Urea derivatives usable in the treatment of cancer

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent claims priority to U.S. Application No. 63 / 210,370, filed on June 14, 2021, U.S. Application No. 63 / 228,351, filed on August 2, 2021, U.S. Application No. 63 / 288,909, filed on December 13, 2021, U.S. Application No. 63 / 316,017, filed on March 3, 2022, U.S. Application No. 63 / 319,236, filed on March 11, 2022, and U.S. Application No. 63 / 348,261, filed on June 2, 2022.TECHNICAL FIELD

[0002] This disclosure provides compounds of Formula (I), Formula (II), and pharmaceutically acceptable salts thereof, that inhibit 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 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 making the same.BACKGROUND

[0003] 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. The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol.2018, 15, 273-291.) Suppression (e.g., pharmacological or genetic) of PI3K / AKT / TOR signaling may cause cancer cell death and regression of tumor growth.

[0004] 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., PI3K / AKT signaling pathway and cancer: An updated review. Ann. Med. 2014, 46, 372-383 and Bauer, T.M. et al., Targeting PI3 kinase in cancer. Pharmacol. Ther. 2015, 146, 53-60.) PI3K consists of three subunits: 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. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.)

[0005] 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 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., Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors, Cancer Discovery, April 2019;9: 482-491.) For example, alpelisib is an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Kα. However, the therapeutic benefit of alpelisib is limited by wild-type PI3Kα inhibition in normal tissues, resulting in dose-limiting toxicities including hyperglycemia.

[0006] 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.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci. 2021, 22, 3464.)

[0007] 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.

[0008] El-Khouly, et al. (Bioorganice & Medicinal Chemistry (2021(31))) describes the synthesis and anticancer and antimicrobial evaluation of benzofuran based derivatives.

[0009] WO 2004 / 108709 describes tetrazol benzofurancarboxamides with PI3K activity as therapeutic agents.SUMMARY

[0010] A compound of Formula (I-A): or a pharmaceutically acceptable salt thereof is provided, wherein: Ring A1 is pyrimidinyl, pyridyl, or pyrazolyl; R 1A< is halogen; R 1B< is halogen or absent; R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is 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; R 4< is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , - C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; wherein R 4< is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is 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, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ); or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0011] This aspect, taken alone or combinable with any other aspect, can include the following features. R 1A< is selected from fluoro and chloro; or wherein R 1A< is fluoro; or wherein R 1B< is halogen; or wherein R 1B< is fluoro.

[0012] This aspect, taken alone or combinable with any other aspect, can include the following features. R 1A< and R 1B< are each fluoro.

[0013] This aspect, taken alone or combinable with any other aspect, can include the following features. R 2< is a C1-C6 alkyl.

[0014] This aspect, taken alone or combinable with any other aspect, can include the following features. R 2< is methyl.

[0015] This aspect, taken alone or combinable with any other aspect, can include the following features. R 3< is a C1-C6 haloalkyl.

[0016] This aspect, taken alone or combinable with any other aspect, can include the following features. R 2< is trifluoromethyl.

[0017] This aspect, taken alone or combinable with any other aspect, can include the following features. Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl.

[0018] This aspect, taken alone or combinable with any other aspect, can include the following features. Ring A1 is 5-pyrimidinyl.

[0019] This aspect, taken alone or combinable with any other aspect, can include the following features. R 4< is -NR A< R B< .

[0020] This aspect, taken alone or combinable with any other aspect, can include the following features. is wherein: R 4B< is selected from -NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0021] A compound selected from the group consisting of the compounds in Table A, Table B, Table C, and Table D is provided.

[0022] A compound which is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof is provided.

[0023] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

[0024] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

[0025] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0026] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0027] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0028] A pharmaceutical composition comprising a compound of any one of the preceding compounds, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients is provided.

[0029] A compound of any one of the preceding compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of any one of the preceding compounds, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients for use in a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0030] A compound for use in a method of treating a solid tumor a human subject, the solid tumor having a mutation in PI3Kα, wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof, and wherein the method includes administering to the subject a therapeutically effective amount of the compound is provided.

[0031] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

[0032] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0033] This aspect, taken alone or combinable with any other aspect, can include the following features. The compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0034] This aspect, taken alone or combinable with any other aspect, can include the following features. 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.Additional Definitions

[0035] 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 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.

[0036] 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.

[0037] 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.

[0038] The term "inhibit" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0039] "API" refers to an active pharmaceutical ingredient.

[0040] 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.

[0041] 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 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.

[0042] 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 s 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.

[0043] 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 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.

[0044] 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.

[0045] 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.

[0046] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0047] 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.

[0048] The term "hydroxyl" refers to an -OH radical.

[0049] The term "cyano" refers to a -CN radical.

[0050] 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, C 1-10 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.

[0051] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0052] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH 3 ).

[0053] 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 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.

[0054] 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.

[0055] 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, 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 of pyridone (e.g., ), pyrimidone (e.g., ), pyridazinone (e.g., ), pyrazinone (e.g., or ), and imidazolone (e.g., ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., "=O") herein is a constituent part of the heteroaryl ring).

[0056] 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-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.

[0057] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0058] 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.

[0059] 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 (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., )): (ii) a single ring atom (spiro-fused ring systems) (e.g., ), or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., ), In addition, atoms making up the compounds of the present embodiments are intended to include all 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 include 13< C and 14< C.

[0060] 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 moiety: Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0061] 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.

[0062] 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

[0063] This disclosure provides compounds of Formula (I-A) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). This disclosure also provides example compounds of Formula (I), Formula (II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), which are not encompassed by the wording of the claims. These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.Example Formulae (I) Compounds not encompassed by the wording of the claims

[0064] Some examples not encompassed by the wording of the claims provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x< ; R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R 1< is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2< is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3< is 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 A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4-10 membered heterocyclyl; each R 4< is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NR A< R B< , (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) -CO 2 H, (viii) -NR A< R B< , (ix) =NR A2< , (x) -C(=O)NR C< R D< , (xi) -SO 2 (NR E< R F< ), (xii) -SO 2 (C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv) -CO 2 (C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< , and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; n is 0, 1, or 2; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO 2 (C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NR B2< R C2< , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO 2 (C1-C6 alkyl), -CO 2 H, and -SO 2 (NH 2 ); or R C< and R D< , 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)NR B1< R C1< , -SO 2 (C1-C6 alkyl), -CO 2 H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each R A2< , R B2< , and R C2< is independently hydrogen or C1-C6 alkyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1< R B1< , =NR A2< , - C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO 2 (C1-C6 alkyl), and -CO 2 H; and wherein the compound is not a compound selected from the group consisting of:

[0065] In some examples not encompassed by the wording of the claims, when Z is NR x< and R 3< is methyl, Ring A is not phenyl.

[0066] Some not encompassed by the wording of the claims provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein, wherein the compound is not a compound selected from the group consisting of: and

[0067] Some excamples not encompassed by the wording of the claims provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein, wherein the compound is not a compound selected from the group consisting of:

[0068] Someexamples not encompassed by the wording of the claims provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein, wherein the compound is not a compound selected from the group consisting of:

[0069] Some examples not encompassed by the wording of the claims provide a compound of Formula (I), having Formula (X): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x< ; R x< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R 1< is an independently selected halogen; m is 0, 1, 2, or 3; R 2< is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3< is 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 A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4-10 membered heterocyclyl; each R 4< is independently selected from the group consisting of: halogen, C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and a 3-6 membered heterocyclyl or 3-6 membered cycloalkyl each optionally substituted with 1 or 2 independently selected R G< ; n is 0, 1, or 2; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO 2 (C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, -C(=O)NR B2< R C2< , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO 2 (C1-C6 alkyl), -SO 2 (NH 2 ; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H; and wherein the compound is not a compound selected from the group consisting of:

[0070] Some examples not encompassed by the wording of the claims provide a compound of Formula (X), or a pharmaceutically acceptable salt thereof, as described herein, wherein the compound is not a compound selected from the group consisting of:

[0071] Some examples not encompassed by the wording of the claims provide a compound of Formula (X), or a pharmaceutically acceptable salt thereof, as described herein, wherein the compound is not a compound selected from the group consisting of:

[0072] In some examples not encompassed by the wording of the claims, the compounds described herein are not compounds that are selected from the group described above (i.e., the "excluded compounds"). In some examples not encompassed by the wording of the claims, the excluded compounds are flat structures, as indicated above. In some examples not encompassed by the wording of the claims, the excluded compounds are specific stereoisomers, e.g. specific enantiomers or diastereomers. In some examples not encompassed by the wording of the claims, the excluded compounds are R isomers. In some examples not encompassed by the wording of the claims, the excluded compounds are S isomers. In some examples not encompassed by the wording of the claims, one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some examples not encompassed by the wording of the claims, the excluded compounds are R isomers. In some examples not encompassed by the wording of the claims, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

[0073] In some examples not encompassed by the wording of the claims, m is 0. In some examples not encompassed by the wording of the claims, m is 1. In some examples not encompassed by the wording of the claims, m is 2. In some examples not encompassed by the wording of the claims, m is 3.

[0074] In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is In some examples not encompassed by the wording of the claims, is

[0075] In some examples not encompassed by the wording of the claims, each R 1< is an independently selected halogen. In some examples not encompassed by the wording of the claims, each R 1< is independently selected from fluoro and chloro. In some examples not encompassed by the wording of the claims, each R 1< is independently selected from fluoro and bromo. In some examples not encompassed by the wording of the claims, each R 1< is fluoro. In some examples not encompassed by the wording of the claims, at least one R 1< is an independently selected halogen. In some examples not encompassed by the wording of the claims, at least one R 1< is independently selected from fluoro and chloro. In some examples not encompassed by the wording of the claims, at least one R 1< is fluoro.

[0076] In some examples not encompassed by the wording of the claims, at least one R 1< is cyano. In some examples not encompassed by the wording of the claims, at least one R 1< is hydroxyl. In some examples not encompassed by the wording of the claims, at least one R 1< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, at least one R 1< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, at least one R 1< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, at least one R 1< is hydroxymethyl. In some examples not encompassed by the wording of the claims, at least one R 1< is unsubstituted C1-C6 alkyl. In some examples not encompassed by the wording of the claims, at least one R 1< is methyl. In some examples not encompassed by the wording of the claims, at least one R 1< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, at least one R 1< is cyclopropyl.

[0077] In some examples not encompassed by the wording of the claims, m is 2; one R 1< is halogen; and the other R 1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, m is 2; one R 1< is fluoro; and the other R 1< is methyl In some examples not encompassed by the wording of the claims, m is 2; one R 1< is halogen; and the other R 1< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, m is 2; one R 1< is halogen; and the other R 1< is cyclopropyl. In some examples not encompassed by the wording of the claims, m is 2; one R 1< is fluoro; and the other R 1< is cyano. In some examples not encompassed by the wording of the claims, m is 2; one R 1< is halogen; and the other R 1< is halogen. In some examples not encompassed by the wording of the claims, m is 2; one R 1< is fluoro; and the other R 1< is fluoro.

[0078] In some examples not encompassed by the wording of the claims, R 2< is hydroxyl. In some examples not encompassed by the wording of the claims, R 2< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R 2< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R 2< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R 2< is hydroxymethyl. In some examples not encompassed by the wording of the claims, R 2< is an unsubstituted C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 2< is unsubstituted C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 2< is methyl.

[0079] In some examples not encompassed by the wording of the claims, R 2< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is difluoromethyl. In some examples not encompassed by the wording of the claims, R 2< is trifluoromethyl.

[0080] In some examples not encompassed by the wording of the claims, R 2< is halogen. In some examples not encompassed by the wording of the claims, R 2< is fluoro. In some examples not encompassed by the wording of the claims, R 2< is chloro.

