoromethyl.

22. R ２ 21. The compound of claim 20, wherein is trifluoromethyl.

23. R ２ The compound of any one of claims 1 to 16, wherein is halogen.

24. R ２ The compound of any one of claims 1 to 16, wherein is hydroxyl.

25. R ２ The compound of any one of claims 1 to 16, wherein is a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro.

26. R ３ The compound of any one of claims 1 to 25, wherein is C1-C6 haloalkyl.

27. R ３ The compound of any one of claims 1 to 26, wherein is difluoromethyl.

28. R ３ The compound of any one of claims 1 to 26, wherein is trifluoromethyl.

29. R ３ The compound of any one of claims 1 to 25, wherein is C1 to C6 alkyl.

30. R ３ The compound of any one of claims 1 to 25 and 29, wherein is Me, Et, or iPr.

31. R ３ is a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl.

32. The compound of any one of claims 1 to 31, wherein Ring A is a 5- to 10-membered heteroaryl.

33. The compound of any one of claims 1 to 32, wherein Ring A is a 5- to 6-membered heteroaryl.

34. The compound of any one of claims 1 to 33, wherein Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl.

35. The compound of any one of claims 1 to 34, wherein Ring A is pyrimidinyl.

36. The compound of any one of claims 1 to 34, wherein ring A is pyridyl.

37. The compound of any one of claims 1 to 34, wherein Ring A is thiazolyl.

38. The compound of any one of claims 1 to 34, wherein ring A is thiophenyl.

39. The compound of any one of claims 1 to 34, wherein Ring A is pyrazolyl.

40. The compound of any one of claims 1 to 32, wherein Ring A is a 9- to 10-membered heteroaryl.

41. 41. The compound of any one of claims 1 to 32 and 40, wherein ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, or imidazo[1,2-a]pyridinyl.

42. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is benzimidazolyl.

43. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is indazolyl.

44. The compound of any one of claims 1 to 32 and 40 to 41, wherein ring A is indolyl.

45. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is quinazolone.

46. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is isobenzofuranonyl.

47. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is isoindolinonyl.

48. The compound according to any one of claims 1 to 32 and 40 to 41, wherein ring A is imidazo[1,2-a]pyridinyl.

49. The compound of any one of claims 1 to 31, wherein ring A is a 6- to 10-membered aryl.

50. 50. The compound of any one of claims 1 to 31 and 49, wherein ring A is phenyl.

51. The compound of any one of claims 1 to 31, wherein Ring A is C3-C8 cycloalkyl.

52. The compound of any one of claims 1 to 31, wherein Ring A is a 4- to 10-membered heterocyclyl.

53. 53. The compound of any one of claims 1 to 31 and 52, wherein Ring A is a 4- to 6-membered heterocyclyl.

54. 54. The compound of any one of claims 1 to 53, wherein n is 1.

55. 54. The compound of any one of claims 1 to 53, wherein n is 2.

56. 1 R ４ is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

57. 1 R ４ The compound of any one of claims 1 to 55, wherein is C1-C6 haloalkyl.

58. 1 R ４ is hydroxyl, cyano, -CO ２ H, halogen, or optionally 1 to 2 hydroxyl or -NR Ａ R Ｂ 56. The compound of any one of claims 1 to 55, wherein the compound is C1-C6 alkyl substituted with

59. 1 R ４ But, -NR Ａ R Ｂ , =NR Ａ２ , —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), or —CO ２ (C1-C6 alkyl).

60. 1 R ４ 56. The compound of any one of claims 1 to 55, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

61. 1 R ４ optionally one or two independently selected R Ｇ 56. The compound of any one of claims 1 to 55, which is a 3- to 9-membered heterocyclyl substituted with

62. 1 R ４ optionally one or two independently selected R Ｇ 56. The compound of any one of claims 1 to 55, wherein the compound is a C3-C6 cycloalkyl substituted with

63. 54. The compound of any one of claims 1 to 53, wherein n is 0.

64. A compound selected from the group consisting of the compounds of Table A or a pharmaceutically acceptable salt thereof.

65. 65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

66. 66. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65.

67. 66. 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 PI3Kα protein, or the expression or activity or level of any of them; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65.

68. A method for treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 65.

69. 65. A method for modulating PI3Kα in a mammalian cell, comprising contacting said mammalian cell with an effective amount of a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

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