PI3k degraders and methods of using same

Abstract

This disclosure provides compounds of Formula (X), and pharmaceutically acceptable salts thereof, that reduce levels of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), as well as methods of making and using same, and compositions comprising Formula (X), and pharmaceutically acceptable salts thereof.

Description

Attorney Docket No.31457_WO PI3K DEGRADERS AND METHODS OF USING SAME TECHNICAL FIELD

[0001] This disclosure provides compounds of Formula (X), and pharmaceutically acceptable salts thereof, that reduce levels of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), as well as methods of making and using same, and compositions comprising Formula (X), and pharmaceutically acceptable salts thereof. BACKGROUND

[0002] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene is a part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several investigators have demonstrated the role of PI3K / AKT signaling is involved in physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis and metastasis. (See, Fruman, D.A. Cell 2017, 170, 605–635 and Janku, F. et al., Nat. Rev. Clin. Oncol.2018, 15, 273–291.) Suppression of PI3K / AKT / TOR signaling may cause cancer cell death and regression of tumor growth.

[0003] The PI3K pathway can be activated via, for example, point mutation(s) of the PIK3CA gene or via inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30–50% human cancers and contributes to resistance to various anti-cancer therapies. (See, Martini, M. et al., Ann. Med. 2014, 46, 372–383 and Bauer, T.M. et al., Pharmacol. Ther. 2015, 146, 53–60.) PI3K consists of three subunits: p85 regulatory subunit, p55 regulatory subunit, and p110 catalytic subunit. According to their different structures and specific substrates, PI3K is divided into 3 classes: classes I, II, and III. Class I PI3Ks include class IA and class IB PI3Ks. Class IA PI3K, a heterodimer of p85 regulatory subunit and p110 catalytic subunit, is the type most clearly implicated in human cancer. Class IA PI3K includes p110α, p110β and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. PIK3CA, the gene encoding the p110α subunit, is frequently mutated or amplified in many human cancers, such as breast cancer, colon cancer, gastric cancer, cervical cancer, prostate cancer, and lung cancer. (See, Samuels Y, et al. Science. 2004;304:554.)

[0004] However, the development of PI3K inhibitors has been problematic for several reasons including (i) adaptive molecular mechanisms upon therapeutic inhibition of PI3K, (ii) inability to 1Attorney Docket No.31457_WO specifically inhibit signaling by PIK3CA mutations while sparing endogenous p110α, (iii) the limited use of these therapies in rational combinations, including those informed with strong mechanistic support, and (iv) dose-limiting toxicities that prevent sustained PI3K pathway suppression. (See, Hanker et al., 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 benefit of alpelisib is limited by wild-type PI3Kα inhibition in normal tissues, resulting in dose-limiting toxicities including hyperglycemia.

[0005] Additionally, there are other factors and compensatory pathways derived from both clinical and in vitro lab studies, which affect PI3K signaling, such as HRAS and KRAS mutations, which reduce susceptibility to PI3K inhibitors (and knockdown of these has shown to improve sensitivity to PI3K inhibitors). (See, Misrha, R.; Int. J. Mol. Sci. 2021, 22, 3464.)

[0006] Domain deletions in PIK3CA can activate PI3K signaling significantly and also enhance the sensitivity to PI3K inhibitors. (See, Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426– 1435.) Thus, targeting PI3Kα represents an approach for the treatment of proliferative disorders such as cancer. SUMMARY

[0007] Some embodiments provide a compound of Formula (X): (Formula (I))-Linker- PTM or a pharmaceutically acceptable salt thereof, wherein: PTM is a cereblon binding moiety, a VHL binding moiety, an RNF126 binding moiety, or a covalent E3 ligase binding moiety;

[0008] Linker is a covalent bond or a C1-C50 alkylene; wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, – P(=O)(RK1)–, –P(=O)N(RK1)–, -S-, -C(=O)-, -S(=O)-, -S(O)2-, -N(RK1)S(O)2-, -S(O)2N(RK1)-, - ndp y y g , g , y y , y ,K1B,-NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; 2Attorney Docket No.31457_WO or two RK1attached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK1Ais independently halogen, hydroxyl, cyano, -C(=O)ORK1B, -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; or two RK1Aattached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK2is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted phenylene, or an optionally substituted 5-10 membered heteroarylene; each RK1Band RK1Care independently selected from hydrogen and an optionally substituted C1-C6 alkyl, or RK1Band RK1Ctogether with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; and Formula (I) is I)Ring B is a 9-membered heteroaryl group; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, C3-C6 cycloalkyl, and Linker-PTM; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, Linker-PTM, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R3is C1-C6 alkyl, C1-C6 haloalkyl, Linker-PTM, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; 3Attorney Docket No.31457_WO each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, = RCRD, ,(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) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, (xviii) C3-C6 cycloalkyl optionally substituted with 1 or 2 independently selected RG, and (xix) Linker-PTM; and wherein one of (ii), (iii), (iv), (ix), (xii), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii) are further optionally substituted with linker-PTM; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(=O)(C1-C6 alkyl), 4Attorney Docket No.31457_WO (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) C3-C6 cycloalkyl optionally substituted with hydroxyl, (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, C3-C6 cycloalkyl, -SO2(C1-C6 alkyl), - CO2H, and -SO2(NH2), or (x) Linker-PTM; or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; and wherein one of R1, R2, R3, R4or a substituent of R4, RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis Linker-PTM.

[0009] Also provided herein is a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0010] Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0011] 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 a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 5Attorney Docket No.31457_WO

[0012] Provided herein is a method of 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 (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0013] This disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising: determining that the 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 (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0014] Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα- associated cancer a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0015] This 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 (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0016] Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same.

[0017] This disclosure also provides a method for reducing PI3Kα protein levels in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof.

[0018] Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions

[0019] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in 6Attorney Docket No.31457_WO organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, 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 that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0020] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0021] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0022] The term "inhibit" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0023] “API” refers to an active pharmaceutical ingredient.

[0024] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0025] 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 a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice 7Attorney Docket No.31457_WO of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0026] 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 biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: 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; acidic amino acids such as aspartic acid and glutamic acid.

[0027] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the 8Attorney Docket No.31457_WO compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0028] As used herein, the terms "subject," "individual," or "patient," are used interchangeably, refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.

[0029] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0030] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0031] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0032] The term "hydroxyl" refers to an -OH radical.

[0033] The term "cyano" refers to a -CN radical.

[0034] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0035] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0036] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon 9Attorney Docket No.31457_WO tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0037] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: 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, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just 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, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0038] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- 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 (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either 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, thiazolyl benzothienyl, 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, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, 10Attorney Docket No.31457_WO benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more .g., o aryl ring).

[0039] The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- 11Attorney Docket No.31457_WO 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, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just 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.

[0040] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0041] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0042] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms 12Attorney Docket No.31457_WO (e [xx 0] rin s stems in which 0 re resents a zero atom brid e (e )) (ii) a iii)a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.). ing up the compounds of the present embodiments are intended to includeall isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0043] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, 13Attorney Docket No.31457_WO phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido.

[0044] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiet . Similarly, apyrimidinyl moiety that is described to be optionallywith hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0045] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0046] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION

[0047] This disclosure provides compounds of Formula (X) and pharmaceutically acceptable salts thereof, that degrade phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, e.g., for treating a condition, disease or disorder in 14Attorney Docket No.31457_WO 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). This disclosure also provides compositions containing the same as well as methods of using and making the same. Compounds of Formula (X)

[0048] Provided herein are compounds of Formula (X): (Formula (I))-Linker-PTM or a pharmaceutically acceptable salt thereof, wherein: PTM is a cereblon binding moiety, a VHL binding moiety, an RNF126 binding moiety, or a covalent E3 ligase recruiter; Linker is a covalent bond or a C1-C50 alkylene; wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, – P(=O)(RK1)–, –P(=O)N(RK1)–, -S-, -C(=O)-, -S(=O)-, -S(O)2-, -N(RK1)S(O)2-, -S(O)2N(RK1)-, - N(RK1)S(O)2N(RK1)-, -N(RK1)C(=O)-, -C(=O)N(RK1)-, -OC(=O)N(RK1)-, -N(RK1)C(=O)O-, and RK2; each RK1is independently hydrogen, halogen, hydroxyl, cyano, -C(=O)ORK1B, -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; or two RK1attached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK1Ais independently halogen, hydroxyl, cyano, -C(=O)ORK1B, -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; or two RK1Aattached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK2is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted phenylene, or an optionally substituted 5-10 membered heteroarylene; 15Attorney Docket No.31457_WO each RK1Band RK1Care independently selected from hydrogen and an optionally substituted C1-C6 alkyl, or RK1Band RK1Ctogether with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; and Formula (I) is I)Ring B is a 9-membered heteroaryl group; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, C3-C6 cycloalkyl, and Linker-PTM; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, Linker-PTM, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R3is C1-C6 alkyl, C1-C6 haloalkyl, Linker-PTM, or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, 6Attorney Docket No.31457_WO (xi) -SO2(NRERF), (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) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, (xviii) C3-C6 cycloalkyl optionally substituted with 1 or 2 independently selected RG, (xix) Linker-PTM; and wherein (ii), (iii), (iv), (ix), (xii), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii) are further optionally substituted with linker-PTM; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 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, (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, C3-C6 cycloalkyl, -SO2(C1-C6 alkyl), - CO2H, and -SO2(NH2), or (x) Linker-PTM; or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; 17Attorney Docket No.31457_WO each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; and wherein one of R1, R2, R3, R4or a substituent of R4, RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis Linker-PTM. of , , , , of nts,Attorney Docket No.31457_WO , me , , me , of ,Attorney Docket No.31457_WO ,

[0052] In some embodiments, is selected from the group consisting ofmeembodiments, s selected from the group consisting o ,, , meembodiments, s selected from the group consisting ,20Attorney Docket No.31457_WO , of , tedfrom the group consisting andis selected from the group, , meAttorney Docket No.31457_WO , , , up and up , , me ,Attorney Docket No.31457_WO , , nts, , , InAttorney Docket No.31457_WO of , , ,,, ,Attorney Docket No.31457_WO , of ts, ted . ,p y . 25Attorney Docket No.31457_WO ts, , the ndB are independently selected from R1.nts, , theg p g 26Attorney Docket No.31457_WO and, wherein R1Aand R1Bare independently selected from R1.nts, . nts, . nts,Attorney Docket No.31457_WO nts,1) ereof, wherein:Z is O or NRx; Rxis hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or Linker-PTM; and R1, R2, R3, R4, RA, m and Ring A are as described herein. In some embodiments, the compound of Formula (X) is Formula (X-A1): 1)Z is O or NRx; Rxis hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or Linker-PTM; and R1, R2, R3, R4, RA, m and Ring A are as described herein. In some embodiments, each R1is an independently selected halogen. In some embodiments, each R1is independently selected from fluoro and chloro. In some embodiments, each R1is independently selected from fluoro and bromo. In some embodiments, each R1is fluoro. In some embodiments, at least one R1is an independently selected halogen. In some embodiments, 28Attorney Docket No.31457_WO at least one R1is independently selected from fluoro and chloro. In some embodiments, at least one R1is fluoro.

[0060] In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R1is C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R1is C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R1is hydroxymethyl. In some embodiments, at least one R1is unsubstituted C1-C6 alkyl. In some embodiments, at least one R1is methyl. In some embodiments, at least one R1is C3-C6 cycloalkyl. In some embodiments, at least one R1is cyclopropyl.

[0061] In some embodiments, m is 2; one R1is halogen; and the other R1is C1-C6 alkyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is methyl In some embodiments, m is 2; one R1is halogen; and the other R1is C3-C6 cycloalkyl. In some embodiments, m is 2; one R1is halogen; and the other R1is cyclopropyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is cyano. In some embodiments, m is 2; one R1is halogen; and the other R1is halogen. In some embodiments, m is 2; one R1is fluoro; and the other R1is fluoro.

[0062] In some embodiments, R1is Linker-PTM.

[0063] In some embodiments, R2is hydroxyl. In some embodiments, R2is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R2is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R2is C1-C3 alkyl substituted with hydroxyl. In some embodiments, R2is hydroxymethyl. In some embodiments, R2is an unsubstituted C1-C6 alkyl. In some embodiments, R2is unsubstituted C1-C3 alkyl. In some embodiments, R2is methyl.

[0064] In some embodiments, R2is a C1-C6 haloalkyl. In some embodiments, R2is a C1-C3 haloalkyl. In some embodiments, R2is difluoromethyl. In some embodiments, R2is trifluoromethyl.

[0065] In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0066] In some embodiments, R2is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C6 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 1 fluoro. 29Attorney Docket No.31457_WO In some embodiments, R2is C3-C4 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is an unsubstituted C3-C6 cycloalkyl.

[0067] In some embodiments, R2is Linker-PTM.

[0068] In some embodiments, R3is a C1-C6 alkyl. In some embodiments, R3is a C1-C3 alkyl. In some embodiments, R3is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0069] In some embodiments, R3is a C1-C6 haloalkyl. In some embodiments, R3is a C1-C3 haloalkyl. In some embodiments, R3is difluoromethyl. In some embodiments, R3is trifluoromethyl.

[0070] In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 fluoro at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R3is C3- C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 methyl at the position of the C3-C6 cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is an unsubstituted C3-C6 cycloalkyl. In some embodiments, the R3C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0071] In some embodiments, R3is Linker-PTM.

[0072] 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.

[0073] In some embodiments, Ring A is a C3-C8 cycloalkyl. In some embodiments, Ring A is a C5-C6 cycloalkyl. In some embodiments, Ring A is cyclohexyl.

[0074] 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 30Attorney Docket No.31457_WO some embodiments, Ring A is a 9 membered heteroaryl, wherein the point of attachment to the urea nitrogen atom in Formula (I) is on a 6-membered ring of Ring A. In some embodiments, Ring A is a 9 membered heteroaryl, wherein the point of attachment to the urea nitrogen atom in Formula (I) is on a 5-membered ring of Ring A.

[0075] 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, . In some embodiments, Ring A isselected from the group consisting , wherein “*” indicates the attachment point to the u

[0076] 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 groups 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 selected from the group consisting of , wherein “*” indicates the attachment pg . me embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is 5-pyrimidinyl. In some embodiments, Ring A is 31Attorney Docket No.31457_WO , wherein “*” indicates the attachment point to the urea nitrogen atom in Formulabodiments, 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.

[0077] In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2- or 7-yl, O .1. In some embodiments, n is 2.

[0080] In some embodiments, one R4is C1-C6 alkyl. In some embodiments, one R4is unsubstituted C1-C6 alkyl. In some embodiments, one R4is C1-C4 alkyl. In some embodiments, one R4is t-butyl. In some embodiments, one R4is methyl.

[0081] In some embodiments, one R4is C1-C6 alkyl substituted with Linker-PTM.

[0082] In some embodiments, one R4is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R4is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R4is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cyclopropyl. In some embodiments, one R4is C1-C6 alkoxy substituted with hydroxyl. In some embodiments, one R4is C1-C6 alkoxy substituted with 32Attorney Docket No.31457_WO C3-C6 cycloalkyl. In some embodiments, one R4is C1-C6 alkoxy substituted with cyclopropyl. In some embodiments, R4is C1-C6 alkoxy. In some embodiments, R4is C1-C3 alkoxy. In some embodiments, one R4is methoxy.

[0083] In some embodiments, one R4is C1-C6 alkoxy substituted with Linker-PTM.