[0081] In some examples not encompassed by the wording of the claims, R 2< is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 2< is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 2< is C3-C6 cycloalkyl substituted with 1 fluoro. In some examples not encompassed by the wording of the claims, R 2< is C3-C6 cycloalkyl substituted with 2 fluoro. In some examples not encompassed by the wording of the claims, R 2< is C3-C4 cycloalkyl substituted with 1 fluoro. In some examples not encompassed by the wording of the claims, R 2< is C3-C4 cycloalkyl substituted with 2 fluoro. In some examples not encompassed by the wording of the claims, R 2< is an unsubstituted C3-C6 cycloalkyl.

[0082] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 3< is methyl, ethyl, t-butyl, or isopropyl. In some examples not encompassed by the wording of the claims, R 3< is methyl, ethyl, or isopropyl. In some examples not encompassed by the wording of the claims, R 3< is methyl. In some examples not encompassed by the wording of the claims, R 3< is ethyl. In some examples not encompassed by the wording of the claims, R 3< is isopropyl.

[0083] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is difluoromethyl. In some examples not encompassed by the wording of the claims, R 3< is trifluoromethyl.

[0084] In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 fluoro. In some examples not encompassed by the wording of the claims, R 3< is 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 examples not encompassed by the wording of the claims, R 3< is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 or 2 methyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 methyl. In some examples not encompassed by the wording of the claims, R 1< is 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 examples not encompassed by the wording of the claims, R 3< is an unsubstituted C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, the R 3< C3-C6 cycloalkyl is cyclopropyl. In some examples not encompassed by the wording of the claims, R 3< is cyclopropyl. In some examples not encompassed by the wording of the claims, R 3< is cyclobutyl. In some examples not encompassed by the wording of the claims, R 3< is cyclopentyl. In some examples not encompassed by the wording of the claims, R 3< is cyclohexyl.

[0085] In some examples not encompassed by the wording of the claims, Ring A is a 6-10 membered aryl. In some examples not encompassed by the wording of the claims, Ring A is phenyl, naphthyl, or tetrahydronaphthyl. In some examples not encompassed by the wording of the claims, Ring A is phenyl.

[0086] In some examples not encompassed by the wording of the claims, Ring A is a C3-C8 cycloalkyl. In some examples not encompassed by the wording of the claims, Ring A is a C5-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, Ring A is cyclohexyl.

[0087] In some examples not encompassed by the wording of the claims, Ring A is a 5-10 membered heteroaryl. In some examples not encompassed by the wording of the claims, Ring A is a 9-10 membered heteroaryl. In some examples not encompassed by the wording of the claims, Ring A is a 9 membered heteroaryl. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, 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.

[0088] In some examples not encompassed by the wording of the claims, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl. In some examples not encompassed by the wording of the claims, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-6-yl, orimidazo[1,2-a]pyridinyl. In some examples not encompassed by the wording of the claims, Ring A is benzimidazolyl, indazolyl, indolyl, or imidazo[1,2-a]pyridinyl. In some examples not encompassed by the wording of the claims, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, In some examples not encompassed by the wording of the claims, Ring A is selected from the group consisting of wherein "*" indicates the attachment point to the urea nitrogen atom in Formula (I).

[0089] In some examples not encompassed by the wording of the claims, Ring A is a 5-6 membered heteroaryl. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, Ring A is selected from the groups consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some examples not encompassed by the wording of the claims, Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. In some examples not encompassed by the wording of the claims, Ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some examples not encompassed by the wording of the claims, Ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some examples not encompassed by the wording of the claims, Ring A is selected from the group consisting of and wherein "*" indicates the attachment point to the urea nitrogen atom in Formula (I). In some examples not encompassed by the wording of the claims, Ring A is pyrimidinyl. In some examples not encompassed by the wording of the claims, Ring A is 5-pyrimidinyl. In some examples not encompassed by the wording of the claims, Ring A is wherein "*" indicates the attachment point to the urea nitrogen atom in Formula (I). In some examples not encompassed by the wording of the claims, Ring A is a 4-10 membered heterocyclyl. In some examples not encompassed by the wording of the claims, Ring A is a 6-9 membered heterocyclyl. In some examples not encompassed by the wording of the claims, Ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopyranyl-1,1-dioxide.

[0090] In some examples not encompassed by the wording of the claims, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, In some examples not encompassed by the wording of the claims, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl,

[0091] In some examples not encompassed by the wording of the claims, Ring A is selected from the group consisting of 3-piperidinyl, and

[0092] In some examples not encompassed by the wording of the claims, n is 0. In some examples not encompassed by the wording of the claims, n is 1. In some examples not encompassed by the wording of the claims, n is 2.

[0093] In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is unsubstituted C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C4 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is t-butyl. In some examples not encompassed by the wording of the claims, one R 4< is methyl.

[0094] In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cyclopropyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy substituted with C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkoxy substituted with cyclopropyl. In some examples not encompassed by the wording of the claims, R 4< is C1-C6 alkoxy. In some examples not encompassed by the wording of the claims, R 4< is C1-C3 alkoxy. In some examples not encompassed by the wording of the claims, one R 4< is methoxy.

[0095] In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, one R 4< is difluoromethyl. In some examples not encompassed by the wording of the claims, one R 4< is trifluoromethyl.

[0096] In some examples not encompassed by the wording of the claims, one R 4< is hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is cyano. In some examples not encompassed by the wording of the claims, one R 4< is -CO 2 H. In some examples not encompassed by the wording of the claims, one R 4< is halogen. In some examples not encompassed by the wording of the claims, one R 4< is fluoro. In some examples not encompassed by the wording of the claims, one R 4< is chloro.

[0097] In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl optionally substituted with 1-2 hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl substituted with 1-2 hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl substituted with 1 hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl substituted with 2 hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C3 alkyl substituted with 2 hydroxyl. In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, one R 4< is C1-C6 alkyl substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, one R 4< is methyl or ethyl substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, one R 4< is an unsubstituted C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is methyl.

[0098] In some examples not encompassed by the wording of the claims, one R 4< is -NR A< R B< .

[0099] In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl or - C(=O)NR B2< R C2< . In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NH 2 . In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is -C(=O)O(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is -C(=O)OCH 3 . In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4-6 membered heterocyclyl (e.g., oxetanyl), In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is butyl substituted with hydroxyl (e.g., 2-hydroxy-2-methyl-1-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0100] In some examples not encompassed by the wording of the claims, both of R B2< and R C2< are hydrogen. In some examples not encompassed by the wording of the claims, one of R B2< and R C2< is hydrogen and the other of R B2< and R C2< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R B2< and R C2< is hydrogen and the other of R B2< and R c2< is methyl. In some examples not encompassed by the wording of the claims, both of R B2< and R C2< are methyl.

[0101] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 haloalkyl.

[0102] In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of one of R A< and R B< is C1-C6 haloalkyl.

[0103] In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)NR C< R D< .

[0104] In some examples not encompassed by the wording of the claims, R C< and R D< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is methyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each methyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is C1-C6 alkyl and the other of R C< and R D< is C1-C3 alkyl.

[0105] In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is C1-C6 alkyl and the other of R C< and R D< is C1-C6 haloalkyl.

[0106] In some examples not encompassed by the wording of the claims, R C< and R D< , 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)NR B1< R C1< , -SO 2 (C1-C6 alkyl), -CO 2 H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some examples not encompassed by the wording of the claims, R C< and R D< , 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)NI O< 'R c< ', -SO 2 (C1-C6 alkyl), -CO 2 H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0107] In some examples not encompassed by the wording of the claims, R B1< and R C1< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R B1< and R C1< is hydrogen and the other of R B1< and R C1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R B1< and R C1< is hydrogen and the other of R B1< and R C1< is methyl. In some examples not encompassed by the wording of the claims, R B1< and R C1< are each independently selected C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R B1< and R C1< are each methyl.

[0108] In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0109] In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 (NR E< R F< ). In some examples not encompassed by the wording of the claims, R E< and R F< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is methyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each methyl.

[0110] In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is C1-C6 alkyl and the other of R E< and R F< is C1-C6 haloalkyl.

[0111] In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 Et. In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 Me.

[0112] In some examples not encompassed by the wording of the claims, one R 4< is - S(=O)(=NH)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -S(=O)(=NH)(C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -S(=O)(=NH)Me.

[0113] In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)(C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)Me.

[0114] In some examples not encompassed by the wording of the claims, one R 4< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is -CO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one R 4< is - CO 2 Me.

[0115] In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl. In some examples not encompassed by the wording of the claims, one R 4< is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some examples not encompassed by the wording of the claims, one R 4< is tetrazolyl substituted with methyl. In some examples not encompassed by the wording of the claims, one R 4< is pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is unsubstituted pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is 1-pyrazolyl.

[0116] In some examples not encompassed by the wording of the claims, one R 4< is 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 4 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 5 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 7-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, the R 4< heterocyclyl is a spirocycle. In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered heterocyclyl substituted with 1 R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered heterocyclyl substituted with 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is an unsubstituted 3-6 membered heterocyclyl.

[0117] In some examples not encompassed by the wording of the claims, one R 4< is a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered cycloalkyl substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered cycloalkyl substituted with 1 R G< . In some examples not encompassed by the wording of the claims, one R 4< is 3-6 membered cycloalkyl substituted with 2 independently selected R G< . In some examples not encompassed by the wording of the claims, one R 4< is an unsubstituted 3-6 membered cycloalkyl.

[0118] In some examples not encompassed by the wording of the claims, the 1 or 2 independently selected R G< is 1 R G< . In some examples not encompassed by the wording of the claims, the 1 or 2 independently selected R Y< are 2 independently selected R G< . In some examples not encompassed by the wording of the claims, when 2 R G< are present, they are bonded to the same atom, valency permitting. In some examples not encompassed by the wording of the claims, when 2 R G< are present, they are bonded to adjacent atoms, valency permitting. In some examples not encompassed by the wording of the claims, when 2 R G< are present, the 2 R G< are different. In some examples not encompassed by the wording of the claims, when 2 R G< are present, the 2 R G< are the same. In some examples not encompassed by the wording of the claims, one R G< is fluoro. In some examples not encompassed by the wording of the claims, one R G< is cyano. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl. In some examples not encompassed by the wording of the claims, one R G< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one R G< is 2-hydroxy-2-propyl. In some examples not encompassed by the wording of the claims, one R G< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R G< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one R G< is methyl. In some examples not encompassed by the wording of the claims, one R G< is ethyl.

[0119] In some examples not encompassed by the wording of the claims, one R G< is C1-C6 alkoxy.

[0120] In some examples not encompassed by the wording of the claims, one R G< is C1-C3 alkoxy.

[0121] In some examples not encompassed by the wording of the claims, one R G< is methoxy.

[0122] In some examples not encompassed by the wording of the claims, one R G< is -NR A1< R B1< . In some examples not encompassed by the wording of the claims, R A1< and R B1< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is methyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each methyl.

[0123] In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is C1-C6 alkyl and the other of R A1< and R B1< is C1-C6 haloalkyl.

[0124] In some examples not encompassed by the wording of the claims, one R G< is =NR A2< . In some examples not encompassed by the wording of the claims, one R G< is =NH. In some examples not encompassed by the wording of the claims, R A2< is hydrogen. In some examples not encompassed by the wording of the claims, R A2< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A2< is methyl.

[0125] In some examples not encompassed by the wording of the claims, one R G< is - C(=O)NR C1< R D1< . In some examples not encompassed by the wording of the claims, one R G< is - CO 2 NH 2 . In some examples not encompassed by the wording of the claims, one R G< is - CO 2 NHCH 3 . In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is hydrogen. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is methyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is methyl.

[0126] In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is C1-C6 alkyl and the other of R C1< and R D1< is C1-C6 haloalkyl.

