Urea derivatives which can be used to treat cancer

Abstract

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 (PI3Ka). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Ka 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.

Description

[0001] UREA DERIVATIVES WHICH CAN BE USED TO TREAT CANCER

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of 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, the contents of which are hereby incorporated by reference.

[0004] TECHNICAL FIELD

[0005] 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 (PI3Ka). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Ka 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.

[0006] BACKGROUND

[0007] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), 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. ThePI3K 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.

[0008] 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.) 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. 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.) Domain deletions in PIK3CA can activate PI3K signaling significantly and also enhance the sensitivity to PI3K inhibitors. (See, Croessmann, S. et al., Clin. Cancer Res.2018, 24, 1426– 1435.) Thus, targeting PI3Kα represents an approach for the treatment of proliferative disorders such as cancer. SUMMARY Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected fromhydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, - SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H; and wherein the compound is not a compound selected from the group consisting of: , , , , , , , , , , , ,

[0009] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, - SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H; and wherein the compound is not a compound selected from the group consisting of: , , , , , , ,

[0010] ,

[0011] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, - SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H. Some embodiments provide compounds of Formula (I), having Formula (X): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is an independently selected halogen; m is 0, 1, 2, or 3; R2is halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: halogen, C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and a 3-6 membered heterocyclyl or 3-6 membered cycloalkyl each optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, -C(=O)(C1-C6alkyl), -SO2(C1-C6alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6alkyl), -SO2(NH2; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H; and wherein the compound is not a compound selected from the group consisting of: , , , , , , , , , , , ,

[0012] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα- associated disease or disorder a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising: determining that the cancer in the subject is a PI3Kα- associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα- associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. This disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments of the methods and composition described herein include compounds of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is an independently selected halogen; m is 0, 1, 2, or 3; R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4-10 membered heterocyclyl; each R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, - NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), - C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, -C(=O)(C1-C6alkyl), C(=O)O(C1-C6alkyl), - SO2(C1-C6alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H. Also provided herein is a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα- associated disease or disorder a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated disease or disorder in a subject, the method comprising: determining that the cancer in the subject is a PI3Kα- associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα- associated cancer a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same. This disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions 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. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. 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. 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. The term "inhibit" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition). “API” refers to an active pharmaceutical ingredient. 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. 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. 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. 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. 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. 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. The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). 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. The term "hydroxyl" refers to an -OH radical. The term "cyano" refers to a -CN radical. The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3). 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. 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. 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., 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). 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. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. 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. 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) ( r (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 include13C and14C. 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. 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. 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 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 using and making the same. Formulae (I) Compounds Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H; and wherein the compound is not a compound selected from the group consisting of:

[0013] , , , , , , ,

[0014] In some embodiments, when Z is NRxand R3is methyl, Ring A is not phenyl. Some embodiments 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: , , , , ,

[0015] ,

[0016] Some embodiments 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: , , , , , , , , , , , ,

[0017] , , , , Some embodiments 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: , , , , , , , , , , , , , , , Some embodiments provide a compound of Formula (I), having Formula (X): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is an independently selected halogen; m is 0, 1, 2, or 3; R2is halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: halogen, C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, and a 3-6 membered heterocyclyl or 3-6 membered cycloalkyl each optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, -C(=O)(C1-C6alkyl), -SO2(C1-C6alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6alkyl), -SO2(NH2; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H; and wherein the compound is not a compound selected from the group consisting of:

[0018] , , , , , , , , , , ,

[0019] ,

[0020] Some embodiments 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: , , , , , ,

[0021] , , ,

[0022] , , , Some embodiments 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: , , , , , , ,