[0084] In some embodiments, one R4is C1-C6 haloalkyl. In some embodiments, one R4is C1-C3 haloalkyl. In some embodiments, one R4is difluoromethyl. In some embodiments, one R4is trifluoromethyl.

[0085] In some embodiments, one R4is C1-C6 haloalkyl substituted with Linker-PTM.

[0086] In some embodiments, one R4is hydroxyl.

[0087] In some embodiments, one R4is cyano.

[0088] In some embodiments, one R4is –CO2H.

[0089] In some embodiments, one R4is halogen. In some embodiments, one R4is fluoro. In some embodiments, one R4is chloro.

[0090] In some embodiments, one R4is C1-C6 alkyl optionally substituted with 1-2 hydroxyl. In some embodiments, one R4is C1-C6 alkyl substituted with 1-2 hydroxyl. In some embodiments, one R4is C1-C6 alkyl substituted with 1 hydroxyl. In some embodiments, one R4is C1-C6 alkyl substituted with 2 hydroxyl. In some embodiments, one R4is C1-C3 alkyl substituted with 2 hydroxyl. In some embodiments, one R4is C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, one R4is C1-C6 alkyl substituted with -NRARB. In some embodiments, one R4is methyl or ethyl substituted with -NRARB. In some embodiments, one R4is an unsubstituted C1-C6 alkyl. In some embodiments, one R4is methyl.

[0091] In some embodiments, one R4is -NRARB. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NH2. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis -C(=O)O(C1-C6 alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis -C(=O)OCH3. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl (e.g., oxetanyl), In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- 33Attorney Docket No.31457_WO C6 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 3-hydroxy-1-propyl, 2- hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis butyl substituted with hydroxyl (e.g., 2-hydroxy-2-methyl-1-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3 alkyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6 alkyl. In some embodiments, RAand RBare each C1-C3 alkyl. In some embodiments, RAand RBare each methyl.

[0092] In some embodiments, both of RB2and RC2are hydrogen. In some embodiments, one of RB2and RC2is hydrogen and the other of RB2and RC2is C1-C6 alkyl. In some embodiments, one of RB2and RC2is hydrogen and the other of RB2and RC2is methyl. In some embodiments, both of RB2and RC2are methyl.

[0093] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 haloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 haloalkyl. In some embodiments, RAand RBare each C1-C6 haloalkyl. In some embodiments, RAand RBare each C1-C3 haloalkyl.

[0094] In some embodiments, one of RAand RBis C1-C6 alkyl and the other of one of RAand RBis C1-C6 haloalkyl.

[0095] In some embodiments, one R4is -NRARBsubstituted with Linker-PTM.

[0096] In some embodiments, one R4is =NRA2. 34Attorney Docket No.31457_WO

[0097] In some embodiments, RA2is hydrogen. In some embodiments, RA2is C1-C6 alkyl.

[0098] In some embodiments, RA2is Linker-PTM.

[0099] In some embodiments, one R4is -C(=O)NRCRD.

[0100] In some embodiments, one R4is -C(=O)NRCRDsubstituted with Linker-PTM.

[0101] In some embodiments, RCand RDare each hydrogen. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C3 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis methyl. In some embodiments, RCand RDare each C1-C6 alkyl. In some embodiments, RCand RDare each C1-C3 alkyl. In some embodiments, RCand RDare each methyl. In some embodiments, one of RCand RDis C1-C6 alkyl and the other of RCand RDis C1-C3 alkyl.

[0102] In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6 haloalkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C3 haloalkyl. In some embodiments, RCand RDare each is C1-C6 haloalkyl. In some embodiments, one of RCand RDis C1-C6 alkyl and the other of RCand RDis C1-C6 haloalkyl.

[0103] In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1- C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0104] In some embodiments, RB1and RC1are each hydrogen. In some embodiments, one of RB1and RC1is hydrogen and the other of RB1and RC1is C1-C6 alkyl. In some embodiments, one of RB1and RC1is hydrogen and the other of RB1and RC1is methyl. In some embodiments, RB1and RC1are each independently selected C1-C6 alkyl. In some embodiments, RB1and RC1are each methyl.

[0105] In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. 35Attorney Docket No.31457_WO

[0106] In some embodiments, one R4is -SO2(NRERF). In some embodiments, REand RFare each hydrogen. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C6 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C3 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis methyl. In some embodiments, REand RFare each is C1-C6 alkyl. In some embodiments, REand RFare each is C1-C3 alkyl. In some embodiments, REand RFare each methyl.

[0107] In some embodiments, one R4is -SO2(NRERF) substituted with Linker-PTM.

[0108] In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1-C6 haloalkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C3 haloalkyl. In some embodiments, REand RFare each C1-C6 haloalkyl. In some embodiments, one of REand RFis C1-C6 alkyl and the other of REand RFis C1-C6 haloalkyl.

[0109] In some embodiments, one of RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis Linker- PTM.

[0110] In some embodiments, RAis Linker-PTM.

[0111] In some embodiments, RA1is Linker-PTM.

[0112] In some embodiments, RBis Linker-PTM.

[0113] In some embodiments, RB1is Linker-PTM.

[0114] In some embodiments, RCis Linker-PTM.

[0115] In some embodiments, RC1is Linker-PTM.

[0116] In some embodiments, RDis Linker-PTM.

[0117] In some embodiments, RD1is Linker-PTM.

[0118] In some embodiments, REis Linker-PTM.

[0119] In some embodiments, RFis Linker-PTM.

[0120] In some embodiments, one R4is -SO2(C1-C6 alkyl). In some embodiments, one R4is - SO2(C1-C3 alkyl). In some embodiments, one R4is -SO2Et. In some embodiments, one R4is - SO2Me.

[0121] In some embodiments, one R4 is -SO2(C1-C6 alkyl) substituted with Linker-PTM.

[0122] In some embodiments, one R4is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, one R4is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, one R4is -S(=O)(=NH)Me.

[0123] In some embodiments, one R4is -S(=O)(=NH)(C1-C6 alkyl) substituted with Linker-PTM. 36Attorney Docket No.31457_WO

[0124] In some embodiments, one R4is -C(=O)(C1-C6 alkyl). In some embodiments, one R4is - C(=O)(C1-C3 alkyl). In some embodiments, one R4is -C(=O)Me.

[0125] In some embodiments, one R4is -C(=O)(C1-C6 alkyl) substituted with Linker-PTM.

[0126] In some embodiments, one R4is -CO2(C1-C6 alkyl). In some embodiments, one R4is -CO2(C1-C3 alkyl). In some embodiments, one R4is -CO2Me.

[0127] In some embodiments, one R4is -CO2(C1-C6 alkyl) substituted with Linker-PTM.

[0128] In some embodiments, one R4is 5-6 membered heteroaryl optionally substituted with C1- C6 alkyl. In some embodiments, one R4is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, one R4is 5-6 membered heteroaryl. In some embodiments, one R4is 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. In some embodiments, one R4is tetrazolyl substituted with methyl. In some embodiments, one R4is pyrazolyl. In some embodiments, one R4is unsubstituted pyrazolyl. In some embodiments, one R4is 1-pyrazolyl.

[0129] In some embodiments, one R4is 5-6 membered heteroaryl substituted with Linker-PTM.

[0130] In some embodiments, one R4is Linker-PTM.

[0131] In some embodiments, one R4is substituted with Linker-PTM when R4is not Linker-PTM.

[0132] In some embodiments, one R4is 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 4 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 5 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 7-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, the R4heterocyclyl is a spirocycle. In some embodiments, one R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, one R4is an unsubstituted 3-6 membered heterocyclyl. 37Attorney Docket No.31457_WO

[0133] In some embodiments, one R4is 3-9 membered heterocyclyl substituted with Linker-PTM.

[0134] In some embodiments, one R4is a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 1 RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 2 independently selected RG. In some embodiments, one R4is an unsubstituted 3-6 membered cycloalkyl. In some embodiments, the 1 or 2 independently selected RGis 1 RG. In some embodiments, the 1 or 2 independently selected RGare 2 independently selected RG. In some embodiments, when 2 RGare present, they are bonded to the same atom, valency permitting. In some embodiments, when 2 RGare present, they are bonded to adjacent atoms, valency permitting. In some embodiments, when 2 RGare present, the 2 RGare different. In some embodiments, when 2 RGare present, the 2 RGare the same. In some embodiments, one RGis fluoro. In some embodiments, one RGis cyano. In some embodiments, one RGis hydroxyl. In some embodiments, one RGis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one RGis 2-hydroxy-2-propyl. In some embodiments, one RGis C1-C6 alkyl. In some embodiments, one RGis C1-C3 alkyl. In some embodiments, one RGis methyl. In some embodiments, one RGis ethyl.

[0135] In some embodiments, one R4is 3-6 membered cycloalkyl substituted Linker-PTM.

[0136] In some embodiments, one RGis C1-C6 alkoxy. In some embodiments, one RGis C1-C3 alkoxy. In some embodiments, one RGis methoxy.

[0137] In some embodiments, one RGis -NRA1RB1. In some embodiments, RA1and RB1are each hydrogen. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6 alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3 alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. In some embodiments, RA1and RB1are each C1-C6 alkyl. In some embodiments, RA1and RB1are each methyl.

[0138] In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1- C6 haloalkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3 haloalkyl. In some embodiments, RA1and RB1are each C1-C6 haloalkyl. In some embodiments, one of RA1and RB1is C1-C6 alkyl and the other of RA1and RB1is C1-C6 haloalkyl. 38Attorney Docket No.31457_WO

[0139] In some embodiments, one RGis =NRA2. In some embodiments, one RGis =NH. In some embodiments, RA2is hydrogen. In some embodiments, RA2is C1-C6 alkyl. In some embodiments, RA2is methyl.

[0140] In some embodiments, one RGis -C(=O)NRC1RD1. In some embodiments, one RGis - CO2NH2. In some embodiments, one RGis -CO2NHCH3. In some embodiments, RC1and RD1are each is hydrogen. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6 alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3 alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. In some embodiments, RC1and RD1are each is C1-C6 alkyl. In some embodiments, RC1and RD1are each is C1-C3 alkyl. In some embodiments, RC1and RD1are each is methyl.

[0141] In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1- C6 haloalkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3 haloalkyl. In some embodiments, RC1and RD1are each is C1-C6 haloalkyl. In some embodiments, one of RC1and RD1is C1-C6 alkyl and the other of RC1and RD1is C1-C6 haloalkyl.

[0142] In some embodiments, one RGis -CO2(C1-C6 alkyl). In some embodiments, one RGis - CO2CH3. In some embodiments, one RGis C1-C6 haloalkyl. In some embodiments, one RGis trifluoromethyl. In some embodiments, one RGis difluoromethyl. In some embodiments, one RGis C3-C6 cycloalkyl. In some embodiments, one RGis cyclopropyl. In some embodiments, one RGis -CO2H.

[0143] In some embodiments, one RGis C1-C6 haloalkoxy. In some embodiments, one RGis C1- C3 haloalkoxy. In some embodiments, one RGis difluoromethoxy. In some embodiments, one RGis trifluoromethoxy.

[0144] In some embodiments, one RGis -SO2(C1-C6 alkyl). In some embodiments, one RGis - SO2CH3.

[0145] In some embodiments, the R4is 3-9 membered heterocyclyl. In some embodiments, the R4is a 3-6 membered heterocyclyl. In some embodiments, the R4is a 5-6 membered heterocyclyl. In some embodiments, the R4is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, the R4is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. In some embodiments, the R4is 3-9 membered 39Attorney Docket No.31457_WO heterocyclyl selected from the group consistin ,and. In some embodiments, the R4i wherein Q is a C1-C3 alkylene in whichore carbons is optionally replaced-, NH, O, or S. In some embodiments, Q is a C1-C3 alkylene in which one or more carbons is optionally replaced by –C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene in which one or more carbons is optionally replaced by – C(=O)- or NH. In some embodiments, the R4is 3-9 membered heterocyclyl selected from the group consisting .

[0146] In some-6 membered heterocyclyl. In some embodiments, R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments, R4is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments, R4is selected from the group consisting of .

[0147] In some embodiments, the R4bstituted with Linker-PTM.

[0148] In some embodiments , wherein: X is selected from N and CR4A2; R4A1and R4A2ae epe e y se ec e o ydrogen, C1-C3 alkyl optionally substituted with -NRARB,, methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, X is N. In some embodiments, X is CR4A2. In some embodiments, R4A1and, when present, R4A2are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, 40Attorney Docket No.31457_WO hydroxyl, methoxy, amino, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2Me, and azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, X is N and R4A1is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0149] In some embodiments, X is N; and R4A1is selected from amino or an azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl.

[0150] In some embodiments , wherein: R4B is selected from -NRARBand 4-6 membered gen ring member and optionallysubstituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0151] In some embodiments , wherein: R4B is selected from -NRARBand 4-6 memberedrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2- propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0152] In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some 41Attorney Docket No.31457_WO embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2- propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3 alkyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6 alkyl. In some embodiments, RAand RBare each C1-C3 alkyl. In some embodiments, RAand RBare each methyl.

[0153] In some embodiments, R4Bis amino or a 4-6 membered heterocyclyl having one nitrogen atom and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0154] In some embodiments, R4Bi ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinylolinyl, each optionally containing 1-2 =O, and each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. In some embodiments, R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,p onally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. In some embodiments, R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,eac opt onally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. In some embodiments, R4B; wherein Ring B is42Attorney Docket No.31457_WO azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6 alkyl. In some embodiments, Ring B is azetidinyl.

[0155] In some embodiments, Ring B is unsubstituted.

[0156] In some embodiments, Ring B is substituted with 1 RG. In some embodiments, RGis fluoro. In some embodiments, RGis cyano. In some embodiments, RGis amino, In some embodiments, RGis hydroxyl. In some embodiments, RGis C1-C3 alkyl. In some embodiments, RGis methyl. In some embodiments, RGis ethyl. In some embodiments, RGis -CO2CH3. In some embodiments, RGis methoxy. In some embodiments, RGis methoxy.

[0157] In some embodiments, Ring B is substituted with 2 RG. In some embodiments, each RGis fluoro. In some embodiments, each RGis C1-C3 alkyl. In some embodiments, each RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis ethyl. In some embodiments, one RGis amino and the other RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis cyclopropyl. In some embodiments, one RGis fluoro and the other RG1is methyl. In some embodiments, one RGis hydroxyl and the other RGis fluoro. In some embodiments, one RGis hydroxyl and the other RGis trifluoromethyl. In some embodiments, each RGis bonded to the position of Ring B para to the nitrogen that is bonded to Ring A.

[0158] In some embodiments , wherein 1 or 2 independentlyselected RGattach at the 3-position of the azetidine. In some embodiments, isselected from the group consisting o andis selected from the group consisting of,theAttorney Docket No.31457_WOgroup consisting of , , , , ,,

[0160] In some embodiments, Z is NRx.

[0161] In some embodiments, Rxis hydrogen.

[0162] In some embodiments, Rxis C1-C6 alkyl. In some embodiments, Rxis C1-C3 alkyl. In some embodiments, Rxis methyl. In some embodiments, Rxis ethyl. In some embodiments, Rxis n-propyl. In some embodiments, Rxis isopropyl.

[0163] In some embodiments, Rxis C3-C6 cycloalkyl. In some embodiments, Rxis C3-C4 cycloalkyl. In some embodiments, Rxis cyclopropyl. In some embodiments, Rxis cyclobutyl.

[0164] In some embodiments, Rxis Linker-PTM.