[0127] In some examples not encompassed by the wording of the claims, one R G< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R G< is -CO 2 CH 3 . In some examples not encompassed by the wording of the claims, one R G< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one R G< is trifluoromethyl. In some examples not encompassed by the wording of the claims, one R G< is difluoromethyl. In some examples not encompassed by the wording of the claims, one R G< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R G< is cyclopropyl. In some examples not encompassed by the wording of the claims, one R G< is -CO 2 H.

[0128] In some examples not encompassed by the wording of the claims, one R G< is C1-C6 haloalkoxy. In some examples not encompassed by the wording of the claims, one R G< is C1-C3 haloalkoxy. In some examples not encompassed by the wording of the claims, one R G< is difluoromethoxy. In some examples not encompassed by the wording of the claims, one R G< is trifluoromethoxy.

[0129] In some examples not encompassed by the wording of the claims, one R G< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R G< is -SO 2 CH 3 .

[0130] In some examples not encompassed by the wording of the claims, the R 4< 3-9 membered heterocyclyl is a 3-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. In some examples not encompassed by the wording of the claims, the R 4< 3-9 membered heterocyclyl is selected from the group consisting of In some examples not encompassed by the wording of the claims, the R 4< 3-9 membered heterocyclyl (e.g., the R 4< 3-6 membered heterocyclyl) is wherein Q is a C1-C3 alkylene in which one or more carbons is optionally replaced by -C(=O)-, NH, O, or S. In some examples not encompassed by the wording of the claims, Q is a C1-C3 alkylene in which one or more carbons is optionally replaced by -C(=O)- or NH. In some examples not encompassed by the wording of the claims, Q is a C1-C2 alkylene in which one or more carbons is optionally replaced by -C(=O)- or NH. In some examples not encompassed by the wording of the claims, the R 4< 3-9 membered heterocyclyl is selected from the group consisting of

[0131] In some examples not encompassed by the wording of the claims, one R 4< is unsubstituted 3-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< 3-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< is azetidinyl, morpholinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, R 4< is selected from the group consisting

[0132] In some examples not encompassed by the wording of the claims, is wherein: X is selected from N and CR 4A2< ; R 4A1< and R 4A2< are independently selected from hydrogen, C1-C3 alkyl optionally substituted with -NR A< R B< ,, methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, X is N. In some examples not encompassed by the wording of the claims, X is CR 4A2< . In some examples not encompassed by the wording of the claims, R 4A1< and, when present, R 4A2< are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, - C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , -SO 2 Me, and azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, X is N and R 4A1< is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0133] In some examples not encompassed by the wording of the claims, X is N; and R 4A1< is selected from amino or an azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl.

[0134] In some examples not encompassed by the wording of the claims, is wherein: R 4B< is selected from -NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0135] In some examples not encompassed by the wording of the claims, is wherein: R 4B< is selected from -NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH 2 , =NH, difluoromethoxy, -S(O) 2 Me, -CO 2 H, C1-C6 haloalkyl, and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R G1< is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, - C(O)NH 2 , =NH, difluoromethoxy, -S(O) 2 Me, -CO 2 H, C1-C6 haloalkyl, and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0136] In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0137] In some examples not encompassed by the wording of the claims, R 4B< is amino or a 4-6 membered heterocyclyl having one nitrogen atom and optionally substituted with 1-2 independently selected R G< ; wherein R G< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0138] In some examples not encompassed by the wording of the claims, R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each optionally containing 1-2 =O, and each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO 2 CH 3 , and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO 2 CH 3 , and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, Ring B is azetidinyl.

[0139] In some examples not encompassed by the wording of the claims, Ring B is unsubstituted.

[0140] In some examples not encompassed by the wording of the claims, Ring B is substituted with 1 R G< . In some examples not encompassed by the wording of the claims, R G< is fluoro. In some examples not encompassed by the wording of the claims, R G< is cyano. In some examples not encompassed by the wording of the claims, R G< is amino, In some examples not encompassed by the wording of the claims, R G< is hydroxyl. In some examples not encompassed by the wording of the claims, R G< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R G< is methyl. In some examples not encompassed by the wording of the claims, R G< is ethyl. In some examples not encompassed by the wording of the claims, R G< is -CO 2 CH 3 . In some examples not encompassed by the wording of the claims, R G< is methoxy. In some examples not encompassed by the wording of the claims, R G< is methoxy.

[0141] In some examples not encompassed by the wording of the claims, Ring B is substituted with 2 R G< . In some examples not encompassed by the wording of the claims, each R G< is fluoro. In some examples not encompassed by the wording of the claims, each R G< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, each R G< is methyl. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl and the other R G< is methyl. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl and the other R G< is ethyl. In some examples not encompassed by the wording of the claims, one R G< is amino and the other R G< is methyl. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl and the other R G< is cyclopropyl. In some examples not encompassed by the wording of the claims, one R G< is fluoro and the other R G1< is methyl. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl and the other R G< is fluoro. In some examples not encompassed by the wording of the claims, one R G< is hydroxyl and the other R G< is trifluoromethyl. In some examples not encompassed by the wording of the claims, each R G< is bonded to the position of Ring B para to the nitrogen that is bonded to Ring A.

[0142] In some examples not encompassed by the wording of the claims, is wherein 1 or 2 independently selected R G< attach at the 3-position of the azetidine. In some examples not encompassed by the wording of the claims, is selected from the group consisting of In some examples not encompassed by the wording of the claims, is selected from the group consisting of In some examples not encompassed by the wording of the claims, is selected from the group consisting of

[0143] In some examples not encompassed by the wording of the claims, Z is O.

[0144] In some examples not encompassed by the wording of the claims, Z is NR x< .

[0145] In some examples not encompassed by the wording of the claims, R x< is hydrogen.

[0146] In some examples not encompassed by the wording of the claims, R x< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R x< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R x< is methyl. In some examples not encompassed by the wording of the claims, R x< is ethyl. In some examples not encompassed by the wording of the claims, R x< is n-propyl. In some examples not encompassed by the wording of the claims, R x< is isopropyl.

[0147] In some examples not encompassed by the wording of the claims, R x< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, R x< is C3-C4 cycloalkyl. In some examples not encompassed by the wording of the claims, R x< is cyclopropyl. In some examples not encompassed by the wording of the claims, R x< is cyclobutyl.

[0148] In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0149] In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is trifluoromethyl.

[0150] In some examples not encompassed by the wording of the claims, m is 2, one R 4< is halogen, and the other R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, m is 2, one R 4< is chloro, and the other R 4< is -SO 2 CH 3 .

[0151] In some examples not encompassed by the wording of the claims, m is 2, one R 4< is C1-C6 alkoxy, and the other R 4< is -C(=O)NR C< R D< .

[0152] In some examples not encompassed by the wording of the claims, m is 2, one R 4< is methoxy, and the other R 4< is -C(O)NHCH 3 . In some examples not encompassed by the wording of the claims, Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO 2 H, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , -SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0153] In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0154] In some examples not encompassed by the wording of the claims, each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; and n is 1 or 2.

[0155] In some examples not encompassed by the wording of the claims, each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0156] In some examples not encompassed by the wording of the claims, each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: -NHR B< , and 4-6 membered heterocyclyl optionally substituted with 1-2 R G< ; and n is 1 or 2.

[0157] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0158] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is trifluoromethyl.

[0159] In some examples not encompassed by the wording of the claims, Z is O; m is 2, one R 4< is halogen, and the other R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, m is 2, one R 4< is chloro, and the other R 4< is -SO 2 CH 3 .

[0160] In some examples not encompassed by the wording of the claims, Z is O; m is 2, one R 4< is C1-C6 alkoxy, and the other R 4< is -C(=O)NR C< R D.<

[0161] In some examples not encompassed by the wording of the claims, Z is O; m is 2, one R 4< is methoxy, and the other R 4< is -C(O)NHCH 3 . In some examples not encompassed by the wording of the claims, Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO 2 H, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , -SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0162] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0163] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; and n is 1 or 2.

[0164] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0165] In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: -NHR B< , and 4-6 membered heterocyclyl optionally substituted with 1-2 R G< ; and n is 1 or 2.

[0166] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0167] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; and R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, Z is O; each R 1< is fluoro; m is 1 or 2; R 2< is methyl; and R 3< is trifluoromethyl.

[0168] In some examples not encompassed by the wording of the claims, Z is NR x< ; m is 2, one R 4< is halogen, and the other R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, m is 2, one R 4< is chloro, and the other R 4< is -SO 2 CH 3 .

[0169] In some examples not encompassed by the wording of the claims, Z is NR x< ; m is 2, one R 4< is C1-C6 alkoxy, and the other R 4< is -C(=O)NR C< R D< .

[0170] In some examples not encompassed by the wording of the claims, Z is NR x< ; m is 2, one R 4< is methoxy, and the other R 4< is -C(O)NHCH 3 . In some examples not encompassed by the wording of the claims, Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO 2 H, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , -SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0171] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0172] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro; m is 1 or 2; R 2< is a C1-C6 alkyl; R 3< is a C1-C6 alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; and n is 1 or 2.

[0173] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH 2 , -C(=O)NH 2 , -C(=O)NHMe, -SO 2 NH 2 , - SO 2 NHMe, -SO 2 Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0174] In some examples not encompassed by the wording of the claims, Z is NR x< ; each R 1< is fluoro, cyano, or methyl; m is 1 or 2; R 2< is a C1-C3 alkyl; R 3< is a C1-C3 alkyl or C1-C3 haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R 4< is independently selected from the group consisting of: -NHR B< , and 4-6 membered heterocyclyl optionally substituted with 1-2 R G< ; and n is 1 or 2.

[0175] In some embodiments, the compound of Formula (I) is Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is 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; R 4< is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , - C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (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 R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; wherein R 4< is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is 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, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ); or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0176] In some embodiments, Ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, Ring A1 is pyrimidinyl. In some embodiments, Ring A1 is pyridyl. In some embodiments, Ring A1 is pyrazolyl.

[0177] In some embodiments, Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, Ring A1 is 5-pyrimidinyl. In some embodiments, Ring A1 is 3-pyridyl. In some embodiments, Ring A1 is 4-pyrazolyl.

[0178] In some embodiments of Formula (I-A), is wherein: R 4B< is selected from -NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0179] In some embodiments of Formula (I-A), R A< and R B< are each hydrogen.

[0180] In some embodiments of Formula (I-A), R A< and R B< are each 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered heterocyclyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 haloalkyl.

[0181] In some embodiments of Formula (I-A), R A< and R B< are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl.

[0182] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ) . In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl.

[0183] In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C3 alkyl. In some embodiments of Formula (I-A), R A< and R B< are each methyl.

[0184] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0185] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C 1-C6 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with - SO 2 (C1-C6 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C3 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 CH 3 , e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl).

[0186] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (NH 2 ), e.g., 1-sulfamoylpropan-2-yl . In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (NH 2 ).

[0187] In some embodiments of Formula (I-A), R 4B< is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G< ; wherein R G< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0188] In some embodiments of Formula (I-A), R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, and C1-C6 alkyl. In some embodiments of Formula (I-A), Ring B is azetidinyl.

[0189] In some embodiments of Formula (I-A), Ring B is unsubstituted.

[0190] In some embodiments of Formula (I-A), Ring B is substituted with 1 R G< . In some embodiments of Formula (I-A), R G< is fluoro. In some embodiments of Formula (I-A), R G< is cyano. In some embodiments of Formula (I-A), R G< is hydroxyl. In some embodiments of Formula (I-A), R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), R G< is methyl. In some embodiments of Formula (I-A), R G< is -CO 2 CH 3 .

[0191] In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected R G< . In some embodiments of Formula (I-A), each R G< is fluoro. In some embodiments of Formula (I-A), each R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), each R G< is methyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is methyl. In some embodiments of Formula (I-A), one R G< is fluoro and the other R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), one R G< is fluoro and the other R G< is methyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is fluoro. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is trifluoromethyl.