[0023] , , , In some embodiments, the compounds described herein are not compounds that are selected from the group described above (i.e., the “excluded compounds”). In some embodiments, the excluded compounds are flat structures, as indicated above. In some embodiments, the excluded compounds are specific stereoisomers, e.g. specific enantiomers or diastereomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, In some embodiments, In some embodiments, In some embodiments, In some embodiments, In some embodiments, s . In some embodiments, In some embodiments, In some embodiments, . In some embodiments, . In some embodiments, . In some embodiments, each R1is an independently selected halogen. In some embodiments, each R1is independently selected from fluoro and chloro. In some embodiments, each R1is independently selected from fluoro and bromo. In some embodiments, each R1is fluoro. In some embodiments, at least one R1is an independently selected halogen. In some embodiments, at least one R1is independently selected from fluoro and chloro. In some embodiments, at least one R1is fluoro. In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is hydroxyl. In some embodiments, at least one R1is C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, at least one R1is C1-C6alkyl substituted with hydroxyl. In some embodiments, at least one R1is C1-C3alkyl substituted with hydroxyl. In some embodiments, at least one R1is hydroxymethyl. In some embodiments, at least one R1is unsubstituted C1-C6alkyl. In some embodiments, at least one R1is methyl. In some embodiments, at least one R1is C3-C6cycloalkyl. In some embodiments, at least one R1is cyclopropyl. In some embodiments, m is 2; one R1is halogen; and the other R1is C1-C6alkyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is methyl In some embodiments, m is 2; one R1is halogen; and the other R1is C3-C6cycloalkyl. In some embodiments, m is 2; one R1is halogen; and the other R1is cyclopropyl. In some embodiments, m is 2; one R1is fluoro; and the other R1is cyano. In some embodiments, m is 2; one R1is halogen; and the other R1is halogen. In some embodiments, m is 2; one R1is fluoro; and the other R1is fluoro. In some embodiments, R2is hydroxyl. In some embodiments, R2is C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, R2is C1-C6alkyl substituted with hydroxyl. In some embodiments, R2is C1-C3alkyl substituted with hydroxyl. In some embodiments, R2is hydroxymethyl. In some embodiments, R2is an unsubstituted C1-C6alkyl. In some embodiments, R2is unsubstituted C1-C3alkyl. In some embodiments, R2is methyl. In some embodiments, R2is a C1-C6haloalkyl. In some embodiments, R2is a C1-C3haloalkyl. In some embodiments, R2is difluoromethyl. In some embodiments, R2is trifluoromethyl. In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R2is C3-C6cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C6cycloalkyl substituted with 2 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 1 fluoro. In some embodiments, R2is C3-C4 cycloalkyl substituted with 2 fluoro. In some embodiments, R2is an unsubstituted C3-C6cycloalkyl. In some embodiments, R3is a C1-C6alkyl. In some embodiments, R3is a C1-C3alkyl. In some embodiments, R3is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl. In some embodiments, R3is a C1-C6haloalkyl. In some embodiments, R3is a C1-C3haloalkyl. In some embodiments, R3is difluoromethyl. In some embodiments, R3is trifluoromethyl. In some embodiments, R3is C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 fluoro. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 fluoro at the position of the C3-C6cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R3is C3-C6cycloalkyl optionally substituted with 1 or 2 methyl. In some embodiments, R3is C3- C6 cycloalkyl substituted with 1 or 2 methyl. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 methyl. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 methyl at the position of the C3-C6cycloalkyl that is bonded to the methine of Formula (I). In some embodiments, R3is an unsubstituted C3-C6cycloalkyl. In some embodiments, the R3C3-C6cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl. In some embodiments, Ring A is a 6-10 membered aryl. In some embodiments, Ring A is phenyl, naphthyl, or tetrahydronaphthyl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a C3-C8cycloalkyl. In some embodiments, Ring A is a C5-C6 cycloalkyl. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is a 5-10 membered heteroaryl. In some embodiments, Ring A is a 9-10 membered heteroaryl. In some embodiments, Ring A is a 9 membered heteroaryl. In some embodiments, Ring A is a 9 membered heteroaryl, wherein the point of attachment to the urea nitrogen atom in Formula (I) is on a 6-membered ring of Ring A. In some embodiments, Ring A is a 9 membered heteroaryl, wherein the point of attachment to the urea nitrogen atom in Formula (I) is on a 5-membered ring of Ring A. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-6-yl, or imidazo[1,2- a]pyridinyl. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, or imidazo[1,2- a]pyridinyl. In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7- imidazo[1,2-a]pyridinyl, In some embodiments, Ring A is selected from the group consisting wherein “*” indicates the attachment point to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is a 5-6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, Ring A is selected from the groups consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. In some embodiments, Ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, Ring A is 5- pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, Ring A is selected from the group consisting of wherein “*” indicates the attachment point to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is 5-pyrimidinyl. In some embodiments, Ring A is , wherein “*” indicates the attachment point to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is a 4-10 membered heterocyclyl. In some embodiments, Ring A is a 6-9 membered heterocyclyl. In some embodiments, Ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopyranyl-1,1-dioxide. In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2- a]pyridinyl, , , , , , or . In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7- imidazo[1,2-a]pyridinyl, , , . In some embodiments, Ring A is selected from the group consisting of 3-piperidinyl, In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, one R4is C1-C6alkyl. In some embodiments, one R4is unsubstituted C1-C6alkyl. In some embodiments, one R4is C1-C4 alkyl. In some embodiments, one R4is t-butyl. In some embodiments, one R4is methyl. In some embodiments, one R4is C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl. In some embodiments, one R4is C1-C6alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl. In some embodiments, one R4is C1-C6alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cyclopropyl. In some embodiments, one R4is C1-C6alkoxy substituted with hydroxyl. In some embodiments, one R4is C1-C6alkoxy substituted with C3-C6cycloalkyl. In some embodiments, one R4is C1-C6alkoxy substituted with cyclopropyl. In some embodiments, R4is C1-C6alkoxy. In some embodiments, R4is C1-C3alkoxy. In some embodiments, one R4is methoxy. In