[0165] In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1- C6 alkyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0166] In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1- C6 haloalkyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl.

[0167] In some embodiments, m is 2, one R4is halogen, and the other R4is -SO2(C1-C6 alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3.

[0168] In some embodiments, m is 2, one R4is C1-C6 alkoxy, and the other R4is -C(=O)NRCRD.

[0169] In some embodiments, m is 2, one R4is methoxy, and the other R4is –C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and 44Attorney Docket No.31457_WO n is 1 or 2.

[0170] In some embodiments, PTM is a VHL binding moiety. , or* represents the point of attachment of PTM to the Linker; RW3is hydrogen, halogen, or C1-C6 alkyl; RW4is hydrogen, (-C(=O))q1-C1-C6 alkyl, (-C(=O))q1-C1-C6 haloalkyl, (-C(=O))q1-C3-C6 cycloalkyl optionally substituted with halogen; and q1 is 0 or 1 In some embodiments, PTM is a cereblon binding moiety. 45Attorney Docket No.31457_WO

[0172] In some embodiments, the cereblon binding moiet ,, , ,Attorney Docket No.31457_WO , , , ,Attorney Docket No.31457_WOAttorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO O NH , , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , , , , , ,Attorney Docket No.31457_WO , , , , , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , orRW1is hydrogen or C1-C6 alkyl; each RW2is independently halogen, OH, -NH2, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy optionally substituted with C3-C7 cycloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4- 6 membered heterocyclyl, C6-C10 aryl, or C3-C6 cycloalkoxy; and q is 0, 1, or 2.

[0173] In some embodiments, PTM is an RNF126 binding moiety. In some embodiments, RNF126 binding moiety wherein R’ is C1-C6 alkyl or C1-C6 haloalkyl and * represen s e po n o connec on o TM to Linker. In some embodiments, 56Attorney Docket No.31457_WO RNF126 binding moiet , wherein * represents the point of connection of PTM to L r is a covalent bond.

[0174] In some embodiments, PTM is covalent E3 ligase recruiter. In some embodiments, the , ornts, Linker is a covalent bond.

[0175] In some embodiments, Linker is attached to Ring A.

[0176] In some embodiments, Linker is attached to Ring B.

[0177] In some embodiments, Linker is a covalent bond or a C1-C50 alkylene; wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, –P(=O)(RK1)–, –P(=O)N(RK1)–, -S-, -C(=O)-, -S(=O)-, -S(O)2-, 1)-,1B, - NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; 57Attorney Docket No.31457_WO or two RK1attached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK1Ais independently halogen, hydroxyl, cyano, -SF5, -C(=O)ORK1B , -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C1-C6 alkoxy, or an optionally substituted phosphine oxide; or two RK1Aattached to the same or adjacent atoms inK, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4- 12 membered heterocyclyl; each RK2is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted phenylene, or an optionally substituted 5-10 membered heteroarylene; each RK1Band RK1Care independently selected from hydrogen and an optionally substituted C1-C6 alkyl, or RK1Band RK1Ctogether with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl.

[0178] In some embodiments, Linker includes RK2. In some embodiments, RK2is an optionally substituted C3-C10 cycloalkylene. In some embodiments, RK2is an optionally substituted 4-12 membered heterocyclylene. In some embodiments, RK2is an optionally substituted phenylene. In some embodiments, RK2is an optionally substituted 5-10 membered heteroarylene. In some embodiments, RK2is an optionally substituted 5 membered heteroarylene. In some embodiments, RK2is an optionally substituted triazole.

[0179] In some embodiments, Linker is selected from the group consisting of: ethylene, 1,3- propylene, 1,4-butylene, 1,5-pentylene, 1,8-octylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1, 4- , , ,Attorney Docket No.31457_WO , , , , , , , , , , ,Attorney Docket No.31457_WO , , , , , , , , , , ,Attorney Docket No.31457_WO , , , , , , , , , , , ,Attorney Docket No.31457_WO , , , , , , , ,Attorney Docket No.31457_WO ,m is 1 or 2; R2is a C1-C6 alkyl; R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; 63Attorney Docket No.31457_WO each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2.

[0181] In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1-C6 alkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0182] In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1-C6 haloalkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl.

[0183] In some embodiments, Z is O; m is 2, one R4is halogen, and the other R4is -SO2(C1-C6 alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3.

[0184] In some embodiments, Z is O; m is 2, one R4is C1-C6 alkoxy, and the other R4is - C(=O)NRCRD.

[0185] In some embodiments, Z is O; m is 2, one R4is methoxy, and the other R4is –C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is O; 64Attorney Docket No.31457_WO each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and 65Attorney Docket No.31457_WO n is 1 or 2. In some embodiments, Z is O; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2.

[0186] In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1-C6 alkyl. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0187] In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; and R3is a C1-C6 haloalkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl.

[0188] In some embodiments, Z is NRx; m is 2, one R4is halogen, and the other R4is -SO2(C1- C6 alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3.

[0189] In some embodiments, Z is NRx; m is 2, one R4is C1-C6 alkoxy, and the other R4is - C(=O)NRCRD.

[0190] In some embodiments, Z is NRx; m is 2, one R4is methoxy, and the other R4is – C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; 66Attorney Docket No.31457_WO R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0191] In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6 alkyl; R3is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is 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, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro, cyano, or methyl; 67Attorney Docket No.31457_WO m is 1 or 2; R2is a C1-C3 alkyl; R3is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2.

[0192] In some embodiments, the compound of Formula (I) is Formula (I-A): ) ereof, wherein:R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 68Attorney Docket No.31457_WO hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0193] It is understood in the context of the compounds of Formula (X) that when compounds of Formula (I) are described herein, it is necessary to remove a hydrogen from the compounds of Formula (I) for the attachment of the -Linker-PTM group. Brackets, for example as shown in Formula (X-A) below, can be used to indicate that the -Linker-PTM group can be attached to any position on the compound of Formula (I) after removal of said hydrogen atom.

[0194] In some embodiments, the compound of Formula (X) is Formula (X-A): (X-A) or aherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; 69Attorney Docket No.31457_WO wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0195] In some embodiments, the compound of Formula (I) is Formula (I-J): J)of, wherein: Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 70Attorney Docket No.31457_WO membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0196] In some embodiments, the compound of Formula (X) is Formula (X-J): 2 J); R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 71Attorney Docket No.31457_WO membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0197] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is pyrimidinyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is pyridyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is pyrazolyl.

[0198] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is 5-pyrimidinyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is 3-pyridyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring A1 is 4- pyrazolyl.

[0199] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J)Formulae (I-A), (X-A), (I- J), and (X-J), , wherein: R4Bis selected from -NRARBand 4-6 membered hetgen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0200] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J)Formulae (I-A), (X-A), (I- J), and (X-J), RAand RBare each hydrogen. 72Attorney Docket No.31457_WO

[0201] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J)Formulae (I-A), (X-A), (I- J), and (X-J), RAand RBare each 4-6 membered heterocyclyl. In some embodiments Formulae (I- A), (X-A), (I-J), and (X-J), of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl.

[0202] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each C1-C6 haloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 haloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 haloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1-C6 haloalkyl.

[0203] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with 73Attorney Docket No.31457_WO hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X- A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C6 alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl.

[0204] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and - SO2(NH2) . In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of Formulae (I-A), (X- A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis methyl. 74Attorney Docket No.31457_WO

[0205] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each C1- C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I- J), and (X-J), RAand RBare each C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C3 alkyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I- J), and (X-J), one of RAand RBis methyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each C1-C6 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each C1-C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare each methyl.

[0206] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2- hydroxyethyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0207] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of 75Attorney Docket No.31457_WO Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of Formulae (I-A), (X- A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1- C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formulae (I-A), (X-A), (I- J), and (X-J), RAand RBare both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0208] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl . In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one of RAand RBis C1-C6 alkyl hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RAand RBare both C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), R4Bis 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0209] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), R4B, denoted as “Ring B” with respect to of Formulae (I-A), (X-A), (I-J), and (X-J); wB is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring B is azetidinyl.

[0210] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring B is unsubstituted.

[0211] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring B is substituted with 1 RG. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RGis fluoro. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RGis cyano. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RGis hydroxyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RGis C1-C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), 76Attorney Docket No.31457_WO and (X-J), RGis methyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), RGis -CO2CH3.

[0212] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), Ring B is substituted with 2 independently selected RG. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), each RGis fluoro. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), each RGis C1- C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), each RGis methyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis hydroxyl and the other RGis C1-C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis hydroxyl and the other RGis methyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis fluoro and the other RGis C1-C3 alkyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis fluoro and the other RGis methyl. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis hydroxyl and the other RGis fluoro. In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), one RGis hydroxyl and the other RGis trifluoromethyl.

[0213] In some embodiments of Formulae (I-A), (X-A), (I-J), and (X-J is G, wherein 1 or 2 independently selected R is at the 3-position of the azetidine. Insome embodiments of Formulae (I-A), (X-A), (I-J), and (X-J), is selected from the group consisting ,lae, 77Attorney Docket No.31457_WO ) ereof, wherein:R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0215] In some embodiments, R1Aand R1Bare each fluoro;

[0216] In some embodiments, R2is a C1-C6 alkyl. In some embodiments, R2is a C1-C3 alkyl. In some embodiments, R2is methyl.

[0217] In some embodiments, R2is a C1-C6 haloalkyl. In some embodiments, R2is a C1-C3 haloalkyl. In some embodiments, R2is a trifluoromethyl. 78Attorney Docket No.31457_WO

[0218] In some embodiments, R3is a C1-C6 alkyl. In some embodiments, R3is a C1-C3 alkyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0219] In some embodiments, R3is a C1-C6 haloalkyl. In some embodiments, R3is a C1-C3 haloalkyl. In some embodiments, R3is a trifluoromethyl.

[0220] In some embodiments, R3is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is unsubstituted C3-C6 cycloalkyl. In some embodiments, the R3C3-C6 cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl.

[0221] In some embodiments, the compound of Formula (X) is Formula (X-B): B)R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with 79Attorney Docket No.31457_WO hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H and Linker and PTM are as described herein.

[0222] In some embodiments, the compound of Formula (I) is Formula (I-C): ) reof, wherein:R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H.

[0223] In some embodiments, the compound of Formula (X) is Formula (X-C): 80Attorney Docket No.31457_WO R2R1AR3C)R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H; and Linker and PTM are as described herein.

[0224] In some embodiments, the compound of Formula (I) is Formula (I-D): )thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); 81Attorney Docket No.31457_WO R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0225] In some embodiments, the compound of Formula (X) is Formula (X-D): R2D)R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered 82Attorney Docket No.31457_WO heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0226] In some embodiments, the compound of Formula (I) is Formula (I-E): )thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; 83Attorney Docket No.31457_WO each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0227] In some embodiments, the compound of Formula (X) is Formula (X-E): R2R1AR3E)R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; Each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0228] In some embodiments, the compound of Formula (I) is Formula (I-F): 84Attorney Docket No.31457_WO F) ereof, wherein:R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; and each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0229] In some embodiments, the compound of Formula (X) is Formula (X-F): R2F), R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); 85Attorney Docket No.31457_WO R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0230] In some embodiments, the compound of Formula (I) is Formula (I-G): )thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered 86Attorney Docket No.31457_WO heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0231] In some embodiments, the compound of Formula (X) is Formula (X-G): R2R1AG)R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; 87Attorney Docket No.31457_WO each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0232] In some embodiments, the compound of Formula (I) is Formula (I-K): ) reof, wherein:Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H. 88Attorney Docket No.31457_WO

[0233] In some embodiments, the compound of Formula (X) is Formula (X-K): K)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R4is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0234] In some embodiments, the compound of Formula (I) is Formula (I-L): 89Attorney Docket No.31457_WO L) reof, wherein:Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H.

[0235] In some embodiments, the compound of Formula (X) is Formula (X-L): L), Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; 90Attorney Docket No.31457_WO R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H; and Linker and PTM are as described herein.

[0236] In some embodiments, the compound of Formula (I) is Formula (I-M): ) ohereof, wherein: Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered 91Attorney Docket No.31457_WO heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0237] In some embodiments, the compound of Formula (X) is Formula (X-M): M)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; 92Attorney Docket No.31457_WO each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0238] In some embodiments, the compound of Formula (I) is Formula (I-N): ) o hereof, wherein:Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0239] In some embodiments, the compound of Formula (X) is Formula (X-N): 93Attorney Docket No.31457_WO N)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0240] In some embodiments, the compound of Formula (I) is Formula (I-O): )p y p reof, wherein: 94Attorney Docket No.31457_WO Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0241] In some embodiments, the compound of Formula (X) is Formula (X-O): O)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; 95Attorney Docket No.31457_WO R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0242] In some embodiments, the compound of Formula (I) is Formula (I-P): P) othereof, wherein: Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; 96Attorney Docket No.31457_WO each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0243] In some embodiments, the compound of Formula (X) is Formula (X-P): P)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or a C1-C6 haloalkyl; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; 97Attorney Docket No.31457_WO each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and Linker and PTM are as described herein.

[0244] In some embodiments, the compound of Formula (I) is Formula (I-Q): ) o eof, wherein:Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or C1-C6 haloalkyl; R3is a C1-C6 alkyl or a C1-C6 haloalkyl; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0245] In some embodiments, the compound of Formula (X) is Formula (X-Q): 98Attorney Docket No.31457_WO Q)Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R1Ais halogen; R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6 alkyl or C1-C6 haloalkyl; R3is a C1-C6 alkyl or a C1-C6 haloalkyl; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; and Linker and PTM are as described herein.

[0246] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C6 alkyl optionally substituted with -NRARB. In some embodiments of any of Formulae (I-B)-(I-Q) and (X- B)-(X-Q), R4is C1-C3 alkyl optionally substituted with -NRARB. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is methyl optionally substituted with -NRARB. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C4 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is methyl. 99Attorney Docket No.31457_WO

[0247] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C6 alkoxy. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C3 alkoxy. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is methoxy.

[0248] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is C1-C3 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is trifluoromethyl.

[0249] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is cyano. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is –CO2H. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy- 2-propyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis C1-C3 alkyl 100Attorney Docket No.31457_WO and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis methyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 alkyl. In some embodiments of any of Formulae (I-B)- (I-Q) and (X-B)-(X-Q), RAand RBare each C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each methyl.

[0250] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis C1-C6 alkyl and the other of one of RAand RBis C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1-C6 haloalkyl.

[0251] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each 4-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X- B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3- yl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl.

[0252] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand 101Attorney Docket No.31457_WO RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)- (I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)- (I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis cis- or trans- 3-hydroxycyclobutyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis C1-C6 alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl.

[0253] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and - SO2(NH2).

[0254] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl,, e.g., 1-cyclopropyl-2- 102Attorney Docket No.31457_WO hydroxyethyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0255] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis C1-C6 alkyl and the other of RAand RBis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis C1-C6 alkyl hydrogen and the other of RAand RBis C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), RAand RBare both C1-C6 alkyl substituted with -SO2(NH2).

[0256] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is - C(=O)NRCRD. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RDare each hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RCand RDis hydrogen and the other of RCand RDis C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RCand RDis hydrogen and the other of RCand RDis C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RCand RDis hydrogen and the other of RCand RDis methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RDare each C1-C6 alkyl. In some embodiments 103Attorney Docket No.31457_WO of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RDare each C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RDare each methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RCand RDis hydrogen and the other of RCand RDis C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)- (I-Q) and (X-B)-(X-Q), RCand RDare each is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RCand RDis C1-C6 alkyl and the other of RCand RDis C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0257] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is - SO2(NRERF). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), REand RFare each hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of REand RFis hydrogen and the other of REand RFis C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of REand RFis hydrogen and the other of REand RFis methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), REand RFare each is C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), REand RFare each is C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)- (X-Q), REand RFare each methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X- B)-(X-Q), one of REand RFis hydrogen and the other of REand RFis C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), REand RFare each C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of REand RFis C1-C6 alkyl and the other of REand RFis C1-C6 haloalkyl.