[0192] In some embodiments of Formula (I-A), is wherein 1 or 2 independently selected R G< is at the 3-position of the azetidine. In some embodiments of Formula (I-A), is selected from the group consisting of and In some embodiments of Formula (I-A), is selected from the groups consisting of

[0193] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-B): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is 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; R 4< is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , - C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (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 R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is 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, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ); or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0194] In some examples not encompassed by the wording of the claims, R 1A< and R 1B< are each fluoro;

[0195] In some examples not encompassed by the wording of the claims, R 2< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 2< is a C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 2< is methyl.

[0196] In some examples not encompassed by the wording of the claims, R 2< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is a trifluoromethyl.

[0197] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 3< is methyl, ethyl, or isopropyl. In some examples not encompassed by the wording of the claims, R 3< is methyl. In some examples not encompassed by the wording of the claims, R 3< is ethyl. In some examples not encompassed by the wording of the claims, R 3< is isopropyl.

[0198] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is a trifluoromethyl.

[0199] In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is unsubstituted C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, the R 3< C3-C6 cycloalkyl is cyclopropyl. In some examples not encompassed by the wording of the claims, R 3< is cyclopropyl.

[0200] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 alkyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is C1-C3 alkyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is methyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is C1-C4 alkyl. In some examples not encompassed by the wording of the claims, R 4< is methyl.

[0201] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 alkoxy. In some examples not encompassed by the wording of the claims, R 4< is C1-C3 alkoxy. In some examples not encompassed by the wording of the claims, R 4< is methoxy.

[0202] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 4< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 4< is trifluoromethyl.

[0203] In some examples not encompassed by the wording of the claims, R 4< is hydroxyl. In some examples not encompassed by the wording of the claims, R 4< is cyano. In some examples not encompassed by the wording of the claims, R 4< is -CO 2 H. In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0204] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of one of R A< and R B< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 haloalkyl.

[0205] In some examples not encompassed by the wording of the claims, R A< and R B< are each 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered heterocyclyl. In some examples not encompassed by the wording of the claims of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 1,1-dioxidotetrahydrothiophen-3-yl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered heterocyclyl.

[0206] In some examples not encompassed by the wording of the claims, R A< and R B< are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is unsubstituted 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is cis- or trans-3-hydroxycyclobutyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl.

[0207] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), and - SO 2 (NH 2 ).

[0208] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0209] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 CH 3 , e.g., 1-(methylsulfonyl)propan-2-yl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl).

[0210] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (NH 2 ), e.g., 1-sulfamoylpropan-2-yl . In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with - SO 2 (NH 2 ).

[0211] In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)NR C< R D< . In some examples not encompassed by the wording of the claims, R C< and R D< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is methyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each methyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is C1-C6 alkyl and the other of R C< and R D< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0212] In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 (NR E< R F< ). In some examples not encompassed by the wording of the claims, R E< and R F< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R F< and R F< is methyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each methyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R F< and R F< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is C1-C6 alkyl and the other of R E< and R F< is C1-C6 haloalkyl.

[0213] In some examples not encompassed by the wording of the claims, R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -SO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -SO 2 Me. In some examples not encompassed by the wording of the claims, R 4< is -SO 2 Et.

[0214] In some examples not encompassed by the wording of the claims, R 4< is -S(=0)(=NH)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is - S(=O)(=NH)(C1-C4 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -S(=O)(=NH)Me. In some examples not encompassed by the wording of the claims, R 4< is -C(=O)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -C(=O)(C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -C(=O)Me.

[0215] In some examples not encompassed by the wording of the claims, R 4< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -CO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -CO 2 Me.

[0216] In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 4< is 5-6 membered heteroaryl. In some examples not encompassed by the wording of the claims, R 4< is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some examples not encompassed by the wording of the claims, R 4< is pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is tetrazolyl substituted with methyl. In some examples not encompassed by the wording of the claims, one R 4< is pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is unsubstituted pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is 1-pyrazolyl.

[0217] In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 1 R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 2 independently selected R G< .

[0218] In some examples not encompassed by the wording of the claims, R G< is fluoro. In some examples not encompassed by the wording of the claims, R G< is cyano. In some examples not encompassed by the wording of the claims, R G< is hydroxyl. In some examples not encompassed by the wording of the claims, R G< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R G< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R G< is methyl.

[0219] In some examples not encompassed by the wording of the claims, R G< is C1-C6 alkoxy. In some examples not encompassed by the wording of the claims, R G< is C1-C3 alkoxy. In some examples not encompassed by the wording of the claims, R G< is methoxy.

[0220] In some examples not encompassed by the wording of the claims, one R G< is -NR A1< R B1< . In some examples not encompassed by the wording of the claims, R A1< and R B1< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is methyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each methyl.

[0221] In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is C1-C6 alkyl and the other of R A1< and R B1< is C1-C6 haloalkyl.

[0222] In some examples not encompassed by the wording of the claims, one R G< is - C(=O)NR C1< R D1< . In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is hydrogen. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is methyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is methyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is C1-C6 alkyl and the other of R C1< and R D1< is C1-C6 haloalkyl.

[0223] In some examples not encompassed by the wording of the claims, one R G< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R G< is -CO 2 CH 3 .

[0224] In some examples not encompassed by the wording of the claims, one R G< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one R G< is trifluoromethyl.

[0225] In some examples not encompassed by the wording of the claims, one R G< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R G< is cyclopropyl.

[0226] In some examples not encompassed by the wording of the claims, R G< is -CO 2 H.

[0227] In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1- morpholinyl, or 4-tetrahydropyranyl.

[0228] In some examples not encompassed by the wording of the claims, R 4< is unsubstituted 3-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< is azetidinyl, morpholinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, R 4< is selected from the group consisting of

[0229] In some examples not encompassed by the wording of the claims, R 4< is selected from - NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0230] In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0231] In some examples not encompassed by the wording of the claims, R 4< is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G< ; wherein R G< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0232] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-C): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , and -CO 2 H.

[0233] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-D): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0234] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-E): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0235] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-F): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H; and wherein the compound is not

[0236] Some examples not encompassed by the wording of the claims provide a compound of Formula (I-F), wherein the compound is not a compound selected from the group consisting of:

[0237] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-G): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0238] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein: R 1A< is halogen; R 1B< is halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or C1-C6 haloalkyl; R 3< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 4< is 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, -NR A< R B< , and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R B< , R C1< , and R D1< is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NR B2< R C2< , -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each R A2< , R B2< , and R C2< is independently hydrogen or C1-C6 alkyl; each R G< is independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NR A2< , -C(=O)NR C1< R D1< , C1-C6 haloalkoxy, - SO 2 (C1-C6 alkyl), and -CO 2 H.

[0239] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-J): or a pharmaceutically acceptable salt thereof, wherein: R x< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is 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; R 4< is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , - C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=0)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (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 R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; wherein R 4< is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is 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, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ); or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0240] In some examples not encompassed by the wording of the claims, Ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some examples not encompassed by the wording of the claims, Ring A1 is pyrimidinyl. In some examples not encompassed by the wording of the claims, Ring A1 is pyridyl. In some examples not encompassed by the wording of the claims, Ring A1 is pyrazolyl.

[0241] In some examples not encompassed by the wording of the claims, Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some examples not encompassed by the wording of the claims, Ring A1 is 5-pyrimidinyl. In some examples not encompassed by the wording of the claims, Ring A1 is 3-pyridyl. In some examples not encompassed by the wording of the claims, Ring A1 is 4-pyrazolyl.

[0242] In some embodiments of Formula (I-A), is wherein: R 4B< is selected from -NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0243] In some embodiments of Formula (I-A), R A< and R B< are each hydrogen.

[0244] In some embodiments of Formula (I-A), R A< and R B< are each 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered heterocyclyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 haloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 haloalkyl.

[0245] In some embodiments of Formula (I-A), R A< and R B< are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl.

[0246] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ) . In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl.

[0247] In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (I-A), R A< and R B< are each C1-C6 alkyl. In some embodiments of Formula (I-A), R A< and R B< are each C1-C3 alkyl. In some embodiments of Formula (I-A), R A< and R B< are each methyl.

[0248] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0249] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with - SO 2 (C1-C6 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C3 alkyl). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 CH 3 , e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl).

[0250] In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some embodiments of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (NH 2 ), e.g., 1-sulfamoylpropan-2-yl . In some embodiments of Formula (I-A), one of R A< and R B< is C1-C6 alkyl hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some embodiments of Formula (I-A), R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (NH 2 ).

[0251] In some embodiments of Formula (I-A), R 4B< is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G< ; wherein R G< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0252] In some embodiments of Formula (I-A), R 4B< is wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 R G< independently selected from fluoro, hydroxyl, and C1-C6 alkyl. In some embodiments of Formula (I-A), Ring B is azetidinyl.

[0253] In some embodiments of Formula (I-A), Ring B is unsubstituted.

[0254] In some embodiments of Formula (I-A), Ring B is substituted with 1 R G< . In some embodiments of Formula (I-A), R G< is fluoro. In some embodiments of Formula (I-A), R G< is cyano. In some embodiments of Formula (I-A), R G< is hydroxyl. In some embodiments of Formula (I-A), R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), R G< is methyl. In some embodiments of Formula (I-A), R G< is -CO 2 CH 3 .

[0255] In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected R G< . In some embodiments of Formula (I-A), each R G< is fluoro. In some embodiments of Formula (I-A), each R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), each R G< is methyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is methyl. In some embodiments of Formula (I-A), one R G< is fluoro and the other R G< is C1-C3 alkyl. In some embodiments of Formula (I-A), one R G< is fluoro and the other R G< is methyl. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is fluoro. In some embodiments of Formula (I-A), one R G< is hydroxyl and the other R G< is trifluoromethyl.

[0256] In some embodiments of Formula (I-A), is wherein 1 or 2 independently selected R G< is at the 3-position of the azetidine. In some embodiments of Formula (I-A), is selected from the group consisting of and In some embodiments of Formula (I-A), is selected from the groups consisting of

[0257] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-K): or a pharmaceutically acceptable salt thereof, wherein: R x< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is 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; R 4< is independently selected from the group consisting of: C1-C6 alkyl optionally substituted with -NR A< R B< , C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , - C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=0)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (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 R G< , and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is 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, -SO 2 (C1-C6 alkyl), and -SO 2 (NH 2 ); or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0258] In some examples not encompassed by the wording of the claims, R 1A< and R 1B< are each fluoro; In some examples not encompassed by the wording of the claims, R 2< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 2< is a C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 2< is methyl.

[0259] In some examples not encompassed by the wording of the claims, R 2< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 2< is a trifluoromethyl.

[0260] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R 3< is methyl, ethyl, or isopropyl. In some examples not encompassed by the wording of the claims, R 3< is methyl. In some examples not encompassed by the wording of the claims, R 3< is ethyl. In some examples not encompassed by the wording of the claims, R 3< is isopropyl.

[0261] In some examples not encompassed by the wording of the claims, R 3< is a C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is a C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 3< is a trifluoromethyl.

[0262] In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is C3-C6 cycloalkyl substituted with 1 or 2 fluoro. In some examples not encompassed by the wording of the claims, R 3< is unsubstituted C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, the R 3< C3-C6 cycloalkyl is cyclopropyl. In some examples not encompassed by the wording of the claims, R 3< is cyclopropyl.

[0263] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 alkyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is C1-C3 alkyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is methyl optionally substituted with -NR A< R B< . In some examples not encompassed by the wording of the claims, R 4< is C1-C4 alkyl. In some examples not encompassed by the wording of the claims, R 4< is methyl.

[0264] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 alkoxy. In some examples not encompassed by the wording of the claims, R 4< is C1-C3 alkoxy. In some examples not encompassed by the wording of the claims, R 4< is methoxy.

[0265] In some examples not encompassed by the wording of the claims, R 4< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R 4< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, R 4< is trifluoromethyl.

[0266] In some examples not encompassed by the wording of the claims, R 4< is hydroxyl. In some examples not encompassed by the wording of the claims, R 4< is cyano. In some examples not encompassed by the wording of the claims, R 4< is -CO 2 H. In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0267] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of one of R A< and R B< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 haloalkyl.

[0268] In some examples not encompassed by the wording of the claims, R A< and R B< are each 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered heterocyclyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered heterocyclyl. In some examples not encompassed by the wording of the claims of Formula (I-A), one of R A< and R B< is hydrogen and the other of R A< and R B< is 1,1-dioxidotetrahydrothiophen-3-yl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered heterocyclyl.

[0269] In some examples not encompassed by the wording of the claims, R A< and R B< are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is unsubstituted 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 3 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 4 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is cis- or trans-3-hydroxycyclobutyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 5 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is 6 membered cycloalkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is 3-6 membered cycloalkyl substituted with hydroxyl.

[0270] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), and - SO 2 (NH 2 ).

[0271] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with cyclopropyl and hydroxyl,, e.g., 1-cyclopropyl-2-hydroxyethyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0272] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 CH 3 , e.g., 1-(methylsulfonyl)propan-2-yl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with -SO 2 (C1-C6 alkyl).

[0273] In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with -SO 2 (NH 2 ), e.g., 1-sulfamoylpropan-2-yl . In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C6 alkyl hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with -SO 2 (NH 2 ). In some examples not encompassed by the wording of the claims, R A< and R B< are both C1-C6 alkyl substituted with - SO 2 (NH 2 ).

[0274] In some examples not encompassed by the wording of the claims, one R 4< is -C(=O)NR C< R D< . In some examples not encompassed by the wording of the claims, R C< and R D< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is methyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each methyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is hydrogen and the other of R C< and R D< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C< and R D< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C< and R D< is C1-C6 alkyl and the other of R C< and R D< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R C< and R D< , together with the nitrogen atom to which they are attached form azetidine or piperazine.

[0275] In some examples not encompassed by the wording of the claims, one R 4< is -SO 2 (NR E< R F< ). In some examples not encompassed by the wording of the claims, R E< and R F< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is methyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each methyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is hydrogen and the other of R E< and R F< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R E< and R F< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R E< and R F< is C1-C6 alkyl and the other of R E< and R F< is C1-C6 haloalkyl.

[0276] In some examples not encompassed by the wording of the claims, R 4< is -SO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -SO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -SO 2 Me. In some examples not encompassed by the wording of the claims, R 4< is -SO 2 Et.

[0277] In some examples not encompassed by the wording of the claims, R 4< is -S(=0)(=NH)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is - S(=O)(=NH)(C1-C4 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -S(=O)(=NH)Me. In some examples not encompassed by the wording of the claims, R 4< is -C(=O)(C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -C(=O)(C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -C(=O)Me.

[0278] In some examples not encompassed by the wording of the claims, R 4< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -CO 2 (C1-C3 alkyl). In some examples not encompassed by the wording of the claims, R 4< is -CO 2 Me.

[0279] In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one R 4< is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R 4< is 5-6 membered heteroaryl. In some examples not encompassed by the wording of the claims, R 4< is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some examples not encompassed by the wording of the claims, R 4< is pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is tetrazolyl substituted with methyl. In some examples not encompassed by the wording of the claims, one R 4< is pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is unsubstituted pyrazolyl. In some examples not encompassed by the wording of the claims, one R 4< is 1-pyrazolyl.

[0280] In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 1 R G< . In some examples not encompassed by the wording of the claims, R 4< is 3-6 membered heterocyclyl substituted with 2 independently selected R G< .

[0281] In some examples not encompassed by the wording of the claims, R G< is fluoro. In some examples not encompassed by the wording of the claims, R G< is cyano. In some examples not encompassed by the wording of the claims, R G< is hydroxyl. In some examples not encompassed by the wording of the claims, R G< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R G< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R G< is methyl.

[0282] In some examples not encompassed by the wording of the claims, R G< is C1-C6 alkoxy. In some examples not encompassed by the wording of the claims, R G< is C1-C3 alkoxy. In some examples not encompassed by the wording of the claims, R G< is methoxy.

[0283] In some examples not encompassed by the wording of the claims, one R G< is -NR A1< R B1< . In some examples not encompassed by the wording of the claims, R A1< and R B1< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is methyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each methyl.

[0284] In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is hydrogen and the other of R A1< and R B1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R A1< and R B1< are each C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R A1< and R B1< is C1-C6 alkyl and the other of R A1< and R B1< is C1-C6 haloalkyl.

[0285] In some examples not encompassed by the wording of the claims, one R G< is - C(=O)NR C1< R D1< . In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is hydrogen. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is methyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is methyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is hydrogen and the other of R C1< and R D1< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, R C1< and R D1< are each is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one of R C1< and R D1< is C1-C6 alkyl and the other of R C1< and R D1< is C1-C6 haloalkyl.

[0286] In some examples not encompassed by the wording of the claims, one R G< is -CO 2 (C1-C6 alkyl). In some examples not encompassed by the wording of the claims, one R G< is -CO 2 CH 3 .

[0287] In some examples not encompassed by the wording of the claims, one R G< is C1-C6 haloalkyl. In some examples not encompassed by the wording of the claims, one R G< is trifluoromethyl.

[0288] In some examples not encompassed by the wording of the claims, one R G< is C3-C6 cycloalkyl. In some examples not encompassed by the wording of the claims, one R G< is cyclopropyl.

[0289] In some examples not encompassed by the wording of the claims, R G< is -CO 2 H.

[0290] In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, the R 4< 3-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0291] In some examples not encompassed by the wording of the claims, R 4< is unsubstituted 3-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< is a 5-6 membered heterocyclyl. In some examples not encompassed by the wording of the claims, R 4< is azetidinyl, morpholinyl, or tetrahydropyranyl. In some examples not encompassed by the wording of the claims, R 4< is selected from the group consisting of

[0292] In some examples not encompassed by the wording of the claims, R 4< is selected from - NR A< R B< and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G1< ; wherein R G1< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0293] In some examples not encompassed by the wording of the claims, R A< and R B< are each hydrogen. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C6 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is C1-C3 alkyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is hydrogen and the other of R A< and R B< is methyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl optionally substituted with hydroxyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is C1-C3 alkyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is C1-C3 alkyl substituted with hydroxyl. In some examples not encompassed by the wording of the claims, one of R A< and R B< is methyl and the other of R A< and R B< is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C6 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each C1-C3 alkyl. In some examples not encompassed by the wording of the claims, R A< and R B< are each methyl.

[0294] In some examples not encompassed by the wording of the claims, R 4< is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected R G< ; wherein R G< is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0295] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-L): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=0)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , and -CO 2 H.

[0296] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-M): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0297] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-N): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0298] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-O): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=0)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0299] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-P): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3< is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4< is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO 2 H, -NR A< R B< , -C(=O)NR C< R D< , -SO 2 (NR E< R F< ), -SO 2 (C1-C6 alkyl), -S(=O)(=NH)(C1\-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO 2 (C1-C6 alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R A1< , R B< , R B1< , R C< , R C1< , R D< , R D1< , R E< , and R F< is independently hydrogen or C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl; or R C< and R D< , together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each R G< is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1< R B1< , -C(=O)NR C1< R D1< , -CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO 2 H.

[0300] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is Formula (I-Q): or a pharmaceutically acceptable salt thereof, wherein: R X< is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A< is halogen; R 1B< is halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R 1A< ); R 2< is a C1-C6 alkyl or C1-C6 haloalkyl; R 3< is a C1-C6 alkyl or a C1-C6 haloalkyl; R 4< is 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, -NR A< R B< , and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G< ; each R A< , R B< , R C1< , and R D1< is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NR B2< R C2< , -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; each R A2< , R B2< , and R C2< is independently hydrogen or C1-C6 alkyl; each R G< is independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NR A2< , -C(=O)NR C1< R D1< , C1-C6 haloalkoxy, - SO 2 (C1-C6 alkyl), and -CO 2 H.

[0301] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0302] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0303] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0304] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein.

[0305] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein.

[0306] In some examples not encompassed by the wording of the claims, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R 3< , R 4< , and Ring A are as described herein.Non-Limiting Exemplary Compounds

[0307] In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-195 (e.g., Compounds 1-276), or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof. Table A Structure Structure

[0309] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table B, or a pharmaceutically acceptable salt thereof. Table B Structure Structure

[0310] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C, or a pharmaceutically acceptable salt thereof. Table C Structure Structure

[0311] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table D, or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions and Administration General

[0312] In some embodiments, a chemical entity (e.g., a compound that inhibits PI3Kα, or a pharmaceutically acceptable salt thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0313] In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from pharmaceutically acceptable excipients may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).Routes of Administration and Composition Components

[0314] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0315] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0316] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0317] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0318] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0319] Intratumoral injections are discussed, e.g., in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" Neoplasia. 2006, 10, 788-795.

[0320] Pharmaceutically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0321] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating pharmaceutically acceptable excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0322] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0323] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such pharmaceutically acceptable excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0324] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0325] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0326] In certain embodiments, the pharmaceutically acceptable excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage forms, pharmaceutically acceptable excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0327] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802.

[0328] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0329] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0330] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0331] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[0332] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.Dosages

[0333] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0334] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 150 mg / Kg; from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0. 1 mg / Kg to about 200 mg / Kg; from about 0. 1 mg / Kg to about 150 mg / Kg; from about 0. 1 mg / Kg to about 100 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0. 1 mg / Kg to about 10 mg / Kg; from about 0. 1 mg / Kg to about 5 mg / Kg; from about 0. 1 mg / Kg to about 1 mg / Kg; from about 0. 1 mg / Kg to about 0.5 mg / Kg).Regimens

[0335] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0336] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.Compositions for Use in Methods of Treatment Indications

[0337] Provided herein are compositions for use in methods of inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Ka), encoded by PIK3CA gene. For example, provided herein are inhibitors of PI3Kα useful for 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 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).

[0338] A "PI3Kα inhibitor" as used herein includes any compound exhibiting PI3Kα inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Kα inhibitor can be selective for a PI3Kα having one or more mutations.

[0339] The ability of test compounds to act as inhibitors of PI3Kα may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound / kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.

[0340] Potency of a PI3Kα inhibitor as provided herein can be determined by EC 50 value. A compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC 50 value. In some embodiments, the substantially similar conditions comprise determining a PI3Kα - dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A594 cells, U2OS cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing a wild type PI3Kα, a mutant PI3Kα, or a fragment of any thereof).

[0341] Potency of a PI3Kα inhibitor as provided herein can also be determined by IC 50 value. A compound with a lower IC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC 50 value. In some embodiments, the substantially similar conditions comprise determining a PI3Kα-dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, SKOV3, T47D, CAL33, BT20, HSC2, OAW42, NCI, HCC1954, NCIH1048, Detroit562, A594 cells, U2OS cells, A431 cells, A594 cells, U2OS cells, Ba / F3 cells, or 3T3 cells expressing a wild type PI3Kα, a mutant PI3Kα, or a fragment of any thereof).

[0342] The selectivity between wild type PI3Kα and PI3Kα containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, abiomarker of PI3Kα activity, or proliferation assays where cell proliferation is dependent on mutant PI3Kα kinase activity.

[0343] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of 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 exhibit nanomolar potency against a PI3Kα kinase including one or more mutations, for example, the mutations in Tables 1 and 2.

[0344] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of 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 nanomolar potency against a PI3Kα protein including an activating mutation, with minimal activity against related kinases (e.g., wild type PI3Kα). Inhibition of wild type PI3Kα can cause undesireable side effects (e.g., hyperglycemia and skin rashes) that can impact quality of life and compliance. In some cases, the inhibititon of wild type PI3Kα can lead to dose limiting toxicities. See, e.g., Hanker, et al., Cancer Disc. 2019, 9, 4, 482-491. Mutant-selective inhibitors may reduce the risk of such dose limiting toxicities, including hyperglycemia, observed with inhibitors of wild type PI3Kα.