[0258] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -SO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -SO2(C1-C3 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -SO2Me. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -SO2Et.

[0259] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is - S(=O)(=NH)(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- )(=NH)(C1-C4 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and 4 is -S(=O)(=NH)Me.104Attorney Docket No.31457_WO

[0260] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -C(=O)(C1- C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is - C(=O)(C1-C3 alkyl). In some embodiments of any of Formulae (I-B)-(I- R4is -C(=O)Me.

[0261] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -CO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -CO2(C1-C3 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is -CO2Me.

[0262] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is 5-6 membered heteroaryl substituted with C1- C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 5-6 membered heteroaryl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 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. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is pyrazolyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is tetrazolyl substituted with methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is pyrazolyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is unsubstituted pyrazolyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one R4is 1-pyrazolyl.

[0263] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments of any of Formulae (I- B)-(I-Q) and (X-B)-(X-Q), R4is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG.

[0264] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis fluoro. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis cyano. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis hydroxyl. In some 105Attorney Docket No.31457_WO embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis methyl.

[0265] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis C1-C6 alkoxy. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis C1-C3 alkoxy. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis methoxy.

[0266] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis - NRA1RB1. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RA1and RB1are each hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RA1and RB1are each C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RA1and RB1are each C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RA1and RB1are each methyl.

[0267] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RA1and RB1are each C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RA1and RB1is C1-C6 alkyl and the other of RA1and RB1is C1-C6 haloalkyl.

[0268] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis - C(=O)NRC1RD1. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RC1and RD1are each is hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RC1and RD1are each is C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RC1and RD1are each is methyl. In 106Attorney Docket No.31457_WO some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RC1and RD1are each is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RC1and RD1is C1-C6 alkyl and the other of RC1and RD1is C1-C6 haloalkyl.

[0269] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis - CO2(C1-C6 alkyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis -CO2CH3.

[0270] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RG is C1-C6 haloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis trifluoromethyl.

[0271] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis C3-C6 cycloalkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one RGis cyclopropyl.

[0272] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RGis -CO2H.

[0273] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), the R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), the R43-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments of any of Formulae (I-B)- (I-Q) and (X-B)-(X-Q), the R43-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1- piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0274] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is unsubstituted 3-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), R4is a 5-6 membered heterocyclyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is selected from the group consisting .

[0275] In some ey )-(I-Q) and (X-B)-(X-Q), R4is selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally 107Attorney Docket No.31457_WO substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0276] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each hydrogen. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1- propyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1- propyl or 1-hydroxy-2-propyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)- (X-Q), one of RAand RBis hydrogen and the other of RAand RBis C1-C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X- B)-(X-Q), RAand RBare each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X- Q), one of RAand RBis C1-C3 alkyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis methyl and the other of RAand RBis C1-C3 alkyl substituted with hydroxyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1-C6 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each C1- 108Attorney Docket No.31457_WO C3 alkyl. In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), RAand RBare each methyl.

[0277] In some embodiments of any of Formulae (I-B)-(I-Q) and (X-B)-(X-Q), R4is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0278] In some embodiments, the compound of Formula (I) is Formula (I-H): ) reof, wherein:R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H.

[0279] In some embodiments, the compound of Formula (X) is Formula (X-H): H), R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 109Attorney Docket No.31457_WO cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; and Linker and PTM are as described herein.

[0280] In some embodiments, the compound of Formula (X-H) is Formula (X-Ha): a),R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; and Linker and PTM are as described herein.

[0281] In some embodiments, the compound of Formula (I) is 110Attorney Docket No.31457_WO alt thereof, wherein R3, R4, and Ring A are as described herein.

[0282] In some embodiments, the compound of Formula (X) is R3, R4, and Ring A are as described herein.

[0283] In some embodiments, the compound of Formula (I) islt thereof, wherein R3, R4, and Ring A are as described herein.

[0284] In some embodiments, the compound of Formula (X) is, n R3, R4, and Ring A are as described herein.

[0285] In some embodiments, the compound of Formula (I) iso a p a aceu ca y accep a e salt thereof, wherein R3, R4, and Ring A are as described herein.

[0286] In some embodiments, the compound of Formula (X) is 111Attorney Docket No.31457_WO R3, R4, and Ring A are as described herein.

[0287] In some embodiments, the compound of Formula (I) is lt thereof, wherein R3, R4, and Ring A are as described herein.

[0288] In some embodiments, the compound of Formula (X) isn R3, R4, and Ring A are as described herein

[0289] In some embodiments, the compound of Formula (I) is Formula (I-1) )eof.

[0290] In some embodiments, the compound of Formula (X) is Formula (X-1) 1)p y p , inker and PTM are as described herein 112Attorney Docket No.31457_WO

[0291] In some embodiments, the compound of Formula (I) is Formula (I-2) 2) reof.

[0292] In some embodiments, the compound of Formula (X) is Formula (X-2) (X-2)ein Linker and PTM are as described herein.

[0293] For the avoidance of doubt, the compounds of Formula (X), and pharmaceutically acceptable salts thereof disclosed herein each contain a single -Linker-PTM moiety. Non-Limiting Exemplary Compounds

[0294] In some embodiments, the compound of Formula (I) is a compound disclosed in PCT / US2022 / 033255 or PCT / US2023 / 075902, which are hereby incorporated by reference in their entireties.

[0295] In some embodiments, the compound of Formula (I) is selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof, wherein the -Linker- PTM is bound to the compound of Formula (I) as described herein. Table A Structure Structure113Attorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WO F F119Attorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WO F FAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WO F O NHAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WOAttorney Docket No.31457_WO, p und of Formula (I) is selected from the group consisting of the compounds in Table B, or a pharmaceutically acceptable salt thereof, wherein the -Linker- PTM is bound to the compound of Formula (I), as described herein. Table B Structure178Attorney Docket No.31457_WO

[0297] In some embodiments, the compound of Formula (X) is selected from the group consisting of the compounds in Table C, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (X) is selected from the group consisting of the compounds in Examples 3-10, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (X) is selected from the group consisting of the compounds in Examples 11-79, or a pharmaceutically acceptable salt thereof. Table C Cmpd.179Attorney Docket No.31457_WO 4Attorney Docket No.31457_WO 9Attorney Docket No.31457_WO 14Attorney Docket No.31457_WO 18Attorney Docket No.31457_WO 22Attorney Docket No.31457_WO 26Attorney Docket No.31457_WO 30Attorney Docket No.31457_WO 34187Attorney Docket No.31457_WO 37Attorney Docket No.31457_WO 41Attorney Docket No.31457_WO 45Attorney Docket No.31457_WO 49Attorney Docket No.31457_WO 53Attorney Docket No.31457_WO 57Attorney Docket No.31457_WO 61194Attorney Docket No.31457_WO 64Attorney Docket No.31457_WO 68Attorney Docket No.31457_WO 73Attorney Docket No.31457_WO 77Pharmaceutical Compositions

[0298] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Methods of Treatment Indications

[0299] Provided herein are methods of treating or preventing diseases or disorders associated with dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same (i.e., a PI3Kα-associated disease or disorder), such as PIK3CA-related overgrowth syndromes ((PROS), see, e.g., Venot, et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., as 198Attorney Docket No.31457_WO macrocephaly-capillary malformation (MCAP) and hemimegalencephaly), congenital lipomatous (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal anomalies (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-associated cancer).

[0300] In some embodiments, the compounds provided herein can exhibit selective binding to PI3Kα. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Kα. In some embodiments, the compounds provided herein can selectively bind to a PI3Kα kinase including one or more mutations, for example, the mutations in Tables 1 and 2.

[0301] In some embodiments, the mutation in PI3Kα 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, and combinations thereof.

[0302] In some embodiments, the mutation in PI3Kα 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, and combinations thereof.

[0303] In some embodiments, the mutation in PI3Kα 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, and combinations thereof.

[0304] In some embodiments, the mutation in PI3Kα 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, and combinations thereof.

[0305] In some embodiments, the mutation in PI3Kα is two mutations 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.

[0306] In some embodiments, the mutation in PI3Kα is two mutations 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. 199Attorney Docket No.31457_WO

[0307] In some embodiments, the mutation in PI3Kα is two mutations 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.

[0308] In some embodiments, the mutation in PI3Kα is two mutations 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.

[0309] In some embodiments, the mutation in PI3Kα 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.

[0310] In some embodiments, the mutation in PI3Kα 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.

[0311] In some embodiments, the mutation in PI3Kα 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.

[0312] In some embodiments, the mutation in PI3Kα 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.

[0313] In some embodiments, the compounds provided herein can exhibit selective binding to mutant PI3Kα. For example, the compounds provided herein can bind to an alloseric site in the kinase domain. In some embodiments, the compounds provided herein can exhibit selective binding to a PI3Kα protein including an activating mutation, with minimal activity against related kinases (e.g., wild type PI3Kα). Reduction of wild type PI3Kα protein levels can cause undesireable side effects (e.g., hyperglycemia and skin rashes) that can impact quality of life and compliance. In some cases, the reduction of wild type PI3Kα protein levels can lead to dose limiting toxicities. See, e.g., Hanker, et al., Cancer Disc. 2019, 9, 4, 482-491. Mutant-selective compounds may reduce the risk of such dose limiting toxicities, including hyperglycemia, observed with inhibitors of wild type PI3Kα.

[0314] In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, selectively targets PI3Kα. For example, a compound 200Attorney Docket No.31457_WO of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, selectively targets PI3Kα over another kinase or non-kinase target.

[0315] In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, selectively targets mutant PI3Kα (e.g., PI3KαH1047R) over wild-type PI3Kα.

[0316] A compound of Formula (X) (e.g., a compound of Formula (X-1)), or pharmaceutically acceptable salts thereof, is useful for treating diseases and disorders which can be treated with a PI3Kα degrader, such as PI3Kα-associated diseases and disorders, e.g., PIK3CA-related overgrowth syndromes (PROS) and proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0317] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (a PI3Kα-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1 or Table 2. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Kα -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0318] In some embodiments, the subject is a pediatric subject. See, e.g., Berhman RE, et al., Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery and First, Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. 201Attorney Docket No.31457_WO

[0319] In certain embodiments, compounds of Formula (X), or pharmaceutically acceptable salts thereof, are useful for preventing diseases and disorders as defined herein (for example, PIK3CA- related overgrowth syndromes (PROS) and cancer). The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0320] The term “PI3Kα-associated disease or disorder” as used herein refers to diseases or disorders associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Kα protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3Kα-associated disease or disorder include, for example, PIK3CA-related overgrowth syndromes (PROS), brain disorders (e.g., as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly), congenital lipomatous (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal anomalies (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-associated cancer).

[0321] The term “PI3Kα-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Kα-associated cancer are described herein.

[0322] The phrase “dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kα that includes a deletion of at least one amino acid as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with one or more point mutations as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with at least one inserted amino acid as compared to a wild type PI3Kα, a gene duplication that results in an increased level of PI3Kα in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3Kα in a cell), an alternative spliced version of PI3Kα mRNA that results in PI3Kα having a deletion of at least one amino acid in the PI3Kα as compared to the wild type PI3Kα), or increased expression (e.g., increased levels) of a wild type PI3Kα in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non- cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or 202Attorney Docket No.31457_WO expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3Kα that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non-limiting examples of PI3Kα point mutations / substitutions / insertions / deletions are described in Table 1 and Table 2.

[0323] The term “activating mutation” in reference to PI3Kα describes a mutation in a PIK3CA gene that results in the expression of PI3Kα that has an increased kinase activity, e.g., as compared to a wild type PI3Kα, e.g., when assayed under identical conditions. For example, an activating mutation can be a mutation in a PIK3CA gene that results in the expression of a PI3Kα that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type a PI3Kα, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a PIK3CA that results in the expression of a PI3Kα that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type PI3Kα, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a PIK3CA gene that results in the expression of a PI3Kα that has 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 inserted as compared to a wild type PI3Kα, e.g., the exemplary wild type PI3Kα described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art.

[0324] The term “wild type” or “wild-type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Kα mRNA) or protein (e.g., a PI3Kα) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.

[0325] The term “wild type PI3Kα” or “wild-type PI3Kα” describes a normal PI3Kα nucleic acid (e.g., a PIK3CA or PI3Kα mRNA) or protein that is found in a subject that does not have a PI3Kα- associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and / or is not suspected of having a PI3Kα- associated disease), or is found in a cell or tissue from a subject that does not have a PI3Kα- associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and / or is not suspected of having a PI3Kα- associated disease). 203Attorney Docket No.31457_WO

[0326] Provided herein is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need thereof, comprising administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more independently selected additional therapeutic agents, as described herein. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof and one or more independently selected additional therapeutic agents. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more a PI3Kα protein substitutions / point mutations / insertions. Non-limiting examples of PI3Kα protein substitutions / insertions / deletions are described in Table 1 and Table 2.

[0327] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0328] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0329] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) testing or having tested a subject to determine that the subject has a PI3Kα-associated cancer, and (b) administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0330] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and 204Attorney Docket No.31457_WO (b) administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0331] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and (b) administering to the subject a combination therapy comprising a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0332] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more independently selected additional therapeutic agents.

[0333] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject of a combination therapy comprising a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0334] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject (a) a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents. 205Attorney Docket No.31457_WO

[0335] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising: (a) a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0336] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) testing or having tested a subject to determine that the subject has a PI3Kα-associated cancer, and (b) administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0337] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and 206Attorney Docket No.31457_WO (b) administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0338] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and (b) administering to the subject a combination therapy comprising a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0339] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject (a) a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 207Attorney Docket No.31457_WO and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0340] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject of a combination therapy comprising a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0341] In some embodiments, the one or more PI3Kα protein substitution / insertion / deletion are 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 PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047R. In some embodiments, the one or more PI3Kα protein substitution / insertion / deletions are selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, and H1047R.

[0342] In some embodiments, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor.

[0343] In some embodiments, the cancer was refractory to one or more prior therapies. In some embodiments, the subject experienced dose-limiting toxicity to one or more prior therapies. In some embodiments, the one or more prior therapies comprises a PI3K inhibitor.

[0344] In some embodiments, the cancer is unresectable and / or metastatic. 208Attorney Docket No.31457_WO

[0345] In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is unresectable. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is metastatic brain cancer, as described herein. In some embodiments, the cancer is metastatic spinal cord cancer, as described herein.

[0346] In some embodiments, the cancer is selected from breast cancer (including both HER2+and HER2- breast cancer, ER+breast cancer, and triple negative breast cancer), endometrial cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), esophageal cancer (including esophageal squamous cell carcinoma), ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, gastric cancer, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), prostate cancer, kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0347] In some embodiments, the cancer is selected from breast cancer (including both HER2+and HER2- breast cancer, ER+breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.

[0348] In some embodiments, the cancer is a gynecologic cancer. In some embodiments, the gynecologic cancer is endometrial cancer, ovarian cancer, or cervical cancer.