[0345] In some examples not encompassed by the wording of the claims, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα over another kinase or non-kinase target.

[0346] In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of PI3Kα containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1 or Table 2) relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of PI3Kα having a combination of mutations described herein relative to inhibition of wild type PI3Kα.

[0347] In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some examples not encompassed by the wording of the claims, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα.

[0348] Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases and disorders which can be treated with a PI3Kα inhibitor, 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).

[0349] 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).

[0350] In some embodiments, the subject is a pediatric subject.

[0351] The term "pediatric subject" as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term "pediatric" can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson 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 MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0352] In certain examples not encompassed by the wording of the claims, compounds of Formula (I), 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.

[0353] 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).

[0354] 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.

[0355] 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 noncancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or 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.

[0356] 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.

[0357] 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.

[0358] 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).

[0359] Provided herein in an example not encompassed by the claims is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need of such treatment, the method 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some examples not encompassed by the wording of the claims, 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.

[0360] In some examples not encompassed by the wording of the claims, the PI3Kα protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M10431, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some examples not encompassed by the wording of the claims, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid.

[0361] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor.

[0362] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the cancer (e.g., PI3Kα-associated 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 squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, 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), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0363] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the cancer (e.g., PI3Kα-associated 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.

[0364] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0365] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the PI3Kα-associated cancer is breast cancer. In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the PI3Kα-associated cancer is lung cancer.

[0366] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, the PI3Kα-associated cancer is selected from the cancers described in Table 1 and Table 2. Table 1. PI3Kα Protein Amino Acid Substitutions / Insertions / Deletions A< Amino Acid Position Non-Limiting Exemplary Mutations Non-Limiting Exemplary PI3Kα Associated Cancer(s) 1M1 (Translation Start Site)Astrocytoma Glioblastoma Multiforme4R4* (Nonsense Mutation)Glioblastoma Multiforme9E9GStomach Adenocarcinoma10L10_M16delGlioblastoma Multiforme11W11L, W11S, W11_P18del (In Frame Deletion)Lung Adenocarcinoma, Oligodendroglioma, Uterine Endometrioid Carcinoma12G12DUterine Endometrioid Carcinoma13I13TColon Adenocarcinoma19R19IUterine Endometrioid Carcinoma27P27THepatocellular Carcinoma36C36YUterine Endometrioid Carcinoma38R38C, R38H, R38L, R38SUterine Endometrioid CarcinomaPapillary Renal Cell CarcinomaPapillary Stomach AdenocarcinomaMucinous Adenocarcinoma of the Colon and RectumGlioblastoma MultiformeCervical Squamous Cell CarcinomaHepatocellular CarcinomaUterine Endometrioid CarcinomaDiffuse Type Stomach AdenocarcinomaLung Squamous Cell CarcinomaUterine Endometrioid Carcinoma39E39G, E39KUterine Endometrioid CarcinomaGlioblastoma Multiforme57P57LCutaneous Melanoma65E65KLung Squamous Cell Carcinoma66S66CBladder Urothelial Carcinoma69I69NColon Adenocarcinoma71V71IHead and Neck Squamous Cell Carcinoma75Q75EBladder Urothelial CarcinomaCervical Squamous Cell CarcinomaHead and Neck Squamous Cell Carcinoma78E78* (nonsense mutation)Lung Squamous Cell Carcinoma80E80KUterine Mixed Endometrial Carcinoma81E81* (nonsense mutation), E81del (in frame deletion), E81KColon AdenocarcinomaGlioblastoma MultiformeColon AdenocarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaGlioblastoma MultiformeUterine Endometrioid CarcinomaLung Squamous Cell CarcinomaMucinous Adenocarcinoma of the Colon and RectumBreast Invasive Ductal CarcinomaCervical Squamous Cell CarcinomaHead and Neck Squamous Cell Carcinoma83F83L, F83SBreast Invasive Lobular Carcinoma84D84HLung Adenocarcinoma86T86SHepatocellular Carcinoma87R87TLung Adenocarcinoma88R88QBreast Invasive Ductal CarcinomaRectal AdenocarcinomaColon AdenocarcinomaProstate AdenocarcinomaCervical Squamous Cell CarcinomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorTubular Stomach AdenocarcinomaOligodendrogliomaMucinous Stomach AdenocarcinomaGlioblastoma MultiformeStomach AdenocarcinomaUterine Endometrioid CarcinomaUterine Mixed Endometrial CarcinomaHead and Neck Squamous Cell CarcinomaMucinous Adenocarcinoma of the Colon and RectumBreast Invasive Lobular CarcinomaIntestinal Type Stomach AdenocarcinomaBladder Urothelial Carcinoma90C90G, C90R, C90YGlioblastoma MultiformeCervical Squamous Cell Carcinoma93R93P, R93Q, R93WMucinous Adenocarcinoma of the Colon and RectumStomach AdenocarcinomaGlioblastoma MultiformeUterine Endometrioid CarcinomaTubular Stomach AdenocarcinomaMucinous Stomach AdenocarcinomaBladder Urothelial CarcinomaCervical Squamous Cell CarcinomaColon Adenocarcinoma102I102delUterine Endometrioid Carcinoma103E103G, E103_G106delins D (In Frame Deletion), E103_P104del (In Frame Deletion)Glioblastoma MultiformeBreast Invasive Ductal Carcinoma104P104L, P104R, P104TBreast Invasive Ductal CarcinomaHead and Neck Squamous Cell CarcinomaLung AdenocarcinomaColon AdenocarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinoma105V105del, V105_R108delUterine Endometrioid CarcinomaBreast Invasive Ductal Carcinoma106G106D, G106R, G106S, G106V, G106_R108del (In Frame Deletion), G106_N107del (In Frame Deletion)Uterine Mixed Endometrial CarcinomaBreast Invasive Ductal CarcinomaMucinous Adenocarcinoma of the Colon and RectumMucinous CarcinomaOligodendrogliomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaUterine Endometrioid CarcinomaRectal AdenocarcinomaLung Squamous Cell CarcinomaCervical Squamous Cell CarcinomaTubular Stomach AdenocarcinomaUterine Endometrioid Carcinoma107N107SUterine Endometrioid CarcinomaLung Adenocarcinoma108R108C, R108H, R108LProstate AdenocarcinomaUterine Endometrioid CarcinomaGlioblastoma MultiformeUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorMucinous Adenocarcinoma of the Colon and RectumTubular Stomach AdenocarcinomaColon AdenocarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaUterine Mixed Endometrial CarcinomaBreast Invasive Ductal CarcinomaLung Squamous Cell Carcinoma109E109_I112delins D (In Frame Deletion)Breast Invasive Ductal Carcinoma110E110delUterine Endometrioid CarcinomaOligodendrogliomaBreast Invasive Lobular CarcinomaBreast Invasive Ductal CarcinomaUterine Mixed Endometrial CarcinomaColon AdenocarcinomaHead and Neck Squamous Cell CarcinomaLung AdenocarcinomaPapillary Thyroid Cancer111K111del, K111E, K111N, K111R, K111_L113del (In Frame Deletion)Uterine Endometrioid CarcinomaBreast Invasive Ductal CarcinomaOligodendrogliomaHead and Neck Squamous Cell CarcinomaColon AdenocarcinomaIntestinal Type Stomach AdenocarcinomaStomach AdenocarcinomaUterine Endometrioid CarcinomaLung AdenocarcinomaEsophageal AdenocarcinomaLung Squamous Cell CarcinomaGlioblastoma Multiforme113L113delUterine Endometrioid Carcinoma115R115L, R115PSerous Ovarian CancerBladder Urothelial CarcinomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorUterine Endometrioid CarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaRectal AdenocarcinomaCervical Squamous Cell Carcinoma116E116KRectal Adenocarcinoma118G118DGlioblastoma MultiformeBreast Invasive Ductal CarcinomaUterine Endometrioid CarcinomaBladder Urothelial CarcinomaOligodendrogliomaEsophageal AdenocarcinomaAstrocytomaLung Squamous Cell CarcinomaBreast Invasive Lobular CarcinomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaMucinous CarcinomaUterine Mixed Endometrial CarcinomaStomach AdenocarcinomaPancreatic AdenocarcinomaPapillary Thyroid CancerRectal Adenocarcinoma123M123ILung Adenocarcinoma124P124ALung Adenocarcinoma151V151MBladder Urothelial Carcinoma Astrocytoma165Y165HUterine Mixed Endometrial Carcinoma170N170SUterine Endometrioid Carcinoma182Y182HStomach Adenocarcinoma213H213NCutaneous Melanoma224A224SColon Adenocarcinoma239L239RColon Adenocarcinoma258D258NRectal Adenocarcinoma262L262ICutaneous Melanoma266P266TUterine Endometrioid Carcinoma267L267MCutaneous Melanoma272Y272* (Nonsense Mutation)Renal Clear Cell Carcinoma274R274KBladder Urothelial Carcinoma279L279IUterine Endometrioid Carcinoma282M282VUterine Endometrioid Carcinoma292S292IGlioblastoma Multiforme296Q296ELung Adenocarcinoma300D300VLung Squamous Cell Carcinoma310R310CUterine Endometrioid Carcinoma322T322AUterine Endometrioid Carcinoma335R335GHead and Neck Squamous Cell Carcinoma337K337NRectal Adenocarcinoma339L339ICervical Squamous Cell CarcinomaUterine Endometrioid Carcinoma342T342SLung Adenocarcinoma344V344A, V344G, V344MUterine Endometrioid CarcinomaMucinous Adenocarcinoma of the Colon and RectumColon AdenocarcinomaCervical Squamous Cell CarcinomaRectal AdenocarcinomaHead and Neck Squamous Cell CarcinomaBreast Invasive Carcinoma (NOS)Uterine Mixed Endometrial CarcinomaGlioblastoma Multiforme345N345H, N345I, N345K, N345T, N345YBreast Invasive Lobular CarcinomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaUterine Endometrioid CarcinomaBreast Invasive Carcinoma (NOS)Lung AdenocarcinomaMucinous Adenocarcinoma of the Colon and RectumBladder Urothelial CarcinomaColon AdenocarcinomaLeiomyosarcomaGlioblastoma MultiformeUterine Endometrioid CarcinomaSeminomaTubular Stomach AdenocarcinomaBreast Invasive Ductal CarcinomaHead and Neck Squamous Cell CarcinomaStomach AdenocarcinomaDiffuse Type Stomach AdenocarcinomaProstate AdenocarcinomaBreast Invasive Ductal CarcinomaOligodendroglioma350D350G, D350NLung Squamous Cell CarcinomaBreast Invasive Ductal CarcinomaUterine Endometrioid CarcinomaColon AdenocarcinomaUterine Endometrioid CarcinomaMucinous Stomach AdenocarcinomaLung AdenocarcinomaBreast Invasive Lobular Carcinoma351I351TUterine Endometrioid Carcinoma357R357QUterine Endometrioid CarcinomaMucinous Adenocarcinoma of the Colon and Rectum Colon Adenocarcinoma359G359RUterine Endometrioid Carcinoma363G363AHead and Neck Squamous Cell Carcinoma364G364RUterine Mixed Endometrial CarcinomaIntestinal Type Stomach AdenocarcinomaColon Adenocarcinoma365E365K, E365VUterine Endometrioid CarcinomaBladder Urothelial CarcinomaMucinous Adenocarcinoma of the Colon and RectumDiffuse Type Stomach AdenocarcinomaBreast Invasive Ductal CarcinomaHead and Neck Squamous Cell Carcinoma366P366RBreast Invasive Ductal Carcinoma378C378F, C378R, C378YUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaUterine Endometrioid CarcinomaOligodendroglioma379S379TCutaneous Melanoma380N380SDiffuse Type Stomach Adenocarcinoma390D390NLung Adenocarcinoma392Y392HUterine Endometrioid Carcinoma398R398HBreast Invasive Ductal Carcinoma399A399TCervical Squamous Cell Carcinoma401R401QUterine Endometrioid Carcinoma405S405FIntestinal Type Stomach Adenocarcinoma406I406VUterine Mixed Endometrial Carcinoma412R412QStomach Adenocarcinoma417E417KBladder Urothelial Carcinoma418E418KUterine Endometrioid CarcinomaRectal AdenocarcinomaMucinous CarcinomaHead and Neck Squamous Cell CarcinomaBladder Urothelial Carcinoma420C420RUterine Endometrioid CarcinomaTubular Stomach AdenocarcinomaLung Squamous Cell CarcinomaBreast Invasive Ductal CarcinomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaColon AdenocarcinomaIntestinal Type Stomach AdenocarcinomaStomach AdenocarcinomaHead and Neck Squamous Cell CarcinomaBreast Invasive Carcinoma (NOS)AstrocytomaCervical Squamous Cell Carcinoma432Y432CCervical Squamous Cell Carcinoma447P447_L455del (In frame Deletion)Breast Invasive Ductal Carcinoma449P449L, P449SUterine Endometrioid Carcinoma450H450_P458del (In Frame Deletion)Breast Invasive Ductal Carcinoma451G451R, G451V, G451_D454del (In Frame Deletion)Head and Neck Squamous Cell CarcinomaBladder Urothelial CarcinomaColon Adenocarcinoma452L452_G460del (In Frame Deletion)Breast Invasive Ductal Carcinoma453E453del, E453K, E453Q, E453_G460delins DDF (in Frame Deletion), E453_L455delOligodendrogliomaUterine Mixed Endometrial CarcinomaIntestinal Type Stomach AdenocarcinomaBreast Invasive Ductal CarcinomaBreast Invasive Lobular CarcinomaHead and Neck Squamous Cell CarcinomaAstrocytomaStomach AdenocarcinomaBladder Urothelial CarcinomaLung Squamous Cell CarcinomaCervical Squamous Cell CarcinomaLung AdenocarcinomaMucinous CarcinomaUterine Endometrioid CarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaGlioblastoma MultiformeColon Adenocarcinoma454D454YUterine Endometrioid Carcinoma455L455_G463del (In Frame Deletion)Glioblastoma Multiforme463G463_N465delins D (In Frame Deletion)Uterine Endometrioid Carcinoma469E469A, E469delinsDK (In Frame Insertion)Rectal AdenocarcinomaBreast Invasive Ductal Carcinoma471P471A, P471LBladder Urothelial CarcinomaRectal AdenocarcinomaUterine Endometrioid CarcinomaOligoastrocytomaHepatocellular Carcinoma474E474AProstate Adenocarcinoma475L475FCutaneous Melanoma479W479*Uterine Endometrioid Carcinoma495H495L, H495YLung Squamous Cell CarcinomaUterine Endometrioid Carcinoma499S499FBladder Urothelial Carcinoma519R519GHead and Neck Squamous Cell Carcinoma520D520VBreast Invasive Lobular Carcinoma522E522AUterine Endometrioid Carcinoma531L531VBreast Invasive Ductal Carcinoma539P539R, P539SBreast Invasive Ductal CarcinomaPancreatic AdenocarcinomaUterine Endometrioid CarcinomaLung Squamous Cell Carcinoma542E542A, E542G, E542K, E542Q, E542VUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaUterine Endometrioid CarcinomaColon AdenocarcinomaProstate AdenocarcinomaBreast Invasive Ductal CarcinomaBreast Invasive Lobular CarcinomaEndocervical AdenocarcinomaIntestinal Type Stomach AdenocarcinomaProstate AdenocarcinomaPapillary Renal Cell CarcinomaOligoastrocytomaHepatocellular CarcinomaBladder Urothelial CarcinomaMucinous Adenocarcinoma of the Colon and RectumDiffuse Type Stomach AdenocarcinomaLung Squamous Cell CarcinomaSignet Ring Cell Carcinoma of the StomachHead and Neck Squamous Cell CarcinomaBreast Invasive Carcinoma (NOS)Mucinous CarcinomaBreast Invasive Ductal CarcinomaCervical Squamous Cell CarcinomaGlioblastoma MultiformeLung Adenocarcinoma545E545A, E545D, E545G, E545K, E545QUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaUterine Endometrioid CarcinomaColon AdenocarcinomaProstate AdenocarcinomaBreast Invasive Ductal CarcinomaBreast Invasive Lobular CarcinomaEndocervical AdenocarcinomaIntestinal Type Stomach AdenocarcinomaPapillary Renal Cell CarcinomaOligoastrocytomaHepatocellular CarcinomaBladder Urothelial CarcinomaMucinous Adenocarcinoma of the Colon and RectumDiffuse Type Stomach AdenocarcinomaLung Squamous Cell CarcinomaSignet Ring Cell Carcinoma of the StomachHead and Neck Squamous Cell CarcinomaBreast Invasive Carcinoma (NOS)Mucinous CarcinomaCervical Squamous Cell CarcinomaGlioblastoma MultiformeOligodendrogliomaLung AdenocarcinomaSerous Ovarian CancerUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorAstrocytomaRectal AdenocarcinomaStomach AdenocarcinomaCutaneous MelanomaEsophageal Squamous Cell CarcinomaBreast Invasive Mixed Mucinous CarcinomaIntrahepatic CholangiocarcinomaRenal Clear Cell CarcinomaSeminomaEsophageal AdenocarcinomaTubular Stomach AdenocarcinomaUterine Mixed Endometrial Carcinoma546Q546E, Q546H, Q546K, Q546P, Q546RUterine Endometrioid CarcinomaRectal AdenocarcinomaOligodendrogliomaStomach AdenocarcinomaEsophageal AdenocarcinomaBladder Urothelial CarcinomaBreast Invasive Carcinoma (NOS)Breast Invasive Ductal CarcinomaColon AdenocarcinomaGlioblastoma MultiformeUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaUndifferentiated Pleomorphic Sarcoma / Malignant FibrousHistiocytoma / High-Grade Spindle Cell SarcomaAstrocytomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorOligoastrocytomaBreast Invasive Lobular CarcinomaTubular Stomach AdenocarcinomaHead and Neck Squamous Cell CarcinomaCervical Squamous Cell CarcinomaIntestinal Type Stomach Adenocarcinoma547E547D, E547KLung Squamous Cell CarcinomaStomach Adenocarcinoma552W552CBladder Urothelial Carcinoma569L569IUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaProstate Adenocarcinoma576S576YUterine Endometrioid Carcinoma581A581SCutaneous Melanoma589D589NCervical Squamous Cell Carcinoma600E600K, E600VUterine Endometrioid CarcinomaBladder Urothelial CarcinomaLung AdenocarcinomaBreast Invasive Lobular CarcinomaPapillary Stomach Adenocarcinoma603D603HBreast Invasive Ductal Carcinoma604C604RUterine Endometrioid CarcinomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaHead and Neck Squamous Cell Carcinoma606Y606CHead and Neck Squamous Cell Carcinoma607P607QCutaneous Melanoma609P609HColon Adenocarcinoma614F614IBreast Invasive Ductal Carcinoma617R617Q, R617WUterine Endometrioid Carcinoma617R617WUterine Endometrioid Carcinoma629S629CBreast Invasive Ductal Carcinoma636V636LBladder Urothelial Carcinoma642E642KUterine Serous Carcinoma / Uterine Papillary Serous Carcinoma643Q643HUterine Endometrioid Carcinoma658L658FColon Adenocarcinoma667F667LUterine Endometrioid CarcinomaLung Squamous Cell CarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinoma673S673TBreast Invasive Ductal Carcinoma674E674* (Nonsense mutation), E674D, E674QPapillary Thyroid CancerCutaneous MelanomaBladder Urothelial Carcinoma682Q682K, Q682Rfs*18 (Frame Shift Deletion)Cutaneous MelanomaGlioblastoma Multiforme683R683MCutaneous Melanoma684F684LUterine Endometrioid Carcinoma693R693HCervical Squamous Cell Carcinoma710E710QBladder Urothelial Carcinoma711K711NAstrocytoma722E722KColon Adenocarcinoma725D725G, D725NColon Adenocarcinoma Uterine Endometrioid Carcinoma726E726KCervical Squamous Cell CarcinomaUterine Endometrioid CarcinomaBreast Invasive Ductal CarcinomaHepatocellular CarcinomaLung AdenocarcinomaEsophageal Squamous Cell CarcinomaEsophageal AdenocarcinomaRectal AdenocarcinomaHead and Neck Squamous Cell CarcinomaLung Squamous Cell CarcinomaBreast Invasive Lobular CarcinomaBladder Urothelial CarcinomaColon Adenocarcinoma729K729NCutaneous Melanoma732M732IColon Adenocarcinoma737E737KCutaneous Melanoma741R741QSerous Ovarian Cancer744F744IStomach Adenocarcinoma746D746YCutaneous Melanoma749Q749HCutaneous Melanoma752L752VBladder Urothelial Carcinoma766L766FBreast Invasive Ductal Carcinoma770R770QUterine Endometrioid Carcinoma773S773FCutaneous Melanoma777R777M, R777KCutaneous MelanomaColon Adenocarcinoma791E791QBladder Urothelial Carcinoma811M811IUterine Endometrioid Carcinoma816I816SUterine Endometrioid Carcinoma818R818C, R818HCutaneous MelanomaUterine Endometrioid Carcinoma849E849KSerous Ovarian Cancer852R852QLeiomyosarcomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinoma865G865DCutaneous Melanoma866L866F, L866WCervical Squamous Cell CarcinomaUterine Endometrioid Carcinoma879Q879RStomach Adenocarcinoma886K886EUndifferentiated Pleomorphic Sarcoma / Malignant FibrousHistiocytoma / High-Grade Spindle Cell Sarcoma901C901FUterine Endometrioid CarcinomaAstrocytomaBreast Invasive Ductal CarcinomaHead and Neck Squamous Cell Carcinoma903G903EUterine Serous Carcinoma / Uterine Papillary Serous Carcinoma905C905SHead and Neck Squamous Cell Carcinoma909F909CEsophageal Adenocarcinoma914G914RUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaAstrocytoma929L929MUterine Endometrioid Carcinoma930F930VUterine Endometrioid Carcinoma939D939GBreast Invasive Carcinoma (NOS)Uterine Endometrioid CarcinomaBreast Invasive Ductal Carcinoma948K948EIntestinal Type Stomach Adenocarcinoma951R951CRectal Adenocarcinoma953P953SUterine Endometrioid Carcinoma956L956FBladder Urothelial Carcinoma958Q958RUterine Mixed Endometrial Carcinoma970E970KEsophageal Squamous Cell CarcinomaHead and Neck Squamous Cell CarcinomaMucinous Adenocarcinoma of the Colon and RectumColon Adenocarcinoma971C971RHead and Neck Squamous Cell Carcinoma978E978KBladder Urothelial Carcinoma979R979GPancreatic Adenocarcinoma985Y985*Pleural Mesothelioma, Biphasic Type989L989VBreast Invasive Ductal Carcinoma992R992L, R992PBladder Urothelial CarcinomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaMucinous Carcinoma997L997IUterine Endometrioid Carcinoma1002F1002LUterine Endometrioid Carcinoma1004M1004I,Uterine Endometrioid CarcinomaM1004R,Breast Invasive Ductal CarcinomaM1004VBladder Urothelial CarcinomaLung Squamous Cell Carcinoma1005M1005VOligodendroglioma1006L1006RUterine Endometrioid Carcinoma1007G1007RUterine Endometrioid CarcinomaBreast Invasive Ductal CarcinomaHead and Neck Squamous Cell CarcinomaColon AdenocarcinomaEndocervical Adenocarcinoma1012E1012QBladder Urothelial Carcinoma1015S1015YMucinous Adenocarcinoma of the Colon and Rectum1016F 1016CUterine Endometrioid Carcinoma1017D1017NPancreatic Adenocarcinoma1020A1020TUterine Endometrioid Carcinoma1021Y1021C, Y1021HUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorColon AdenocarcinomaBreast Invasive Ductal CarcinomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaUterine Endometrioid CarcinomaStomach AdenocarcinomaMucinous Adenocarcinoma of the Colon and Rectum Tubular Stomach Adenocarcinoma1025T1025A, T1025SUterine Endometrioid CarcinomaBreast Invasive Ductal CarcinomaMucinous Adenocarcinoma of the Colon and Rectum Uterine Mixed Endometrial Carcinoma1023R1023Q †< Colorectal Cancer1026L1026ICutaneous Melanoma1029D1029HUterine Serous Carcinoma / Uterine Papillary Serous Carcinoma1037E1037KBreast Invasive Ductal Carcinoma1040M1040I, M1040VHead and Neck Squamous Cell CarcinomaBreast Invasive Ductal Carcinoma1043M10431, M1043L, M1043T, M1043VBreast Invasive Lobular CarcinomaTubular Stomach AdenocarcinomaUterine Endometrioid CarcinomaMucinous Adenocarcinoma of the Colon and RectumPapillary Thyroid CancerEsophageal Squamous Cell CarcinomaColon AdenocarcinomaBreast Invasive Ductal CarcinomaBladder Urothelial CarcinomaPancreatic AdenocarcinomaOligodendrogliomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaGlioblastoma MultiformeHead and Neck Squamous Cell Carcinoma1044N1044I, N1044K, N1044YUterine Endometrioid CarcinomaBreast Invasive Ductal Carcinoma1045D1045A, D1045VUterine Endometrioid CarcinomaLung Squamous Cell Carcinoma1047H1047L, H1047Q, H1047R, H1047YEsophageal Squamous Cell CarcinomaUterine Endometrioid CarcinomaHepatocellular CarcinomaCutaneous MelanomaMucinous Adenocarcinoma of the Colon and RectumBladder Urothelial CarcinomaCervical Squamous Cell CarcinomaIntrahepatic CholangiocarcinomaUterine Mixed Endometrial CarcinomaBreast Invasive Ductal CarcinomaRenal Clear Cell CarcinomaUterine Serous Carcinoma / Uterine Papillary Serous CarcinomaHead and Neck Squamous Cell CarcinomaLung Squamous Cell CarcinomaBreast Invasive Lobular CarcinomaBreast Invasive Carcinoma (NOS)AstrocytomaColon AdenocarcinomaLeiomyosarcomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorOligodendrogliomaSerous Ovarian CancerMucinous Stomach AdenocarcinomaRectal AdenocarcinomaIntestinal Type Stomach AdenocarcinomaDiffuse Type Stomach AdenocarcinomaProstate AdenocarcinomaLung AdenocarcinomaStomach AdenocarcinomaTubular Stomach AdenocarcinomaAdrenocortical CarcinomaUndifferentiated Pleomorphic Sarcoma / Malignant FibrousHistiocytoma / High-Grade Spindle Cell SarcomaGlioblastoma MultiformeOligoastrocytoma1048H1048RColon AdenocarcinomaRenal Clear Cell Carcinoma1049G1049RIntestinal Type Stomach AdenocarcinomaBladder Urothelial CarcinomaRenal Clear Cell CarcinomaBreast Invasive Ductal CarcinomaBreast Invasive Lobular CarcinomaUterine Endometrioid CarcinomaColon Adenocarcinoma1052T1052KHepatocellular CarcinomaColon Adenocarcinoma1055M1055IUterine Mixed Endometrial Carcinoma1058I1058MUterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor1065H1065LBreast Invasive Lobular Carcinoma1066A1066VUterine Mixed Endometrial Carcinoma1068N1068Y, N1068fs*5 (Frame Shift Insertion)Pleural Mesothelioma, Epithelioid TypeDedifferentiated LiposarcomaHead and Neck Squamous Cell Carcinoma1069* 1069Wext*4 (nonstop Mutation)Glioblastoma Multiforme A< Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075. Table 2. Additional PI3Kα Protein Amino Acid Substitutions / Insertions / Deletions A< Amino Acid Position Non-Limiting Exemplary Mutations Non-Limiting Exemplary PI3Kα Associated Cancer(s) 1043M1043I, M1043L, M1043T, M1043VBreast Invasive Lobular CarcinomaTubular Stomach AdenocarcinomaUterine Endometrioid CarcinomaMucinous Adenocarcinoma of the Colon and RectumPapillary Thyroid CancerEsophageal Squamous Cell CarcinomaColon AdenocarcinomaBreast Invasive Ductal CarcinomaBladder Urothelial CarcinomaPancreatic AdenocarcinomaOligodendrogliomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaGlioblastoma MultiformeHead and Neck Squamous Cell Carcinoma1044N1044I, N1044K, N1044YUterine Endometrioid CarcinomaBreast Invasive Ductal Carcinoma1045D1045A, D1045VUterine Endometrioid CarcinomaLung Squamous Cell Carcinoma1047H1047L, H1047Q, H1047R, H1047YEsophageal Squamous Cell CarcinomaUterine Endometrioid CarcinomaHepatocellular CarcinomaCutaneous MelanomaMucinous Adenocarcinoma of the Colon and RectumBladder Urothelial CarcinomaCervical Squamous Cell CarcinomaIntrahepatic CholangiocarcinomaUterine Mixed Endometrial CarcinomaBreast Invasive Ductal CarcinomaRenal Clear Cell CarcinomaUterine Serous Carcinoma / Uterine Papillary SerousCarcinomaHead and Neck Squamous Cell CarcinomaLung Squamous Cell CarcinomaBreast Invasive Lobular CarcinomaBreast Invasive Carcinoma (NOS)AstrocytomaColon AdenocarcinomaLeiomyosarcomaUterine Carcinosarcoma / Uterine Malignant MixedMullerian TumorOligodendrogliomaSerous Ovarian CancerMucinous Stomach AdenocarcinomaRectal AdenocarcinomaIntestinal Type Stomach AdenocarcinomaDiffuse Type Stomach AdenocarcinomaProstate AdenocarcinomaLung AdenocarcinomaStomach AdenocarcinomaTubular Stomach AdenocarcinomaAdrenocortical CarcinomaUndifferentiated Pleomorphic Sarcoma / Malignant FibrousHistiocytoma / High-Grade Spindle Cell SarcomaGlioblastoma MultiformeOligoastrocytoma1048H1048RColon AdenocarcinomaRenal Clear Cell Carcinoma1049G1049RIntestinal Type Stomach AdenocarcinomaBladder Urothelial CarcinomaRenal Clear Cell CarcinomaBreast Invasive Ductal CarcinomaBreast Invasive Lobular CarcinomaUterine Endometrioid CarcinomaColon Adenocarcinoma1052T1052KHepatocellular CarcinomaColon Adenocarcinoma1055M1055IUterine Mixed Endometrial Carcinoma1058I1058MUterine Carcinosarcoma / Uterine Malignant MixedMullerian Tumor1065H1065LBreast Invasive Lobular Carcinoma1066A1066VUterine Mixed Endometrial Carcinoma1068N1068Y,Pleural Mesothelioma, Epithelioid TypeN1068fs*5 (Frame Shift Insertion)Dedifferentiated LiposarcomaHead and Neck Squamous Cell Carcinoma A< Unless noted otherwise, the mutations of Table 2 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0367] 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.