[0349] In some embodiments, the cancer is endometrial cancer that is not deficient in DNA mismatch repair (dMMR), i.e., the endometrial cancer is not dMMR.

[0350] In some embodiments, the cancer is selected from breast cancer, lung cancer, endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, colorectal cancer, bladder cancer, head and neck cancer, thyroid cancer, prostate cancer, glioma, and cervical cancer.

[0351] In some embodiments, the cancer is breast cancer.

[0352] In some embodiments, the cancer is lung cancer. 209Attorney Docket No.31457_WO

[0353] In some embodiments, the cancer is endometrial cancer.

[0354] In some embodiments, the cancer is esophageal cancer.

[0355] In some embodiments, the cancer is gastric cancer.

[0356] In some embodiments, the cancer is ovarian cancer.

[0357] In some embodiments, the cancer is colorectal cancer.

[0358] In some embodiments, the cancer is bladder cancer.

[0359] In some embodiments, the cancer is head and neck cancer.

[0360] In some embodiments, the cancer is thyroid cancer.

[0361] In some embodiments, the cancer is prostate cancer.

[0362] In some embodiments, the cancer is glioma.

[0363] In some embodiments, the cancer is cervical cancer.

[0364] In some embodiments, the cancer described herein is a HER2+cancer. In some embodiments, the cancer described herein is a HER2- cancer.

[0365] In some embodiments, the cancer described herein is a HER2-low cancer. In some embodiments, the cancer has a HER2 score (e.g., an IHC score) of 0, +1, or +2. In some embodiments, the cancer has a HER2 score (e.g., an IHC score) of 0 or +1. In some embodiments, the cancer has a HER2 score of 0. In some embodiments, the cancer has a HER2 score of +1. In some embodiments, the cancer has a HER2 score of +2. In some embodiments, the cancer has a HER2 score of +2 or +3. In some embodiments, the cancer has a HER2 score of +3.

[0366] In some embodiments, the cancer described herein is a hormone receptor positive (HR+) cancer. In some embodiments, the cancer described herein is a HER2- and HR+cancer. In some embodiments, the cancer described herein is ER+. In some embodiments, the cancer described herein is PR+. In some embodiments, the cancer is HR+ / ER- breast cancer.

[0367] In some embodiments, the cancer described herein is HR+ and has a HER2 score of 0 or +1. In some embodiments, the cancer described herein is HR+ and has a HER2 score of 0. In some embodiments, the cancer described herein is HR+ and has a HER2 score +1.

[0368] In some embodiments, the cancer described herein is HR+ and has a HER2 score of +2 or +3. In some embodiments, the cancer described herein is HR+ and has a HER2 score of +2. In some embodiments, the cancer described herein is HR+ and has a HER2 score +3.

[0369] In some embodiments the subject has been previously identified or determined not to have an activating mutation in AKT and / or PTEN. 210Attorney Docket No.31457_WO

[0370] In some embodiments, the PI3Kα-associated cancer is selected from the cancers described in Table 1 and Table 2. Table 1. PI3Kα Protein Amino Acid Substitutions / Insertions / DeletionsAAmino Acid Non-Limiting Non-Limiting Exemplary PI3Kα Associated Cancer(s) Position Exemplary211Attorney Docket No.31457_WO 78 E78* (nonsense Lung Squamous Cell Carcinoma mutation)Attorney Docket No.31457_WO Bladder Urothelial Carcinoma Cervical Squamous Cell CarcinomaAttorney Docket No.31457_WO Breast Invasive Ductal Carcinoma Lung Squamous Cell Carcinoma214Attorney Docket No.31457_WO 118 G118D Glioblastoma Multiforme Breast Invasive Ductal Carcinoma215Attorney Docket No.31457_WO Uterine Endometrioid Carcinoma 342 T342S Lung AdenocarcinomaAttorney Docket No.31457_WO 359 G359R Uterine Endometrioid CarcinomaAttorney Docket No.31457_WO Astrocytoma Cervical Squamous Cell CarcinomaAttorney Docket No.31457_WO Rectal Adenocarcinoma Uterine Endometrioid Carcinoma219Attorney Docket No.31457_WO E545Q Uterine Endometrioid Carcinoma Colon Adenocarcinoma220Attorney Docket No.31457_WO Glioblastoma Multiforme Uterine Serous Carcinoma / Uterine Papillary Serous usAttorney Docket No.31457_WO 643 Q643H Uterine Endometrioid Carcinoma 658 L658F Colon Adenocarcinoma222Attorney Docket No.31457_WO 770 R770Q Uterine Endometrioid Carcinoma 773 S773F Cutaneous Melanoma us223Attorney Docket No.31457_WO 971 C971R Head and Neck Squamous Cell Carcinoma 978 E978K Bladder Urothelial CarcinomaAttorney Docket No.31457_WO 1037 E1037K Breast Invasive Ductal Carcinoma 1040 M1040I, M1040V Head and Neck Squamous Cell CarcinomaAttorney Docket No.31457_WO Mucinous Stomach Adenocarcinoma Rectal Adenocarcinoma us omCerami 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. 226Attorney Docket No.31457_WO Table 2. Additional PI3Kα Protein Amino Acid Substitutions / Insertions / DeletionsAAmino Acid Non-Limiting Non-Limiting Exemplary PI3Kα Associated Cancer(s) Position Exemplary227Attorney Docket No.31457_WO Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor us omCerami 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 228Attorney Docket No.31457_WO cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0371] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Kα mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Kα having at least one residue deleted (as compared to the wild type PI3Kα protein) resulting in a constitutive activity of a PI3Kα protein domain.

[0372] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3Kα protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity, as compared to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation.

[0373] 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 229Attorney Docket No.31457_WO LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0374] In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable thereof, is useful for treating a cancer that has been identified as having one or more PI3Kα mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0375] Also provided herein are methods for treating a subject identified or diagnosed as having a PI3Kα-associated cancer that include administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the subject that has been identified or diagnosed as having a PI3Kα -associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Kα- associated cancer.

[0376] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0377] Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a PI3Kα-associated cancer in the subject; and (b) administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a PI3Kα- associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any 230Attorney Docket No.31457_WO of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Kα-associated cancer.

[0378] Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents to the subject determined to have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. In some embodiments of these methods, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a PI3Kα-associated cancer, a subject presenting with one or more symptoms of a PI3Kα-associated cancer, or a subject having an elevated risk of developing a PI3Kα- 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 agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art.

[0379] Also provided is a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for use in treating a PI3Kα-associated cancer in a subject identified or diagnosed as having a PI3Kα- associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, where the presence of a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, identifies that the subject has a PI3Kα-associated cancer. Also provided is the use of a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for the manufacture of a medicament for treating a PI3Kα-associated cancer in a subject identified or diagnosed as having a PI3Kα- associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or 231Attorney Docket No.31457_WO expression or activity or level of any of the same where the presence of dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, identifies that the subject has a PI3Kα-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0380] Also provided is a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a PI3Kα-associated cancer. Also provided is the use of a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer. In some embodiments, a subject is identified or diagnosed as having a PI3Kα-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a PI3Kα-associated cancer includes those described herein and known in the art.

[0381] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. In some embodiments, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. In some embodiments, the subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, 232Attorney Docket No.31457_WO a PI3Kα protein, or expression or activity or level of any of the same. In some embodiments, the subject is suspected of having a PI3Kα-associated cancer. In some embodiments, provided herein are methods for treating a PI3Kα-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more PI3Kα protein point mutations / insertions / deletions. Non-limiting examples of PI3Kα protein point mutations / insertions / deletions are described in Table 1 and Table 2. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Kα protein point mutations / insertions / deletions are selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, the cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

[0382] In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. Also provided are methods of treating a subject that include administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same.

[0383] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a 233Attorney Docket No.31457_WO dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the method includes determining that a subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the dysregulation in a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is one or more point mutation in the PIK3CA gene (e.g., any of the one or more of the PI3Kα point mutations described herein). The one or more point mutations in a PIK3CA gene can result, e.g., in the translation of a PI3Kα protein having 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. The one or more mutations in a PIK3CA gene can result, e.g., in the translation of an PI3Kα protein having one or more of the following amino acids: 542, 545, 1043, and 1047 and 1049. In some embodiments, the dysregulation in a PIK3CA gene, a PI3Kα protein protein, or expression or activity or level of any of the same is one or more PI3Kα amino acid substitutions (e.g., any of the PI3Kα amino acid substitution described herein). Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy).

[0384] In some embodiments, an assay used to determine whether the subject has a dysregulation of a PIK3CA gene, or a PI3Kα protein, or expression or activity or level of any of the same, using a sample from a subject can 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, the assays are typically performed, e.g., with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the sample is a 234Attorney Docket No.31457_WO biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a PI3Kα -associated cancer, a subject having one or more symptoms of a PI3Kα-associated cancer, and / or a subject that has an increased risk of developing a PI3Kα-associated cancer).

[0385] In some embodiments, dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same. 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 a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same.

[0386] Also provided herein is a method of inhibiting cell proliferation, comprising contacting a cell with a compound of Formula (X) (e.g., a compound of Formula (X-1)), and one or two independently selected additional therapeutic agents, as defined herein.

[0387] Further provided herein is a method of increasing cell death, comprising contacting a cell with a compound of Formula (X) (e.g., a compound of Formula (X-1)), and one or two independently selected additional therapeutic agents, as defined herein. 235Attorney Docket No.31457_WO

[0388] Some embodiments provide a method for reducing PI3Kα protein levels in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (X), or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and and one or two independently selected additional therapeutic agents as defined herein, to a subject having a cell having aberrant PI3Kα activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell.

[0390] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein.

[0391] Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or two independently selected additional therapeutic agents, as defined herein. Combinations

[0392] The methods described herein relate to, inter alia, treating cancers (e.g., the cancers described herein, such as breast cancer) with a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0393] Such additional therapeutic agents include additional therapeutic moelcules (e.g., small molecules or antibodies), as well as radiation therapy (or radiotherapy) and surgery, such as open surgery or minimally invasive surgery. Compounds of Formula (X), or pharmaceutically acceptable salts thereof (e.g., a compound of Formula (X-1)), therefore may also be useful as 236Attorney Docket No.31457_WO adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action.

[0394] In some embodiments, a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof) can be used prior to administration of one or more independently selected additional therapeutic agents or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof) for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof) reduces the size of the tumor (e.g., the tumor burden) prior to the 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 (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof) for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof) reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0395] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject of a combination therapy comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0396] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject (a) a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional 237Attorney Docket No.31457_WO therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0397] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising: (a) a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0398] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) testing or having tested a subject to determine that the subject has a PI3Kα-associated cancer, and (b) administering to the subject a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0399] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and 238Attorney Docket No.31457_WO (b) administering to the subject a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0400] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has a PI3Kα-associated cancer; and (b) administering to the subject a combination therapy comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0401] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject (a) a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically 239Attorney Docket No.31457_WO acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0402] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, comprising administering to the subject of a combination therapy comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with one additional therapeutic agent. In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is administered with two independently selected additional therapeutic agents.

[0403] In some embodiments, a 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 multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is PI3Kα inhibitor naïve. For example, the subject is naïve to treatment with a selective PI3Kα inhibitor. In some embodiments, a subject is not PI3Kα inhibitor naïve. In some embodiments, a subject is kinase inhibitor naïve. In some embodiments, a subject is not kinase inhibitor naïve. In some embodiments, a subject has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI) or another PI3K inhibitor, such as buparlisib (BKM120), alpelisib (BYL719), WX-037, idelalisib, duvelisib, copanlisib, umbralisib, (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), fimepinostat (CUDC-907), bimiralisib (PQR309), ZSTK474, SF1126, AZD8835, inavolisib (GDC-0077), ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, 240Attorney Docket No.31457_WO GSK1059615, paxalisib (GDC-0084, RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS-9820), AMG319, or GSK2636771.

[0404] In some embodiments of any the methods described herein, the compound of Formula (X) (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 therapeutic (e.g., chemotherapeutic) agents.

[0405] Non-limiting examples of additional therapeutic agents include: other PI3Kα-targeted therapeutic agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, VEGFR inhibitors / VEGF inhibitors, HER2 inhibitors, MEK pathway targeted therapeutic agents (including RAS pathway targeted therapeutic agents, which includes mTOR modulators / inhibitors, as described herein), SHP2 inhibitors, ULK inhibitors, CDK4 / 6 inhibitors, NTRK / ROS inhibitors, ALK inhibitors, RET inhibitors, MET inhibitors, PARP inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, other kinase inhibitors (e.g., Trk inhibitors or multi-kinase inhibitors), KAT6A inhibitors, farnesyl transferase inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERMs / SERDs, including ERα inhibitors or ERα degraders), vinca alkaloids, anti-metabolites, anti- androgens (e.g., androgen receptor (AR) antagonists, AR degraders, AR modulators), alkylating agents, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutics (also called antineoplastic chemotherapeutics), angiogenesis-targeted therapies (e.g., angiogenesis inhibitors), immune-targeted agents (including immunotherapy), radiotherapy, glucocorticoids, antidiarrheal agents (such as loperamide and diphenoxylate-atropine), antihistamines, and retinoic acid.

[0406] As used herein, a PIM inhibitor is any inhibitor of a Provirus Integration site for Moloney leukemia virus kinase (also sometimes referred to as Proviral Insertion site in Murine leukemia virus protein kinase), e.g., PIM1, PIM2, and PIM3, and any isoforms thereof (e.g., PIM-1L (molecular mass of 44^kDa) and PIM-1S (molecular mass of 33^kDa)). PIM kinases regulate cell proliferation, survival, metabolism, cellular trafficking and signaling and are overexpressed in a number of human cancers. Non-limiting examples of PIM1 inhibitors include A47, Abemaciclib (Verzenio; NCT03905889), AZD1208 (NCT01588548), AZD1897, ETH-155008, ETP-390101, ETP-45299, ETP-47551, INCB053914 (Uzansertib), JP11646, K00135, K00486, LGB321, LGH447 (PIM447), PIM447, SEL24 / MEN1703 (SEL24-B489), SGI-1776, and TP-3654 (See, 241Attorney Docket No.31457_WO Belon and Nicot (2023) Mol. Cancer 22(1): 18; Mahata S., et a;. (2022) Med. Oncol. 39(5): 74; Asasti V., et al. (2019) Eur J Med Chem. 172:95-108; Le X., et al. (2016) Cancer Discov. 6(10): 1134-47; Keeton EK, et al. (2014) Blood 123: 905-13; Garcia P., et al. (2013) ASH 122:1666; Grundler R, et al. (2009) J Exp Med.206(9):1957-70; Pogacic V., et al., (2007) Cancer Res. 67(14):6916–6924).

[0407] Exemplary SHP2 inhibitors include JAB-3312, SHP099, SHP099 hydrochloride, SHP504, RMC-3943, AS1949490, SHP394, SHP389, and RMC-4630.

[0408] In some embodiments, the SHP2 inhibitor is RMC-4630.

[0409] Exemplary ULK inhibitors include ULK-101, SBP-7455, SBI-0206965, ULK1-IN-2, MRT68921, MRT68921 dihydrochloride, MRT67307, MRT67307 hydrochloride, XST-14, and GW406108X (CW108X).

[0410] Exemplary NTRK / ROS inhibitors include entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),

[0411] Exemplary ALK inhibitors include crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440.

[0412] Exemplary RET inhibitors include selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

[0413] Exemplary MET inhibitors include capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL- 504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS- 115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).

[0414] Exemplary TRK or multi-targeted kinase inhibitors include altiratinib (DCC-2701), CH7057288, larotrectinib (VITRAKVI®), entrectinib, ANA-12, repotrectinib (TPX-0005), sitravatinib (MGCD516, MG-516), lestaurtinib (CEP-701, KT-5555), tyrphostin AG 879 (AG 879), and selitrectinib (LOXO-195). 242Attorney Docket No.31457_WO

[0415] Exemplary tyrosine kinase inhibitors include axitinib (INLYTA®), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), imatinib (GLIVEC), nilotinib (TASIGNA®), pazopanib (VOTRIENT®), sunitinib (SUTENT®), and vemurafenib

[0416] Exemplary vinca alkaloids include vinorelbine, vinblastine, vincristine, vindesine, and vinflunine.

[0417] Exemplary antimetabolites include methotrexate, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine (XELODA®), floxuridine, cytarabine (ARA-C®), fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, pemetrexed (ALIMTA®), phototrexate, decitabine, vidaza, DFP-11207, and RX-3117, TAS-114

[0418] Exemplary alkylating agents include cyclophosphamide, lomustine, carmustine, streptozocin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, melphalan, busulfan, dacarbazine, temozolomide, altretamine, thiotepa, carboplatin, cisplatin, lurbinectedin, trabectedin, carmustine, oxaliplatin, and oxaliplatin.

[0419] Exemplary checkpoint inhibitors include nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR- 022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO- 201, defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trebananib, FP-1305, enapotamab vedotin (EnaV), and bavituximab.

[0420] Exemplary modulators of the apoptosis pathway include obataclax, oblimersen, ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), Z-VAD-FMK, emricasan, Q-VD-Oph, Z- VAD(OH)-FMK, belnacasan (caspase-1), Z-DEVD-FMK (caspase-3), Q-VD-OphZ-IETD-FMK (caspase-8), PAC-1 (procaspase-3), nutlin-3, nutlin-3a, idasanutlin, HDM201, APR-246, CBL0137, pifithrin-α, pifithrin-μ, Z-VAD-FMK, Emricasan, Q-VD-Oph, Z-VAD(OH)-FMK, pomalidomide, lenalidomide, YM155, Venetoclax (Bcl-2), S63845 (MCL-1), and A-1331852 (BCL-XL).

[0421] Exemplary cytotoxic chemotherapeutics include 5-fluorouracil, gemcitibine, methotrexate, NB1011, cyclophosphamide, dacarbazine, melphalan, tracectedin, temozolomide, doxorubicin, 243Attorney Docket No.31457_WO daunrorubincin, mitoxantrone, vinblastine, paclitaxel, docetaxel, irinotecan, etoposide, and platinum agents such as carboplatin, cisplatin, and oxaliplatin.

[0422] Exemplary topoisomerase inhibitors include etoposide, irinotecan, Camptothecin (CPT), topotecan (TPT), irinotecan, belotecan, indenoisoquinoline, phenanthridines, and indolocarbazoles. Additional examples of topoisomerase inhibitors include aminocamptothecin, CT-2106, crisnatol mesylate, DE-310, elinafide, lucanthone, MLN576, and mitindomide.

[0423] Exemplary angiogenesis-targeted therapies include bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, CM101, IFN-α, IL-12, platelet factor-4, suramin, SU5416 thrombospondin, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, linomide, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib, everolimus, lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST® or Imnovid ®), marimistat, 2-methoxyestradiol (PANZEM), SU5415, SU6668, pemaxanib, sunitinib, vandetanib, vitaxin, YM598, ZD6126, and aflibercept.

[0424] In some embodiments, the angiogenesis targeted therapy is lenalidomide.

[0425] In some embodiments, the angiogenesis targeted therapy is pomalidomide.

[0426] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), maverlertinib (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, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT- 414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), 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), lazertinib (YH25448), epitinib (HMPL-813), olafertinib (CK-101, RX518), MM-151, zorifertinib (AZD3759), vandetanib (ZD6474), PF- 06459988, varlintinib (ASLAN001, ARRY-334543), mobocertinib (AP32788, TAK-788), 244Attorney Docket No.31457_WO pimurutamab (HLX07), befotertinib (D-0316), AEE788 (NVP-AEE788), aumolertinib (formerly almonertinib, HS-10296), avitinib, lapatinib (GW572016), pyrotinib (SHR1258), SCT200, CPGJ602, Sym004 (combination of futuximab and modotuximab), EMD 55900 (MAb-425), modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, RO5083945, laprituximab emtansine (IMGN289), amivantamab (RYBREVANTTM, JNJ-61186372), LY3164530, Pan-HER (Sym013), AMG 595, tuxobertinib (BDTX-189), avatinib, disruptin, CL-387785 (EKI-785, WAY-EKI 785), EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from gefitinib, erlotinib, afatinib, lapatinib, neratinib, osimertinib (AZD-9291, e.g., TAGRISSO®), CL-387785 (EKI-785, WAY- EKI 785), rociletinib (CO-1686), WZ4002, OMP-305B83, trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), RG-7597, and amivantanab.

[0427] In some embodiments, the EGFR inhibitor is lazertinib. In some embodiments, the EGFR inhibitor is amivantanab. In some embodiments, the EGFR inhibitor is trastuzumab.

[0428] Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), fam-trastuzumab deruxtecan (ENHERTU®), lapatinib, KU004, neratinib(e.g., NERLYNX®), 245 envatinib 245 govitecan-hziy (TRODELVY®) dacomitinib (e.g.,VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (irbinitinib, ONT-380, ARRY-380, e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, dacomitinib (PF299804, PF299), pelitinib, margetuximab, AEE-788 (NVP-AEE788), enfortumab vedotin (PADCEV®), and datopotamab deruxtecan.

[0429] In some embodiments, the HER2 inhibitor is fam-trastuzumab deruxtecan. In some embodiments, the HER2 inhibitor is 245envatinib245 govitecan-hziy. In some embodiments, the HER2 inhibitor is datopotamab deruxtecan.

[0430] Exemplary VEGFR inhibitors / VEGF inhibitors include pazopanib, sunitinib,245envatinib245 , cabozantinib, sorafenib, regorafenib, ponatinib, 245envatinib axitinib, ziv-aflibercept, vandetanib, tivozanib, vatalanib, AZD-2932, aflibercept, vanucizumab, BI836880, double antiangiogenic protein (DAAP), and ramucirumab.

[0431] A “MEK pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a MEK pathway including any protein in the RAS 245Attorney Docket No.31457_WO pathway and the RAF pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors, as described herein), AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.

[0432] Non-limiting examples of RAS-targeted therapeutic agents include sotorasib (AMG 510, Lumakras®), adagrasib (MRTX849), tipifarnib (R115777, zarnestra), cysmethynil, UCM-1336, deltarasin, NHTD, RM007, RM008, gefitinib, apatinib, oncrasin-1, vismodegib (GDC-0449), N- (1-Acryloylazetidin-3-yl)-2-(5-bromo-3-(5-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 1H-indol-1-yl) acetamide, 2-((4-((1-(2-(2,4-Dichlorophenoxy) acetyl) piperidin-4-yl) amino)-4- oxobutyl) disulfaneyl)-N,N-dimethylethan-1-aminium, ARS-1620, ARS-853, bemcentinib (BGB324), ABT-737, selumetinib (AZD6244), dactolisib (NVP-BEZ235), PPIN-1, PPIN-2, pan- RAS Inhibitor 3144 (RAS-IN-3144), deltarasin, SML-8-73-1, SML-10-70-1, 1-(2-hydroxyethyl)- 4-(2-methyl-3,5-diphenylpyrazolo[1,5-a] pyrimidin-7-yl) piperazin-1-ium, (2R,4aR)-3-acryloyl- 11-chloro-9-fluoro-10-(6-fluoro-2-hydroxycyclohexa-2,4-dien-1-yl)-2,6-dimethyl-2,3,4,4a- tetrahydro-1H-pyrazino [1’,2’:4,5] pyrazino[2,3-c] quinolin-5(6H)-one, NHTD, PD98059, wortmannin, talniflumate, gefitinib, CPD-0857, KY1022, KYA1797K (ab229170), 0375-0604 246Attorney Docket No.31457_WO (DUN09716), 7773, NSC-658497, JNJ-74699157, PKF115-584 (calphostin C), Kobe0065, Kobe2602, salirasib, 3,3’-(ethylazanediyl)bis(N-phenylpropanamide), ML264, GDC-6036, LY3499446, and D-1553.

[0433] Non-limiting examples of KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, sotorasib (AMG 510), ARS-3248 (JNJ-74699157), ARS1620, AZD4785 (ION651987), SML-8-73-1, SML-10-70-1, VSA9, AA12, adagrasib (MRTX-849), LY3499446, ARS853, and siG12D LODER.

[0434] Non-limiting examples of HRAS-targeted therapeutic agent (e.g., HRAS inhibitors) include tipifarnib (ZARNESTRA®). Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the

[0435] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), mirdametinib (PD0325901), pimasertib (MSC1936369B), SHR7390, TAK-733, RO5126766 (CH5126766), CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0436] In some embodiments, the ERK inhibitor is amerliorex (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, temuterkib (LY-3214996), rineterkib (LTT-462), KO-947, MK- 8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, ravoxertinib (GDC-0994, RG-7482), ASN007, 5Z-7-oxozeaenol (FR148083, L783279, LL-Z 1640-2), 5-iodotubercidin (NSC 113939), ONC201 (TIC10), or a combination thereof.

[0437] In some embodiments, the anti-androgen is leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), enzalutamide (MDV3100, XTANDI®), abiraterone (ZYTIGA®), flutamide (EULEXIN®), AR inhibitor EPI-506, apalutamide (ERLEADA®), and darolutamide (NUBEQA®).

[0438] In some embodiments, the other PI3K inhibitor is another PI3Kα inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719, PIQRAY®), idelalisib, 247Attorney Docket No.31457_WO duvelisib, umbralisib, WX-037, copanlisib (ALIQOPA®, BAY80-6946), dactolisib (NVP- BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), fimepinostat (CUDC- 907), bimiralisib (PQR309), ZSTK474, SF1126, AZD8835, inavolisib (GDC-0077), ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, paxalisib (GDC-0084, RG7666), VS-5584 (SB2343), PKI- 402, wortmannin, LY294002, PI-103, rigosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS-9820), AMG319, GSK2636771, or a combination thereof.

[0439] In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, capivasertib (AZD5363), ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib (GSK2141795), afuresertib (GSK2110183), DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK- 2206, edelfosine, miltefosine, perifosine (KRX-0401), erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427 (CS-0223), 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, miransertib (ARQ092), BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, ONC201 (TIC10), and TAS117.

[0440] In some embodiments, the AKT inhibitor is capivasertib.

[0441] In some embodiments, the mTOR inhibitor is an analog of rapamycin. Examples of analogs of ramapycin include sapanisertib (MLN0128), vistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), everolimus (RAD001, e.g., AFINITOR® or ZORTRESS®), umirolumus, zotarolimus, and RMC-5552. In some embodiments, the mTOR inhibitor is an ATP-competitive mTOR kinase inhibitor, which compete with ATP in the catalytic site of mTOR. Examples of ATP-competitive mTOR kinase inhibitors can include torin-1, torin-2, and vestusertib. Types of ATP-competitive mTOR kinase inhibitors can include mTOR / PI3J dual inhibitors and mTORC1 / mTORC2 dual inhibitors (also called TORCdIs). Examples of mTOR / PI3K dual inhibitors include dactolisib, voxtalisib, BGT226, SF1126, PKI- 248Attorney Docket No.31457_WO 587, NVPBE235. Example of mTORC1 / mTORC2 dual inhibitors include sapanisertib (codenamed INK128), AZD8055, and AZD2014.

[0442] Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0443] In some embodiments, a chemotherapeutic agent includes an anthracycline, alkylating agents, a taxane, a platinum-based agent, mitomycin, gemcitabine, pemetrexed, eribulin (HALAVENTM), or combinations thereof.

[0444] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0445] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin.

[0446] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and lobaplatin. Any of the platinum-based agents can be conjugated to a nanocarrier, such as a gold nanocluster, a gold nanoparticle, or a superparamagnetic iron oxide nanoparticles. See, for example, Zhang et al. 2022. Theranostics. 12(5):2115-2132.

[0447] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP-9883, CEP 9722, E7016 (GPI 21016), iniparib, senaparib (IMP4297), venadaparib-idience (NOV1401, IDX-1197), stenoparib (2X-121), ABT-767, atamparib (RBN-2397), talazoparib (BMN 673), olaparib (KU-0059436, AZD2281, e.g. LYNPARZATM), iniparib (BSI-201, SAR240550), rucaparib (A G-014699, PF-01367338), INO-1001, and amelparib (JPI-289).

[0448] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0449] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include clomifene, cyclofenil, anordrin, broparestrol, nafoxidine, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, afimoxifene, enclomiphene, serophene, arzoxifene, tamoxifen, etacstil (GW-5638, DPC974), fulvestrant (FASLODEX®), brilanestrant, elacestrant (ORSERDUTM), giredestrant, amcenestrant (SAR439859), camizestrant (AZD9833), rintodestrant, imlunestrant, LSZ102, LY3484356, ZN-c5, taragarestrant (D-0502), AZD9496, clotrimazole, fenticonazole, SHR9549, and palazestrant (OP-1250). 249Attorney Docket No.31457_WO

[0450] In some embodiments, the SERM / SERD is palazestrant. In some embodiments, the SERM / SERD is elacestrant. In some embodiments, the SERM / SERD is camizestrant.

[0451] Non-limiting examples of glucocorticoids include dexamethasone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

[0452] In some embodiments, the glucocorticoid is dexamethasone.

[0453] In some embodiments, the additional therapeutic agent is retinoic acid.

[0454] Non-limiting examples of epigenetic agents include EZH2 inhibitors (e.g., tazemetostat, such as TAZVERIK ®, 3-deazaneplanocin A (DZNep or C-c3Ado), EPZ005687, EI1, GSK126, and UNC1999) and HDAC inhibitors (e.g., vorinostat (SAHA) and panobinostat (LBH589)). Non- limiting examples of HDAC inhibitors include hydroxamic acids (or hydroxamates), such as trichostatin A,vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589); cyclic tetrapeptides, such as trapoxin B, and depsipeptides; benzamides, such as entinostat (MS- 275), tacedinaline (CI994), and mocetinostat (MGCD0103); electrophilic ketones; and aliphatic acid compounds such as phenylbutyrate and valproic acid.

[0455] In some emodiments, the epigenetic agent is an EZH2 inhibitor. In some embodiments, the epigenetic agent is tazemetostat. In some embodiments, the EZH2 inhibitor is tazemetostat.

[0456] In some emodiments, the epigenetic agent is a HDAC inhibitor. In some embodiments, the epigenetic agent is vorinostat. In some embodiments, the epigenetic agent is panobinostat. In some embodiments, the HDAC inhibitor is vorinostat. In some embodiments, the HDAC inhibitor is panobinostat.

[0457] Non-limiting examples of KAT6A inhibitors include WM-8014, PF-07248144, CTx- 648 (PF-9363), and CTX-0124143. In some embodiments, the KAT6A inhibitor is WM-8014. In some embodiments, the KAT6A inhibitor is PF-07248144. In some embodiments, the KAT6A inhibitor is CTx-648. In some embodiments, the KAT6A inhibitor is CTX-0124143.