[0368] 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.

[0369] Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)

[0370] In some examples not encompassed by the wording of the claims, compounds of Formula (I), or pharmaceutically acceptable thereof, are 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0371] Also provided herein are example methods not encompassed by the wording of the claims for treating a subject identified or diagnosed as having a PI3Kα-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, the test or assay is provided as a kit. In some examples not encompassed by the wording of the claims, the cancer is an PI3Kα-associated cancer.

[0372] 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).

[0373] Also provided are example methods not encompassed by the wording of the claims 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some examples of these methods not encompassed by the wording of the claims further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some examples not encompassed by the wording of the claims, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some examples not encompassed by the wording of the claims, 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 of the non-limiting examples of assays described herein. In some examples not encompassed by the wording of the claims, the test or assay is provided as a kit. In some examples not encompassed by the wording of the claims, the cancer is an PI3Kα-associated cancer.

[0374] Also provided are example methods not encompassed by the wording of the claims 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. Some examples of these methods not encompassed by the wording of the claims further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some examples of these methods not encompassed by the wording of the claims, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some examples not encompassed by the wording of the claims, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some examples not encompassed by the wording of the claims, 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.

[0375] Also provided in an example not encompassed by the wording of the claims is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a PI3Kα-associated cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of 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 (I), or a pharmaceutically acceptable salt thereof, 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 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 examples not encompassed by the wording of the claims 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 (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some examples not encompassed by the wording of the claims, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some examples not encompassed by the wording of the claims, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some examples not encompassed by the wording of the claims, the assay is a liquid biopsy.

[0376] Also provided in an example not encompassed by the wording of the claims is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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 in an example not encompassed by the wording of the claims is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a PI3Kα-associated cancer. In some examples not encompassed by the wording of the claims, 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.

[0377] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, 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 of any of the compounds for use or the pharmaceutical compositions for use described herein, 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 of any of the compounds for use or the pharmaceutical compositions for use described herein, 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 of any of the compounds for use or the pharmaceutical compositions for use described herein, the subject can be a subject whose tumors 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 any of the compounds for use or the pharmaceutical compositions for use described herein, the subject is suspected of having a PI3Kα-associated cancer. In an example not encompassed by the wording of the claims, 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 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, the PI3Kα protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, 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.

[0378] In some embodiments of any of the compounds for use or the pharmaceutical compositions for use described herein, 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 in an example not encompassed by the wording of the claims are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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.

[0379] In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, the method also includes administering to a subject determined to have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some examples not encompassed by the wording of the claims, 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 examples not encompassed by the wording of the claims, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some examples not encompassed by the wording of the claims, 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, M10431, 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,...

Claims

1. A compound of Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: Ring A1 is pyrimidinyl, pyridyl, or pyrazolyl; R1A is halogen; R1B is halogen or absent; R2 is a C1-C6 alkyl or a C1-C6 haloalkyl; R3 is 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; R4 is 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 R4 is 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 RF is 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 RC and RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; and each RG is 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.

2. The compound of claim 1, wherein R1A and R1B are each fluoro.

3. The compound of claim 1 or 2, wherein R2 is a C1-C6 alkyl.

4. The compound of claim 3, wherein R2 is methyl.

5. The compound of any one of claims 1-4, wherein R3 is a C1-C6 haloalkyl.

6. The compound of claim 5, wherein R2 is trifluoromethyl.

7. The compound of any one of claims 1-6, wherein Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl.

8. The compound of claim 7, wherein Ring A1 is 5-pyrimidinyl.

9. The compound of any one of claims 1-8, wherein R4 is -NRARB.

10. The compound of any one of claims 1-7, wherein is wherein: R4B is selected from -NRARB and 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

11. A compound according to claim 1 selected from the group consisting of: or or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 which is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein the compound is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

15. The compound of claim 12, wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

16. The compound of claim 15, wherein the compound is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

17. The compound of claim 15, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

19. A compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 18 for use in a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

20. A compound of Formula (I-A) as defined in claim 1 for use in a method of treating a solid tumor a human subject, the solid tumor having a mutation in PI3Kα, wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a therapeutically effective amount of the compound.

21. The compound for use of claim 20, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the structure: or a pharmaceutically acceptable salt thereof.

22. The compound for use of claim 20, wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

23. The compound for use of claim 22, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

24. The compound for use of claim 20, wherein 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.