[0458] Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 250Attorney Docket No.31457_WO inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®), atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), avelumab (BAVENCIO®), dostarlimab (JEMPERLI®), retifanlimab (ZYNYZ®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), orAcrixolimab (YBL- 006). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is leramilimab (IMP701, LAG525). In some embodiments, the A2AR inhibitor is ciforadenant (CPI-444). In some embodiments, the TIM-3 inhibitor is sabatolimab (MBG453). In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is onvatilimab (JNJ-61610588). In some embodiments, the IDO inhibitor is indoximod. See, for example, Table 1 of Marin-Acevedo, et al., J Hematol Oncol. 11: 39 (2018), which is incorporated in its entirety herein.

[0459] In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (IBRANCE®, TQB3616, PD-0332991), ribociclib (KISQALI®), abemaciclib (VERZENIO®), voruciclib (P1446A-05), trilaciclib, dalpiciclib (SHR6390), roniciclib (BAY1000394), dinaciclib, flavopiridol (alvociib, L868275, HMR-1275), roscovitine (R-roscovitine, CYC202, seliciclib), riviciclib (P276-00, P276), AT7519, TG02 (SB1317), RGB-286638, dinaciclib (SCH 727965), PHA-793887, ZK-304709, xytocydine, SNS032 (BMS-387032), R547 (R0 4584820), RGB286147, prvalanol A (NG60), meriolin 3, JNJ7706621, indirubin, AZD-5438, 10Z- hymenialdisine, AGO24322, PF-06873600,and KIN-8741.

[0460] In some embodiments, the CDK4 / 6 inhibitor is KIN-8741. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is dalpiciclib. In some embodiments, the CDK4 / 6 inhibitor is voruciclib. In some embodiments, the CDK4 / 6 inhibitor is roniciclib. In some embodiments, the CDK4 / 6 inhibitor is dinaciclib.

[0461] In some embodiments, the additional therapy or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab- 251Attorney Docket No.31457_WO paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, palbociclib (IBRANCE®), buparlisib, sotrastaurin (AEB071), everolimus, exemestane, cisplatin, letrozole, ganitumab (AMG 479), LSZ102, ribociclib (LEE011), cetuximab, luminespib (NVP- AUY922, AUY922), infigratinib (BGJ398), binimetinib (MEK162, ARRY-162, ARRY-438162), LJM716, PIM447 (LGH447, LGB321), imatinib, gemcitabine, encorafenib (LGX818), and amcenestrant.

[0462] In some embodiments, the additional therapeutic agent is everolimus. In some embodiments, additional therapeutic agents may also be administered to treat potential side-effects for particular anticancer therapies and / or as palliative therapy, for example, opioids and corticosteroids. In some embodiments, the additional therapy or therapeutic agent described herein is selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, a sodium-glucose transport protein 2 (SGLT-2) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, metformin, and combinations thereof.

[0463] Non-limiting examples of GLP-1 receptor agonists include liraglutide (NN2211, e.g., VICTOZA®,), dulaglutide (LY2189265, e.g., TRULICITY®), exenatide (e.g., BYETTA®, BYDUREON®, Exendin-4), taspoglutide, lixisenatide (e.g., LYXUMIA®), albiglutide (e.g., TANZEUM®), semaglutide (e.g., OZEMPIC®, RYBELSUS®), ZP2929, NNC0113-0987 (QBR110395), BPI-3016, and TT401.

[0464] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (e.g., INVOKANA®), dapagliflozin (e.g., FARXIGA®), empagliflozin (e.g., JARDIANCE®), ertugliflozin (e.g., STEGLATRO™), ipragliflozin (e.g., SUGLAT®), luseogliflozin (e.g., LUSEFI®), remogliflozin, serfliflozin, licofliglozin, sotagliflozin (e.g., ZYNQUISTATM), and tofogliflozin.

[0465] Non-limiting examples of DPP-4 inhibitors include, sitagliptin (e.g., JANUVIA®), vildagliptin, saxagliptin (e.g., ONGLYZA®), linagliptin (e.g., TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (e.g., NESINA®), omarigliptin, evogliptin, and dutogliptin.

[0466] In some embodiments, the additional therapeutic agent is metformin. In some embodiments, the methods described herein further comprise administering a therapeutically effective amount of metformin to the subject. 252Attorney Docket No.31457_WO

[0467] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one additional therapeutic agent, for example, an aromatase inhibitor, a CDK4 / 6 inhibitor, a SERM / SERD, radiation therapy, an anti-HER2 antibody or antibody-drug conjugate (ADC) thereof, an immunotherapy, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), VEGFR inhibitors / VEGF inhibitors, KAT6A inhibitors (also called MOZ inhibitors or MYST3 inhibitors), PI3Kα inhibitors, MEK pathway targeted therapeutic agents (including RAS pathway targeted therapeutic agents, which includes mTOR inhibitors, as described herein), SHP2 inhibitors, ULK inhibitors, NTRK / ROS inhibitors, ALK inhibitors, RET inhibitors, MET inhibitors, PARP inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, other kinase inhibitors (e.g., Trk inhibitors or multi-kinase inhibitors), farnesyl transferase inhibitors, vinca alkaloids, anti-metabolites, anti-androgens, alkylating agents, checkpoint inhibitors, modulators of the apoptosis pathway; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents including immunotherapy, or an anti-EGFR antibody.

[0468] In some embodiments, the additional therapeutic agent is an antibody or ADC as described herein. In some embodiments, the antibody is daratumumab (e.g., DARZALEX®).

[0469] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one additional therapeutic agent, for example, a HER2 inhibitor, a SERM / SERD, a CDK4 / 6 inhibitor, a MEK inhibitor, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), a multi-kinase inhibitor, and a PI3K inhibitor.

[0470] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one additional therapeutic agent, for example, trastuzumab, pertuzumab, trastuzumab emtansine, fam-trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, tanespimycin, dacomitinib, pelitinib, margetuximab, clomifene, cyclofenil, broparestrol, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, enclomiphene, serophene, tamoxifen, fulvestrant, elacestrant, camizestrant, rintodestrant, clotrimazole, fenticonazole, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, 253Attorney Docket No.31457_WO mirdametinib, pimasertib, alpelisib, idelalisib, duvelisib, copanlisib, umbralisib, ribociclib, triaciclib, dalpiciclib, voruciclib, and roniciclib.

[0471] In some embodiments, the additional therapeutic agent is fulvestrant.

[0472] In some embodiments, the additional therapeutic agent is lapatinib.

[0473] In some embodiments, the additional therapeutic agent is abemaciclib.

[0474] In some embodiments, the additional therapeutic agent is trametinib.

[0475] In some embodiments, the additional therapeutic agent is binimetinib.

[0476] In some embodiments, the additional therapeutic agent is alpelisib.

[0477] In some embodiments, the additional therapeutic agent is palbociclib.

[0478] In some embodiments, the additional therapeutic agent is ribociclib.

[0479] In some embodiments, the additional therapeutic agent is trilaciclib.

[0480] In some embodiments, the additional therapeutic agent is dalpiciclib.

[0481] In some embodiments, the additional therapeutic agent is voruciclib.

[0482] In some embodiments, the additional therapeutic agent is roniciclib.

[0483] In some embodiments, the additional therapeutic agent is dinaciclib.

[0484] In some embodiments, the additional therapeutic agents are palbociclib and clomifene.

[0485] In some embodiments, the additional therapeutic agents are palbociclib and cyclofenil.

[0486] In some embodiments, the additional therapeutic agents are palbociclib and anordrin.

[0487] In some embodiments, the additional therapeutic agents are palbociclib and broparestrol.

[0488] In some embodiments, the additional therapeutic agents are palbociclib and nafoxidine.

[0489] In some embodiments, the additional therapeutic agents are palbociclib and ormeloxifene.

[0490] In some embodiments, the additional therapeutic agents are palbociclib and raloxifene.

[0491] In some embodiments, the additional therapeutic agents are palbociclib and toremifene.

[0492] In some embodiments, the additional therapeutic agents are palbociclib and lasofoxifene.

[0493] In some embodiments, the additional therapeutic agents are palbociclib and bazedoxifene.

[0494] In some embodiments, the additional therapeutic agents are palbociclib and ospemifene.

[0495] In some embodiments, the additional therapeutic agents are palbociclib and afimoxifene.

[0496] In some embodiments, the additional therapeutic agents are palbociclib and enclomiphene.

[0497] In some embodiments, the additional therapeutic agents are palbociclib and serophene.

[0498] In some embodiments, the additional therapeutic agents are palbociclib and arzoxifene.

[0499] In some embodiments, the additional therapeutic agents are palbociclib and tamoxifen. 254Attorney Docket No.31457_WO

[0500] In some embodiments, the additional therapeutic agents are palbociclib and etacstil.

[0501] In some embodiments, the additional therapeutic agents are palbociclib and fulvestrant.

[0502] In some embodiments, the additional therapeutic agents are palbociclib and brilanestrant.

[0503] In some embodiments, the additional therapeutic agents are palbociclib and elacestrant.

[0504] In some embodiments, the additional therapeutic agents are palbociclib and giredestrant.

[0505] In some embodiments, the additional therapeutic agents are palbociclib and amcenestrant.

[0506] In some embodiments, the additional therapeutic agents are palbociclib and camizestrant.

[0507] In some embodiments, the additional therapeutic agents are palbociclib and rintodestrant.

[0508] In some embodiments, the additional therapeutic agents are palbociclib and imlunestrant.

[0509] In some embodiments, the additional therapeutic agents are palbociclib and LSZ102.

[0510] In some embodiments, the additional therapeutic agents are palbociclib and LY3484356.

[0511] In some embodiments, the additional therapeutic agents are palbociclib and ZN-c5.

[0512] In some embodiments, the additional therapeutic agents are palbociclib and taragarestrant.

[0513] In some embodiments, the additional therapeutic agents are palbociclib and AZD9496.

[0514] In some embodiments, the additional therapeutic agents are palbociclib and clotrimazole.

[0515] In some embodiments, the additional therapeutic agents are palbociclib and fenticonazole.

[0516] In some embodiments, the additional therapeutic agents are palbociclib and SHR9549.

[0517] In some embodiments, the additional therapeutic agents are palbociclib and palazestrant.

[0518] In some embodiments, the additional therapeutic agents are ribociclib and clomifene.

[0519] In some embodiments, the additional therapeutic agents are ribociclib and cyclofenil.

[0520] In some embodiments, the additional therapeutic agents are ribociclib and anordrin.

[0521] In some embodiments, the additional therapeutic agents are ribociclib and broparestrol.

[0522] In some embodiments, the additional therapeutic agents are ribociclib and nafoxidine.

[0523] In some embodiments, the additional therapeutic agents are ribociclib and ormeloxifene.

[0524] In some embodiments, the additional therapeutic agents are ribociclib and raloxifene.

[0525] In some embodiments, the additional therapeutic agents are ribociclib and toremifene.

[0526] In some embodiments, the additional therapeutic agents are ribociclib and lasofoxifene.

[0527] In some embodiments, the additional therapeutic agents are ribociclib and bazedoxifene.

[0528] In some embodiments, the additional therapeutic agents are ribociclib and ospemifene.

[0529] In some embodiments, the additional therapeutic agents are ribociclib and afimoxifene.

[0530] In some embodiments, the additional therapeutic agents are ribociclib and enclomiphene. 255Attorney Docket No.31457_WO

[0531] In some embodiments, the additional therapeutic agents are ribociclib and serophene.

[0532] In some embodiments, the additional therapeutic agents are ribociclib and arzoxifene.

[0533] In some embodiments, the additional therapeutic agents are ribociclib and tamoxifen.

[0534] In some embodiments, the additional therapeutic agents are ribociclib and etacstil.

[0535] In some embodiments, the additional therapeutic agents are ribociclib and fulvestrant.

[0536] In some embodiments, the additional therapeutic agents are ribociclib and brilanestrant.

[0537] In some embodiments, the additional therapeutic agents are ribociclib and elacestrant.

[0538] In some embodiments, the additional therapeutic agents are ribociclib and giredestrant.

[0539] In some embodiments, the additional therapeutic agents are ribociclib and amcenestrant.

[0540] In some embodiments, the additional therapeutic agents are ribociclib and camizestrant.

[0541] In some embodiments, the additional therapeutic agents are ribociclib and rintodestrant.

[0542] In some embodiments, the additional therapeutic agents are ribociclib and imlunestrant.

[0543] In some embodiments, the additional therapeutic agents are ribociclib and LSZ102.

[0544] In some embodiments, the additional therapeutic agents are ribociclib and LY3484356.

[0545] In some embodiments, the additional therapeutic agents are ribociclib and ZN-c5.

[0546] In some embodiments, the additional therapeutic agents are ribociclib and taragarestrant.

[0547] In some embodiments, the additional therapeutic agents are ribociclib and AZD9496.

[0548] In some embodiments, the additional therapeutic agents are ribociclib and clotrimazole.

[0549] In some embodiments, the additional therapeutic agents are ribociclib and fenticonazole.

[0550] In some embodiments, the additional therapeutic agents are ribociclib and SHR9549.

[0551] In some embodiments, the additional therapeutic agents are ribociclib and palazestrant.

[0552] In some embodiments, the additional therapeutic agents are abemaciclib and clomifene.

[0553] In some embodiments, the additional therapeutic agents are abemaciclib and cyclofenil.

[0554] In some embodiments, the additional therapeutic agents are abemaciclib and anordrin.

[0555] In some embodiments, the additional therapeutic agents are abemaciclib and broparestrol.

[0556] In some embodiments, the additional therapeutic agents are abemaciclib and nafoxidine.

[0557] In some embodiments, the additional therapeutic agents are abemaciclib and ormeloxifene.

[0558] In some embodiments, the additional therapeutic agents are abemaciclib and raloxifene.

[0559] In some embodiments, the additional therapeutic agents are abemaciclib and toremifene.

[0560] In some embodiments, the additional therapeutic agents are abemaciclib and lasofoxifene.

[0561] In some embodiments, the additional therapeutic agents are abemaciclib and bazedoxifene. 256Attorney Docket No.31457_WO

[0562] In some embodiments, the additional therapeutic agents are abemaciclib and ospemifene.

[0563] In some embodiments, the additional therapeutic agents are abemaciclib and afimoxifene.

[0564] In some embodiments, the additional therapeutic agents are abemaciclib and enclomiphene.

[0565] In some embodiments, the additional therapeutic agents are abemaciclib and serophene.

[0566] In some embodiments, the additional therapeutic agents are abemaciclib and arzoxifene.

[0567] In some embodiments, the additional therapeutic agents are abemaciclib and tamoxifen.

[0568] In some embodiments, the additional therapeutic agents are abemaciclib and etacstil.

[0569] In some embodiments, the additional therapeutic agents are abemaciclib and fulvestrant.

[0570] In some embodiments, the additional therapeutic agents are abemaciclib and brilanestrant.

[0571] In some embodiments, the additional therapeutic agents are abemaciclib and elacestrant.

[0572] In some embodiments, the additional therapeutic agents are abemaciclib and giredestrant.

[0573] In some embodiments, the additional therapeutic agents are abemaciclib and amcenestrant.

[0574] In some embodiments, the additional therapeutic agents are abemaciclib and camizestrant.

[0575] In some embodiments, the additional therapeutic agents are abemaciclib and rintodestrant.

[0576] In some embodiments, the additional therapeutic agents are abemaciclib and imlunestrant.

[0577] In some embodiments, the additional therapeutic agents are abemaciclib and LSZ102.

[0578] In some embodiments, the additional therapeutic agents are abemaciclib and LY3484356.

[0579] In some embodiments, the additional therapeutic agents are abemaciclib and ZN-c5.

[0580] In some embodiments, the additional therapeutic agents are abemaciclib and taragarestrant.

[0581] In some embodiments, the additional therapeutic agents are abemaciclib and AZD9496.

[0582] In some embodiments, the additional therapeutic agents are abemaciclib and clotrimazole.

[0583] In some embodiments, the additional therapeutic agents are abemaciclib and fenticonazole.

[0584] In some embodiments, the additional therapeutic agents are abemaciclib and SHR9549.

[0585] In some embodiments, the additional therapeutic agents are abemaciclib and palazestrant.

[0586] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and two additional independently selected therapeutic agents, for example, a HER2 inhibitor, a SERM / SERD, a CDK4 / 6 inhibitor, a MEK inhibitor, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), a multi-kinase inhibitor, and a PI3K inhibitor. 257Attorney Docket No.31457_WO

[0587] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and two additional independently selected therapeutic agents, for example, trastuzumab, pertuzumab, trastuzumab emtansine, fam- trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, tanespimycin, dacomitinib, pelitinib, margetuximab, clomifene, cyclofenil, broparestrol, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, enclomiphene, serophene, tamoxifen, fulvestrant, elacestrant, camizestrant, rintodestrant, clotrimazole, fenticonazole, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib, pimasertib, alpelisib, idelalisib, duvelisib, copanlisib, and umbralisib.

[0588] In some embodiments, the additional therapeutic agents are fulvestrant and lapatinib.

[0589] In some embodiments, the additional therapeutic agents are fulvestrant and trametinib.

[0590] In some embodiments, the additional therapeutic agents are fulvestrant and binimetinib.

[0591] In some embodiments, the additional therapeutic agents are fulvestrant and alpelisib.

[0592] In some embodiments, the additional therapeutic agents are fulvestrant and trilaciclib.

[0593] In some embodiments, the additional therapeutic agents are fulvestrant and dalpiciclib.

[0594] In some embodiments, the additional therapeutic agents are fulvestrant and voruciclib.

[0595] In some embodiments, the additional therapeutic agents are fulvestrant and roniciclib.

[0596] In some embodiments, the additional therapeutic agents are fulvestrant and dinaciclib.

[0597] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and an ERα inhibitor or degrader (e.g., a SERM or SERD).

[0598] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0599] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0600] In some embodiments, the method comprises administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and alpelisib.

[0601] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and an ERα inhibitor or degrader. 258Attorney Docket No.31457_WO

[0602] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0603] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0604] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and alpelisib.

[0605] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, an ERα inhibitor or degrader, and a CDK4 / 6 inhibitor.

[0606] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, fulvestrant, and a CDK4 / 6 inhibitor.

[0607] In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, fulvestrant, and palbociclib. In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, fulvestrant, and ribociclib. In some embodiments, the method consists essentially of administering a compound of Formula (X), or a pharmaceutically acceptable salt thereof, fulvestrant, and abemaciclib.

[0608] In some embodiments, the method comprises administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and an ERα inhibitor or degrader (e.g., a SERM or SERD).

[0609] In some embodiments, the method comprises administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0610] In some embodiments, the method comprises administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0611] In some embodiments, the method comprises administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and alpelisib.

[0612] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and an ERα inhibitor or degrader. 259Attorney Docket No.31457_WO

[0613] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0614] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0615] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, and alpelisib.

[0616] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, an ERα inhibitor or degrader, and a CDK4 / 6 inhibitor.

[0617] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, fulvestrant, and a CDK4 / 6 inhibitor.

[0618] In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, fulvestrant, and palbociclib. In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, fulvestrant, and ribociclib. In some embodiments, the method consists essentially of administering a compound of Formula (X) (e.g., a compound of Formula (X-1)), or a pharmaceutically acceptable salt thereof, fulvestrant, and abemaciclib. Pharmaceutical Compositions

[0619] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (X), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 260Attorney Docket No.31457_WO EXAMPLES Compound Preparation

[0620] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.

[0621] 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. Although not 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 and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

[0622] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. 261Attorney Docket No.31457_WO Example 1: Preparation of Compound 1 and Compound 2.

[0623] To a mixture of pyrimidine-2,5-diamine (3.0 g, 27.2 mmol) and NaHCO3(11.4g, 135.9 mmol) in THF (300 mL) was added phenyl carbonochloridate (4.5 g, 28.5 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 4 h. After reaction, the reaction mixture was concentrated to give a residue which was purified by silica gel chromatography column (DCM / MeOH from 0 ~ 10%) to give phenyl (2-aminopyrimidin-5-yl)carbamate (2.2 g, 34%) as a brown solid. MS (ESI): mass calcd. for C11H10N4O2, 230.1, m / z found 231.1 [M+H]+. Step 2

[0624] To a solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one (20 g, 116.2 mmol) in DMF (200 mL) were added methyl 2-bromoacetate (19.4 g, 127.9 mmol) and K2CO3 (24.1 g, 174.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After reaction, the insoluble material was filtered off and DBU (17.7 g, 116.2 mmol) was added into the filtrate which was stirred again at 80 °C for 2 h. After reaction, the reaction mixture was concentrated to give a residue which was purified by silica gel chromatography column (PE / DCM 262Attorney Docket No.31457_WO from 0 ~ 35%) to give methyl 5,7-difluoro-3-methylbenzofuran-2-carboxylate (8.4 g, 32%) as off- white solid. MS (ESI): mass calcd. for C11H8F2O3, 226.0, m / z found 227.0 [M+H]+. Step 3

[0625] To a solution of 5,7-difluoro-3-methylbenzofuran-2-carboxylate (8.1 g, 35.8 mmol) in THF (160 mL) was added LiAlH4 (21.5 mL, 21.5 mmol, 1M in THF) at 0 °C. The reaction mixture was stirred at 0oC for 2 h. then slowly quenched with saturated aqueous potassium carbonate (150 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine and dried with Na2SO4 and concentrated to give a residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 30%) to give (5,7-difluoro-3-methylbenzofuran-2-yl)methanol (6.5 g, 91%) as an off-white solid. MS (ESI): mass calcd. for C10H8F2O2, 198.0, m / z found 181.0 [M- H2O+H]+. Step 4

[0626] To a solution of (5,7-difluoro-3-methylbenzofuran-2-yl) methanol (6.5 g, 32.6 mmol) in ACN (65 mL) was added IBX (13.7 g, 49.0 mmol) at room temperature. The reaction mixture was stirred at 80oC for 2 h. The insoluble material was then filtered off and the filtrate was concentrated to give a residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 15%) to give 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (6.1 g, 95%) as an off- white solid. MS (ESI): mass calcd. for C10H6F2O2, 196.0, m / z found 197.1 [M+H]+. Step 5

[0627] To a solution of 5,7-difluoro-3-methylbenzofuran-2-carbaldehyde (6.1 g, 31.1 mmol) in DMF (92 mL) were added trimethyl(trifluoromethyl)silane (8.89 g, 62.2 mmol) and K2CO3(2.1 g, 15.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h and then another batch of K2CO3 (4.3 g, 31.0 mmol) was added into the reaction mixture. The mixture was stirred at room temperature for 16 h and thenH2O (2.8 g, 115.5 mmol) was added, and the reaction mixture was further stirred at 0 ℃ for 1 h. The mixture was quenched with ice water and extracted with EA (200 mL x 3). The combined organic layer was washed with brine and dried with Na2SO4 and concentrated to give a residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 20%) to give 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1- 263Attorney Docket No.31457_WO ol (6.5 g, 78%) as light yellow oil. MS (ESI): mass calcd. for C11H7F5O2, 266.0, m / z found 249.1 [M-H2O+H]+. Step 6

[0628] To a solution of 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-ol (370 mg, 1.39 mmol) in ACN (10 mL) was added IBX (584 mg, 2.08 mmol). The reaction mixture was refluxed for 16 h. After reaction, the mixture was filtered and washed with EA. The filtrate was collected and concentrated to give a residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 20%) to 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan- 1-one (320 mg, 87%) as yellow oil.1H NMR (400 MHz, DMSO) δ 7.82 – 7.74 (m, 2H), 2.65 (s, 3H).Step 7

[0629] A mixture of 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-one (320 mg, 1.21 mmol), hydroxylamine hydrochloride (585 mg, 8.48 mmol) and NaOAc (992 mg, 12.10 mmol) in EtOH (10 mL) was refluxed for 16 h. After reaction, the mixture was concentrated and redissolved in MeOH (10 mL) which was added Raney Ni (50 mg) and one drop of ammonia. The mixture was stirred under H2 at room temperature for 6 h. After reaction, the mixture was filtered and the filtrate was concentrated to givea residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 50%) to give 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethan-1-amine (150 mg, 47%) as light yellow oil. MS (ESI): mass calcd. for C11H8F5NO, 265.0, m / z found 249.1 [M-NH3+H]+. Step 8

[0630] To a mixture of 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine (150 mg, 0.57 mmol), DIEA (219 mg, 1.70 mmol) in DMF (10 mL) was added phenyl (2- aminopyrimidin-5-yl)carbamate (143 mg, 0.62 mmol) at 0 ℃. The reaction mixture was then stirred at room temperature for 16 h thenquenched with water and extracted with EA (50 mL x 3). The combined organic layer was concentrated to give a residue which was purified by silica gel chromatography column (PE / EA from 0 ~ 50%) to give (rac)-1-(2-aminopyrimidin-5-yl)-3-(1- 264Attorney Docket No.31457_WO (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (150 mg, 66%) as light yellow oil. MS (ESI): mass calcd. for: C16H12F5N5O2, 401.1, m / z found 402.1 [M+H]+. Step 9

[0631] (rac)1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroet -hyl ) urea (150 mg) was separated by chiral HPLC to give Compound 1...

Claims

Attorney Docket No.31457_WO WHAT IS CLAIMED IS:

1. A compound having the structure of Formula (X-H): H)R1Ais halogen; R1Bis halogen, cyano, cyclopropyl, or absent; R2is a C1-C6 alkyl or C1-C6 haloalkyl; R3is a C1-C6 alkyl or a C1-C6 haloalkyl; R4is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, - SO2(C1-C6 alkyl), and -CO2H; Linker is is a covalent bond or a C1-C50 alkylene; wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, – P(=O)(RK1)–, –P(=O)N(RK1)–, -S-, -C(=O)-, -S(=O)-, -S(O)2-, -N(RK1)S(O)2-, -S(O)2N(RK1)-, - N(RK1)S(O)2N(RK1)-, -N(RK1)C(=O)-, -C(=O)N(RK1)-, -OC(=O)N(RK1)-, -N(RK1)C(=O)O-, and RK2; 289Attorney Docket No.31457_WO each RK1is independently hydrogen, halogen, hydroxyl, cyano, -C(=O)ORK1B, -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; or two RK1attached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK1Ais independently halogen, hydroxyl, cyano, -C(=O)ORK1B, -NRK1BRK1C, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C1-C6 alkoxy; or two RK1Aattached to the same or adjacent atoms in Linker, together with the atom(s) to which they are attached form an optionally substituted C3-C10 cycloalkyl or an optionally substituted 4-12 membered heterocyclyl; each RK2is independently an optionally substituted C3-C10 cycloalkylene, an optionally substituted 4-12 membered heterocyclylene, an optionally substituted phenylene, or an optionally substituted 5-10 membered heteroarylene; each RK1Band RK1Care independently selected from hydrogen and an optionally substituted C1- C6 alkyl, or RK1Band RK1Ctogether with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl; and PTM is a cereblon binding moiety, a VHL binding moiety, an RNF126 binding moiety, or a covalent E3 ligase recruiter.

2. The compound of Claim 1, wherein R1Aand R1Bare each independently selected halogen.

3. The compound of Claim 1 or , wherein R1Aand R1Bare each fluoro.

4. The compound of Claim 1, wherein R1Ais fluoro and R1Bis absent.

5. The compound of Claim 1, wherein R1Ais fluoro and R1Bis chloro.

6. The compound of any one of Claims 1-5, wherein PTM is a VHL binding moiety. 290Attorney Docket No.31457_WO 7. The compound of any one of Claims 1-6, wherein PTM is , ,8. The compound of any one of Claims 1-5, wherein PTM is a cereblon binding moiety.

9. The compound of any one of Claims 1-5 or 8, where ,291Attorney Docket No.31457_WO , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WOAttorney Docket No.31457_WO , , , , ,Attorney Docket No.31457_WO , , , , , ,Attorney Docket No.31457_WO ,Attorney Docket No.31457_WONH O RW2* q, , , , 300Attorney Docket No.31457_WO , , , or301Attorney Docket No.31457_WO RW1is hydrogen or C1-C6 alkyl; each RW2is independently halogen, OH, -NH2, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 alkoxy optionally substituted with C3-C7 cycloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 4- 6 membered heterocyclyl, C6-C10 aryl, or C3-C6 cycloalkoxy; and q is 0, 1, or 2 10. The compound of any one of Claims 1-5, wherein PTM is an RNF126 binding moiety.

11. The compound of any one of Claims 1-5 or 10, wherein PTM is , , of12. The compound of any one of Claims 1-11, wherein Linker is C1-C50 alkylene, wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, –P(=O)(RK1)–, –P(=O)N(RK1)2–, -S-, -C(=O)-, -S(=O)-, -S(O)2- -. , ne, wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from 302Attorney Docket No.31457_WO the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, –P(=O)(RK1)–, –P(=O)N(RK1)2–, -S-, -C(=O)-, -S(=O)-, -S(O)2- , N(RK1)S(O)2-, -S(O)2N(RK1)2-, -N(RK1)C(=O)-, -C(=O)N(RK1)-, -OC(=O)N(RK1)-, - ne,wherein 0-8 methylene units of the alkylene are independently replaced by a moiety selected from the group consisting of: C2 alkene, C2 alkyne, –C(D)(H)-, -C(RK1A)2-, -O-, -N(RK1)-, –Si(RK1)2–, –Si(OH)(RK1)–, –P(=O)(ORK1)–, –P(=O)(RK1)–, –P(=O)N(RK1)2–, -S-, -C(=O)-, -S(=O)-, -S(O)2- , N(RK1)S(O)2-, -S(O)2N(RK1)2-, -N(RK1)C(=O)-, -C(=O)N(RK1)-, -OC(=O)N(RK1)-, - N(RK1)C(=O)O-, and RK2.

15. The compound of any one of Claims 1-14, wherein Linker is selected from the group consisting of: ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,8-octylene, 1,3- cyclobutylene, 1,3-cyclopentylene, 1, 4-cyclohexylene, 1,4-piperidinyl, ,, , , , , , , ,Attorney Docket No.31457_WO , , , , , , , , , , , ,Attorney Docket No.31457_WO , , , , , , , , , , , ,Attorney Docket No.31457_WO , , , , , , , , , ,Attorney Docket No.31457_WO , , , , ,16. The compound of any one of Claims 1-11, wherein Linker is a covalent bond.

17. The compound of Claim 1, wherein the compound of Formula (X-H) is a compound of Formula (X-Ha) (X-Ha), or a pharmaceuticallyacceptable salt thereof. 307Attorney Docket No.31457_WO 18. A compound selected from the group consisting of the compounds in Table C, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

20. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 19.

21. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 19.

22. A method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 19.

23. A method for reducing PI3Kα protein levels in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Claims 1-18, or a pharmaceutically acceptable salt thereof. 308

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