some embodiments, one R4is C1-C6haloalkyl. In some embodiments, one R4is C1-C3haloalkyl. In some embodiments, one R4is difluoromethyl. In some embodiments, one R4is trifluoromethyl. In some embodiments, one R4is hydroxyl. In some embodiments, one R4is cyano. In some embodiments, one R4is –CO2H. In some embodiments, one R4is halogen. In some embodiments, one R4is fluoro. In some embodiments, one R4is chloro. In some embodiments, one R4is C1-C6alkyl optionally substituted with 1-2 hydroxyl. In some embodiments, one R4is C1-C6alkyl substituted with 1-2 hydroxyl. In some embodiments, one R4is C1-C6alkyl substituted with 1 hydroxyl. In some embodiments, one R4is C1-C6alkyl substituted with 2 hydroxyl. In some embodiments, one R4is C1-C3alkyl substituted with 2 hydroxyl. In some embodiments, one R4is C1-C6alkyl optionally substituted with -NRARB. In some embodiments, one R4is C1-C6alkyl substituted with -NRARB. In some embodiments, one R4is methyl or ethyl substituted with -NRARB. In some embodiments, one R4is an unsubstituted C1-C6alkyl. In some embodiments, one R4is methyl. In some embodiments, one R4is -NRARB. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl or –C(=O)NH2. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis -C(=O)O(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis -C(=O)OCH3. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl (e.g., oxetanyl), In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy- 1-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl or 1-hydroxy-2- propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis butyl substituted with hydroxyl (e.g., 2-hydroxy-2-methyl-1-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, both of RB2and RC2are hydrogen. In some embodiments, one of RB2and RC2is hydrogen and the other of RB2and RC2is C1-C6alkyl. In some embodiments, one of RB2and RC2is hydrogen and the other of RB2and RC2is methyl. In some embodiments, both of RB2and RC2are methyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 haloalkyl. In some embodiments, RAand RBare each C1-C6haloalkyl. In some embodiments, RAand RBare each C1-C3haloalkyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of one of RAand RBis C1-C6haloalkyl. In some embodiments, one R4is -C(=O)NRCRD. In some embodiments, RCand RDare each hydrogen. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C3alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis methyl. In some embodiments, RCand RDare each C1-C6alkyl. In some embodiments, RCand RDare each C1-C3alkyl. In some embodiments, RCand RDare each methyl. In some embodiments, one of RCand RDis C1-C6alkyl and the other of RCand RDis C1-C3alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6haloalkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C3 haloalkyl. In some embodiments, RCand RDare each is C1-C6haloalkyl. In some embodiments, one of RCand RDis C1-C6alkyl and the other of RCand RDis C1-C6haloalkyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1- C6 alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy. In some embodiments, RB1and RC1are each hydrogen. In some embodiments, one of RB1and RC1is hydrogen and the other of RB1and RC1is C1-C6alkyl. In some embodiments, one of RB1and RC1is hydrogen and the other of RB1and RC1is methyl. In some embodiments, RB1and RC1are each independently selected C1-C6alkyl. In some embodiments, RB1and RC1are each methyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. In some embodiments, one R4is -SO2(NRERF). In some embodiments, REand RFare each hydrogen. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C6 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C3 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis methyl. In some embodiments, REand RFare each is C1-C6alkyl. In some embodiments, REand RFare each is C1-C3alkyl. In some embodiments, REand RFare each methyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1-C6haloalkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C3 haloalkyl. In some embodiments, REand RFare each C1-C6haloalkyl. In some embodiments, one of REand RFis C1-C6alkyl and the other of REand RFis C1-C6haloalkyl. In some embodiments, one R4is -SO2(C1-C6alkyl). In some embodiments, one R4is - SO2(C1-C3alkyl). In some embodiments, one R4is -SO2Et. In some embodiments, one R4is - SO2Me. In some embodiments, one R4is -S(=O)(=NH)(C1-C6alkyl). In some embodiments, one R4is -S(=O)(=NH)(C1-C3alkyl). In some embodiments, one R4is -S(=O)(=NH)Me. In some embodiments, one R4is -C(=O)(C1-C6alkyl). In some embodiments, one R4is - C(=O)(C1-C3alkyl). In some embodiments, one R4is -C(=O)Me. In some embodiments, one R4is -CO2(C1-C6alkyl). In some embodiments, one R4is -CO2(C1-C3alkyl). In some embodiments, one R4is -CO2Me. In some embodiments, one R4is 5-6 membered heteroaryl optionally substituted with C1- C6 alkyl. In some embodiments, one R4is 5-6 membered heteroaryl substituted with C1-C6alkyl. In some embodiments, one R4is 5-6 membered heteroaryl. In some embodiments, one R4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, one R4is tetrazolyl substituted with methyl. In some embodiments, one R4is pyrazolyl. In some embodiments, one R4is unsubstituted pyrazolyl. In some embodiments, one R4is 1-pyrazolyl. In some embodiments, one R4is 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 4 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 5 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 7-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, the R4heterocyclyl is a spirocycle. In some embodiments, one R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, one R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, one R4is an unsubstituted 3-6 membered heterocyclyl. In some embodiments, one R4is a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 1 or 2 independently selected RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 1 RG. In some embodiments, one R4is 3-6 membered cycloalkyl substituted with 2 independently selected RG. In some embodiments, one R4is an unsubstituted 3-6 membered cycloalkyl. In some embodiments, the 1 or 2 independently selected RGis 1 RG. In some embodiments, the 1 or 2 independently selected RGare 2 independently selected RG. In some embodiments, when 2 RGare present, they are bonded to the same atom, valency permitting. In some embodiments, when 2 RGare present, they are bonded to adjacent atoms, valency permitting. In some embodiments, when 2 RGare present, the 2 RGare different. In some embodiments, when 2 RGare present, the 2 RGare the same. In some embodiments, one RGis fluoro. In some embodiments, one RGis cyano. In some embodiments, one RGis hydroxyl. In some embodiments, one RGis C1- C6 alkyl optionally substituted with hydroxyl. In some embodiments, one RGis 2-hydroxy-2- propyl. In some embodiments, one RGis C1-C6alkyl. In some embodiments, one RGis C1-C3alkyl. In some embodiments, one RGis methyl. In some embodiments, one RGis ethyl. In some embodiments, one RGis C1-C6alkoxy. In some embodiments, one RGis C1-C3alkoxy. In some embodiments, one RGis methoxy. In some embodiments, one RGis -NRA1RB1. In some embodiments, RA1and RB1are each hydrogen. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. In some embodiments, RA1and RB1are each C1-C6alkyl. In some embodiments, RA1and RB1are each methyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1- C6 haloalkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3haloalkyl. In some embodiments, RA1and RB1are each C1-C6haloalkyl. In some embodiments, one of RA1and RB1is C1-C6alkyl and the other of RA1and RB1is C1-C6haloalkyl. In some embodiments, one RGis =NRA2. In some embodiments, one RGis =NH. In some embodiments, RA2is hydrogen. In some embodiments, RA2is C1-C6alkyl. In some embodiments, RA2is methyl. In some embodiments, one RGis -C(=O)NRC1RD1. In some embodiments, one RGis - CO2NH2. In some embodiments, one RGis -CO2NHCH3. In some embodiments, RC1and RD1are each is hydrogen. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. In some embodiments, RC1and RD1are each is C1-C6alkyl. In some embodiments, RC1and RD1are each is C1-C3alkyl. In some embodiments, RC1and RD1are each is methyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1- C6 haloalkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3haloalkyl. In some embodiments, RC1and RD1are each is C1-C6haloalkyl. In some embodiments, one of RC1and RD1is C1-C6alkyl and the other of RC1and RD1is C1-C6haloalkyl. In some embodiments, one RGis -CO2(C1-C6alkyl). In some embodiments, one RGis - CO2CH3. In some embodiments, one RGis C1-C6haloalkyl. In some embodiments, one RGis trifluoromethyl. In some embodiments, one RGis difluoromethyl. In some embodiments, one RGis C3-C6cycloalkyl. In some embodiments, one RGis cyclopropyl. In some embodiments, one RGis -CO2H. In some embodiments, one RGis C1-C6haloalkoxy. In some embodiments, one RGis C1- C3 haloalkoxy. In some embodiments, one RGis difluoromethoxy. In some embodiments, one RGis trifluoromethoxy. In some embodiments, one RGis -SO2(C1-C6alkyl). In some embodiments, one RGis - SO2CH3. In some embodiments, the R43-9 membered heterocyclyl is a 3-6 membered heterocyclyl. In some embodiments, the R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments, the R43-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, the R43-6 membered heterocyclyl is 1- azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. In some embodiments, the R43-9 membered heterocyclyl is selected from the group consisting of In some embodiments, the R43- 9 membered heterocyclyl (e.g., the R43-6 membered heterocyclyl) is wherein Q is a C1-C3alkylene in which one or more carbons is optionally replaced by –C(=O)-, NH, O, or S. In some embodiments, Q is a C1-C3alkylene in which one or more carbons is optionally replaced by –C(=O)- or NH. In some embodiments, Q is a C1-C2alkylene in which one or more carbons is optionally replaced by –C(=O)- or NH. In some embodiments, the R43-9 membered heterocyclyl is selected from the group consisting In some embodiments, one R4is unsubstituted 3-6 membered heterocyclyl. In some embodiments, R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments, R4is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments, R4is selected from the group consisting of . In some embodiments, , wherein: X is selected from N and CR4A2; R4A1and R4A2are independently selected from hydrogen, C1-C3alkyl optionally substituted with -NRARB,, methoxy, C1-C3haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, X is N. In some embodiments, X is CR4A2. In some embodiments, R4A1and, when present, R4A2are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2Me, and azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, X is N and R4A1is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. In some embodiments, X is N; and R4A1is selected from amino or an azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. In some embodiments, wherein: R4Bis selected from - NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, C1-C6haloalkyl, and C1-C6alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, wherein: R4Bis selected from - NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6haloalkyl, and C1-C6alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2- propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6haloalkyl, and C1-C6alkyl. In some embodiments, RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2- propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, R4Bis amino or a 4-6 membered heterocyclyl having one nitrogen atom and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, R4B ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each optionally containing 1-2 =O, and each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6alkyl. In some embodiments, R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6alkyl. In some embodiments, R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6alkyl. In some embodiments, R4B wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, Ring B is azetidinyl. In some embodiments, Ring B is unsubstituted. In some embodiments, Ring B is substituted with 1 RG. In some embodiments, RGis fluoro. In some embodiments, RGis cyano. In some embodiments, RGis amino, In some embodiments, RGis hydroxyl. In some embodiments, RGis C1-C3alkyl. In some embodiments, RGis methyl. In some embodiments, RGis ethyl. In some embodiments, RGis -CO2CH3. In some embodiments, RGis methoxy. In some embodiments, RGis methoxy. In some embodiments, Ring B is substituted with 2 RG. In some embodiments, each RGis fluoro. In some embodiments, each RGis C1-C3alkyl. In some embodiments, each RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis ethyl. In some embodiments, one RGis amino and the other RGis methyl. In some embodiments, one RGis hydroxyl and the other RGis cyclopropyl. In some embodiments, one RGis fluoro and the other RG1is methyl. In some embodiments, one RGis hydroxyl and the other RGis fluoro. In some embodiments, one RGis hydroxyl and the other RGis trifluoromethyl. In some embodiments, each RGis bonded to the position of Ring B para to the nitrogen that is bonded to Ring A. In some embodiments, is , wherein 1 or 2 independently selected RGattach at the 3-position of the azetidine. In some embodiments, is selected from the group consisting of , , , , and In some embodiments, is selected from the group consisting of , and In some embodiments, is selected from the In some embodiments, Z is O. In some embodiments, Z is NRx. In some embodiments, Rxis hydrogen. In some embodiments, Rxis C1-C6alkyl. In some embodiments, Rxis C1-C3alkyl. In some embodiments, Rxis methyl. In some embodiments, Rxis ethyl. In some embodiments, Rxis n-propyl. In some embodiments, Rxis isopropyl. In some embodiments, Rxis C3-C6cycloalkyl. In some embodiments, Rxis C3-C4 cycloalkyl. In some embodiments, Rxis cyclopropyl. In some embodiments, Rxis cyclobutyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1- C6 alkyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1- C6 haloalkyl. In some embodiments, each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl. In some embodiments, m is 2, one R4is halogen, and the other R4is -SO2(C1-C6alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3. In some embodiments, m is 2, one R4is C1-C6alkoxy, and the other R4is -C(=O)NRCRD. In some embodiments, m is 2, one R4is methoxy, and the other R4is –C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6alkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6haloalkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl. In some embodiments, Z is O; m is 2, one R4is halogen, and the other R4is -SO2(C1-C6alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3. In some embodiments, Z is O; m is 2, one R4is C1-C6alkoxy, and the other R4is - C(=O)NRCRD. In some embodiments, Z is O; m is 2, one R4is methoxy, and the other R4is –C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is O; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6alkyl. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is selected from methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6haloalkyl. In some embodiments, Z is O; each R1is fluoro; m is 1 or 2; R2is methyl; and R3is trifluoromethyl. In some embodiments, Z is NRx; m is 2, one R4is halogen, and the other R4is -SO2(C1- C6 alkyl). In some embodiments, m is 2, one R4is chloro, and the other R4is –SO2CH3. In some embodiments, Z is NRx; m is 2, one R4is C1-C6alkoxy, and the other R4is - C(=O)NRCRD. In some embodiments, Z is NRx; m is 2, one R4is methoxy, and the other R4is – C(O)NHCH3. In some embodiments, Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. In some embodiments, Z is NRx; each R1is fluoro, cyano, or methyl; m is 1 or 2; R2is a C1-C3alkyl; R3is a C1-C3alkyl or C1-C3haloalkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: -NHRB, and 4-6 membered heterocyclyl optionally substituted with 1-2 RG; and n is 1 or 2. In some embodiments, the compound of Formula (I) is Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. 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. 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. In some embodiments of Formula (I-A),4B wherein: R is selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), RAand RBare each hydrogen. In some embodiments of Formula (I-A), RAand RBare each 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1- C6 haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis C1- C6 alkyl and the other of RAand RBis C1-C6haloalkyl. In some embodiments of Formula (I-A), RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2) . In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1- C6 alkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis C1- C3 alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl. In some embodiments of Formula (I-A), RAand RBare each C1-C3alkyl. In some embodiments of Formula (I-A), RAand RBare each methyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl, e.g., 1- cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with - SO2(C1-C6alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C3alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1- C6 alkyl). In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl . In some embodiments of Formula (I-A), one of RAand RBis C1- C6 alkyl hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), R4Bis 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), Ring B is azetidinyl. In some embodiments of Formula (I-A), Ring B is unsubstituted. In some embodiments of Formula (I-A), Ring B is substituted with 1 RG. In some embodiments of Formula (I-A), RGis fluoro. In some embodiments of Formula (I-A), RGis cyano. In some embodiments of Formula (I-A), RGis hydroxyl. In some embodiments of Formula (I-A), RGis C1-C3alkyl. In some embodiments of Formula (I-A), RGis methyl. In some embodiments of Formula (I-A), RGis -CO2CH3. In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected RG. In some embodiments of Formula (I-A), each RGis fluoro. In some embodiments of Formula (I-A), each RGis C1-C3alkyl. In some embodiments of Formula (I-A), each RGis methyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis C1-C3alkyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis methyl. In some embodiments of Formula (I-A), one RGis fluoro and the other RGis C1-C3alkyl. In some embodiments of Formula (I-A), one RGis fluoro and the other RGis methyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis fluoro. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis trifluoromethyl. In some embodiments of Formula , wherein 1 or 2 independently selected RGis at the 3-position of the azetidine. In some embodiments of Formula selected from the group consisting , , , , , , , and . In some embodiments of Formula (I-A), is selected from the groups consisting In some embodiments, the compound of Formula (I) is Formula (I-B): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, R1Aand R1Bare each fluoro; In some embodiments, R2is a C1-C6alkyl. In some embodiments, R2is a C1-C3alkyl. In some embodiments, R2is methyl. In some embodiments, R2is a C1-C6haloalkyl. In some embodiments, R2is a C1-C3haloalkyl. In some embodiments, R2is a trifluoromethyl. In some embodiments, R3is a C1-C6alkyl. In some embodiments, R3is a C1-C3alkyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl. In some embodiments, R3is a C1-C6haloalkyl. In some embodiments, R3is a C1-C3haloalkyl. In some embodiments, R3is a trifluoromethyl. In some embodiments, R3is C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is unsubstituted C3-C6cycloalkyl. In some embodiments, the R3C3-C6cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R4is C1-C6alkyl optionally substituted with -NRARB. In some embodiments, R4is C1-C3alkyl optionally substituted with -NRARB. In some embodiments, R4is methyl optionally substituted with -NRARB. In some embodiments, R4is C1-C4 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is C1-C6alkoxy. In some embodiments, R4is C1-C3alkoxy. In some embodiments, R4is methoxy. In some embodiments, R4is C1-C6haloalkyl. In some embodiments, R4is C1-C3haloalkyl. In some embodiments, R4is trifluoromethyl. In some embodiments, R4is hydroxyl. In some embodiments, R4is cyano. In some embodiments, R4is –CO2H. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1- propyl or 1-hydroxy-2-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1- propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. In some embodiments, RAand RBare each C1-C6haloalkyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of one of RAand RBis C1-C6haloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3haloalkyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6haloalkyl. In some embodiments, RAand RBare each 4-6 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl. In some embodiments, RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis cis- or trans-3-hydroxycyclobutyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with cyclopropyl and hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl,, e.g., 1-cyclopropyl- 2-hydroxyethyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, RAand RBare both C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C3alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, RAand RBare both C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(NH2), e.g., 1- sulfamoylpropan-2-yl . In some embodiments, one of RAand RBis C1-C6alkyl hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments, RAand RBare both C1-C6alkyl substituted with -SO2(NH2). In some embodiments, one R4is -C(=O)NRCRD. In some embodiments, RCand RDare each hydrogen. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C6 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C3 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis methyl. In some embodiments, RCand RDare each C1-C6alkyl. In some embodiments, RCand RDare each C1-C3alkyl. In some embodiments, RCand RDare each methyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6haloalkyl. In some embodiments, RCand RDare each is C1-C6haloalkyl. In some embodiments, one of RCand RDis C1-C6alkyl and the other of RCand RDis C1-C6haloalkyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. In some embodiments, one R4is -SO2(NRERF). In some embodiments, REand RFare each hydrogen. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C6 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis methyl. In some embodiments, REand RFare each is C1-C6alkyl. In some embodiments, REand RFare each is C1-C3alkyl. In some embodiments, REand RFare each methyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1-C6haloalkyl. In some embodiments, REand RFare each C1-C6haloalkyl. In some embodiments, one of REand RFis C1-C6alkyl and the other of REand RFis C1-C6haloalkyl. In some embodiments, R4is -SO2(C1-C6alkyl). In some embodiments, R4is -SO2(C1-C3alkyl). In some embodiments, R4is -SO2Me. In some embodiments, R4is -SO2Et. In some embodiments, R4is -S(=O)(=NH)(C1-C6alkyl). In some embodiments, R4is - S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R4is -S(=O)(=NH)Me. In some embodiments, R4is -C(=O)(C1-C6alkyl). In some embodiments, R4is -C(=O)(C1-C3alkyl). In some embodiments, R4is -C(=O)Me. In some embodiments, R4is -CO2(C1-C6alkyl). In some embodiments, R4is -CO2(C1-C3alkyl). In some embodiments, R4is -CO2Me. In some embodiments, one R4is 5-6 membered heteroaryl optionally substituted with C1- C6 alkyl. In some embodiments, one R4is 5-6 membered heteroaryl substituted with C1-C6alkyl. In some embodiments, R4is 5-6 membered heteroaryl. In some embodiments, R4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R4is pyrazolyl. In some embodiments, one R4is tetrazolyl substituted with methyl. In some embodiments, one R4is pyrazolyl. In some embodiments, one R4is unsubstituted pyrazolyl. In some embodiments, one R4is 1-pyrazolyl. In some embodiments, R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, RGis fluoro. In some embodiments, RGis cyano. In some embodiments, RGis hydroxyl. In some embodiments, RGis C1-C6alkyl. In some embodiments, RGis C1-C3alkyl. In some embodiments, RGis methyl. In some embodiments, RGis C1-C6alkoxy. In some embodiments, RGis C1-C3alkoxy. In some embodiments, RGis methoxy. In some embodiments, one RGis -NRA1RB1. In some embodiments, RA1and RB1are each hydrogen. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. In some embodiments, RA1and RB1are each C1-C6alkyl. In some embodiments, RA1and RB1are each C1-C3alkyl. In some embodiments, RA1and RB1are each methyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1- C6 haloalkyl. In some embodiments, RA1and RB1are each C1-C6haloalkyl. In some embodiments, one of RA1and RB1is C1-C6alkyl and the other of RA1and RB1is C1-C6haloalkyl. In some embodiments, one RGis -C(=O)NRC1RD1. In some embodiments, RC1and RD1are each is hydrogen. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. In some embodiments, RC1and RD1are each is C1-C6alkyl. In some embodiments, RC1and RD1are each is methyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6haloalkyl. In some embodiments, RC1and RD1are each is C1-C6haloalkyl. In some embodiments, one of RC1and RD1is C1-C6alkyl and the other of RC1and RD1is C1-C6haloalkyl. In some embodiments, one RGis -CO2(C1-C6alkyl). In some embodiments, one RGis - CO2CH3. In some embodiments, one RGis C1-C6haloalkyl. In some embodiments, one RGis trifluoromethyl. In some embodiments, one RGis C3-C6cycloalkyl. In some embodiments, one RGis cyclopropyl. In some embodiments, RGis -CO2H. In some embodiments, the R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments, the R43-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, the R43-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4- tetrahydropyranyl. In some embodiments, R4is unsubstituted 3-6 membered heterocyclyl. In some embodiments, R4is a 5-6 membered heterocyclyl. In some embodiments, R4is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments, R4is selected from the group consisting , and . In some embodiments, R4is selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2- propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, R4is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, the compound of Formula (I) is Formula (I-C): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-D): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-E): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-F): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H; and wherein the compound is not . Some embodiments provide a compound of Formula (I-F), wherein the compound is not a compound selected from the group consisting of: . In some embodiments, the compound of Formula (I) is Formula (I-G): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or C1-C6haloalkyl; R3is a C1-C6alkyl or a C1-C6haloalkyl; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, C1-C6haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6alkyl), or C1-C6haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-J): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. 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. 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. In some embodiments of Formula (I-A), , wherein: R4Bis selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), RAand RBare each hydrogen. In some embodiments of Formula (I-A), RAand RBare each 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1- C6 haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3haloalkyl. In some embodiments of Formula (I-A), one of RAand RBis C1- C6 alkyl and the other of RAand RBis C1-C6haloalkyl. In some embodiments of Formula (I-A), RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2) . In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1- C6 alkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis C1- C3 alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (I-A), RAand RBare each C1-C6alkyl. In some embodiments of Formula (I-A), RAand RBare each C1-C3alkyl. In some embodiments of Formula (I-A), RAand RBare each methyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl, e.g., 1- cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments of Formula (I- A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with - SO2(C1-C6alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C3alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments of Formula (I-A), one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1- C6 alkyl). In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl . In some embodiments of Formula (I-A), one of RAand RBis C1- C6 alkyl hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), RAand RBare both C1-C6alkyl substituted with -SO2(NH2). In some embodiments of Formula (I-A), R4Bis 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments of Formula (I-A), Ring B is azetidinyl. In some embodiments of Formula (I-A), Ring B is unsubstituted. In some embodiments of Formula (I-A), Ring B is substituted with 1 RG. In some embodiments of Formula (I-A), RGis fluoro. In some embodiments of Formula (I-A), RGis cyano. In some embodiments of Formula (I-A), RGis hydroxyl. In some embodiments of Formula (I-A), RGis C1-C3alkyl. In some embodiments of Formula (I-A), RGis methyl. In some embodiments of Formula (I-A), RGis -CO2CH3. In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected RG. In some embodiments of Formula (I-A), each RGis fluoro. In some embodiments of Formula (I-A), each RGis C1-C3alkyl. In some embodiments of Formula (I-A), each RGis methyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis C1-C3alkyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis methyl. In some embodiments of Formula (I-A), one RGis fluoro and the other RGis C1-C3alkyl. In some embodiments of Formula (I-A), one RGis fluoro and the other RGis methyl. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis fluoro. In some embodiments of Formula (I-A), one RGis hydroxyl and the other RGis trifluoromethyl. In some embodiments of Formula (I-A), , wherein 1 or 2 independently selected RGis at the 3-position of the azetidine. In some embodiments of Formula selected from the group consisting , , , , , , , and . In some embodiments of Formula (I-A), is selected from the groups consisting In some embodiments, the compound of Formula (I) is Formula (I-K): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen , 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, R1Aand R1Bare each fluoro; In some embodiments, R2is a C1-C6alkyl. In some embodiments, R2is a C1-C3alkyl. In some embodiments, R2is methyl. In some embodiments, R2is a C1-C6haloalkyl. In some embodiments, R2is a C1-C3haloalkyl. In some embodiments, R2is a trifluoromethyl. In some embodiments, R3is a C1-C6alkyl. In some embodiments, R3is a C1-C3alkyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl. In some embodiments, R3is a C1-C6haloalkyl. In some embodiments, R3is a C1-C3haloalkyl. In some embodiments, R3is a trifluoromethyl. In some embodiments, R3is C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl. In some embodiments, R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 fluoro. In some embodiments, R3is C3-C6cycloalkyl substituted with 1 or 2 fluoro. In some embodiments, R3is unsubstituted C3-C6cycloalkyl. In some embodiments, the R3C3-C6cycloalkyl is cyclopropyl. In some embodiments, R3is cyclopropyl. In some embodiments, R4is C1-C6alkyl optionally substituted with -NRARB. In some embodiments, R4is C1-C3alkyl optionally substituted with -NRARB. In some embodiments, R4is methyl optionally substituted with -NRARB. In some embodiments, R4is C1-C4 alkyl. In some embodiments, R4is methyl. In some embodiments, R4is C1-C6alkoxy. In some embodiments, R4is C1-C3alkoxy. In some embodiments, R4is methoxy. In some embodiments, R4is C1-C6haloalkyl. In some embodiments, R4is C1-C3haloalkyl. In some embodiments, R4is trifluoromethyl. In some embodiments, R4is hydroxyl. In some embodiments, R4is cyano. In some embodiments, R4is –CO2H. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1- propyl or 1-hydroxy-2-propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1- propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. In some embodiments, RAand RBare each C1-C6haloalkyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of one of RAand RBis C1-C6haloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3haloalkyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6haloalkyl. In some embodiments, RAand RBare each 4-6 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4 membered heterocyclyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. In some embodiments of Formula (I-A), one of RAand RBis hydrogen and the other of RAand RBis 1,1-dioxidotetrahydrothiophen-3-yl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 6 membered heterocyclyl. In some embodiments, RAand RBare each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis unsubstituted 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 3 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis cis- or trans-3-hydroxycyclobutyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 5 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with cyclopropyl and hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with cyclopropyl and hydroxyl,, e.g., 1-cyclopropyl- 2-hydroxyethyl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, RAand RBare both C1-C6alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(C1-C3alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propan-2-yl. In some embodiments, one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, RAand RBare both C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with -SO2(NH2), e.g., 1- sulfamoylpropan-2-yl . In some embodiments, one of RAand RBis C1-C6alkyl hydrogen and the other of RAand RBis C1-C6alkyl substituted with -SO2(NH2). In some embodiments, RAand RBare both C1-C6alkyl substituted with -SO2(NH2). In some embodiments, one R4is -C(=O)NRCRD. In some embodiments, RCand RDare each hydrogen. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C6 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1- C3 alkyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis methyl. In some embodiments, RCand RDare each C1-C6alkyl. In some embodiments, RCand RDare each C1-C3alkyl. In some embodiments, RCand RDare each methyl. In some embodiments, one of RCand RDis hydrogen and the other of RCand RDis C1-C6haloalkyl. In some embodiments, RCand RDare each is C1-C6haloalkyl. In some embodiments, one of RCand RDis C1-C6alkyl and the other of RCand RDis C1-C6haloalkyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. In some embodiments, one R4is -SO2(NRERF). In some embodiments, REand RFare each hydrogen. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1- C6 alkyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis methyl. In some embodiments, REand RFare each is C1-C6alkyl. In some embodiments, REand RFare each is C1-C3alkyl. In some embodiments, REand RFare each methyl. In some embodiments, one of REand RFis hydrogen and the other of REand RFis C1-C6haloalkyl. In some embodiments, REand RFare each C1-C6haloalkyl. In some embodiments, one of REand RFis C1-C6alkyl and the other of REand RFis C1-C6haloalkyl. In some embodiments, R4is -SO2(C1-C6alkyl). In some embodiments, R4is -SO2(C1-C3alkyl). In some embodiments, R4is -SO2Me. In some embodiments, R4is -SO2Et. In some embodiments, R4is -S(=O)(=NH)(C1-C6alkyl). In some embodiments, R4is - S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R4is -S(=O)(=NH)Me. In some embodiments, R4is -C(=O)(C1-C6alkyl). In some embodiments, R4is -C(=O)(C1-C3alkyl). In some embodiments, R4is -C(=O)Me. In some embodiments, R4is -CO2(C1-C6alkyl). In some embodiments, R4is -CO2(C1-C3alkyl). In some embodiments, R4is -CO2Me. In some embodiments, one R4is 5-6 membered heteroaryl optionally substituted with C1- C6 alkyl. In some embodiments, one R4is 5-6 membered heteroaryl substituted with C1-C6alkyl. In some embodiments, R4is 5-6 membered heteroaryl. In some embodiments, R4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R4is pyrazolyl. In some embodiments, one R4is tetrazolyl substituted with methyl. In some embodiments, one R4is pyrazolyl. In some embodiments, one R4is unsubstituted pyrazolyl. In some embodiments, one R4is 1-pyrazolyl. In some embodiments, R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. In some embodiments, RGis fluoro. In some embodiments, RGis cyano. In some embodiments, RGis hydroxyl. In some embodiments, RGis C1-C6alkyl. In some embodiments, RGis C1-C3alkyl. In some embodiments, RGis methyl. In some embodiments, RGis C1-C6alkoxy. In some embodiments, RGis C1-C3alkoxy. In some embodiments, RGis methoxy. In some embodiments, one RGis -NRA1RB1. In some embodiments, RA1and RB1are each hydrogen. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C3alkyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. In some embodiments, RA1and RB1are each C1-C6alkyl. In some embodiments, RA1and RB1are each C1-C3alkyl. In some embodiments, RA1and RB1are each methyl. In some embodiments, one of RA1and RB1is hydrogen and the other of RA1and RB1is C1- C6 haloalkyl. In some embodiments, RA1and RB1are each C1-C6haloalkyl. In some embodiments, one of RA1and RB1is C1-C6alkyl and the other of RA1and RB1is C1-C6haloalkyl. In some embodiments, one RGis -C(=O)NRC1RD1. In some embodiments, RC1and RD1are each is hydrogen. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C3alkyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. In some embodiments, RC1and RD1are each is C1-C6alkyl. In some embodiments, RC1and RD1are each is methyl. In some embodiments, one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6haloalkyl. In some embodiments, RC1and RD1are each is C1-C6haloalkyl. In some embodiments, one of RC1and RD1is C1-C6alkyl and the other of RC1and RD1is C1-C6haloalkyl. In some embodiments, one RGis -CO2(C1-C6alkyl). In some embodiments, one RGis - CO2CH3. In some embodiments, one RGis C1-C6haloalkyl. In some embodiments, one RGis trifluoromethyl. In some embodiments, one RGis C3-C6cycloalkyl. In some embodiments, one RGis cyclopropyl. In some embodiments, RGis -CO2H. In some embodiments, the R43-6 membered heterocyclyl is a 5-6 membered heterocyclyl. In some embodiments, the R43-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, the R43-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4- tetrahydropyranyl. In some embodiments, R4is unsubstituted 3-6 membered heterocyclyl. In some embodiments, R4is a 5-6 membered heterocyclyl. In some embodiments, R4is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments, R4is selected from the group consisting , and . In some embodiments, R4is selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, RAand RBare each hydrogen. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl optionally substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis propyl substituted with hydroxyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2- propyl). In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1- C3 alkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis methyl. In some embodiments, RAand RBare each C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, RAand RBare each C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis C1-C3alkyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis C1-C3alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis methyl and the other of RAand RBis ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, RAand RBare each C1-C6alkyl. In some embodiments, RAand RBare each C1-C3alkyl. In some embodiments, RAand RBare each methyl. In some embodiments, R4is 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. In some embodiments, the compound of Formula (I) is Formula (I-L): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-M): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, , -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-N): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-O): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-P): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy, C1- C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen or C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl; or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. In some embodiments, the compound of Formula (I) is Formula (I-Q): or a pharmaceutically acceptable salt thereof, wherein: Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; R1Ais halogen; R1Bis halogen, cyano, cyclopropyl, or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or C1-C6haloalkyl; R3is a C1-C6alkyl or a C1-C6haloalkyl; R4is independently selected from the group consisting of: C1-C6alkyl, C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, C1-C6haloalkyl, -NRARB, and 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; each RA, RB, RC1, and RD1is independently hydrogen, 4-6 membered heterocyclyl, C1-C6alkyl optionally substituted with hydroxyl or –C(=O)NRB2RC2, -C(=O)O(C1-C6alkyl), or C1-C6haloalkyl; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H. In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of: , , , or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of: , , , In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0024] . In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein. In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein. In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein. Non-Limiting Exemplary Compounds 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. 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

[0025] 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

[0026] 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 In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table D, or a pharmaceutically acceptable salt thereof.

[0027] Pharmaceutical Compositions and Administration General 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. 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-, ^, 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, 22ndEdition (Pharmaceutical Press, London, UK.2012). Routes of Administration and Composition Components 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). 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. 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. 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. 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. 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. 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. 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. 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.). 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. 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. 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. 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. 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, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. 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. 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.)). 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. 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 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. 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 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). 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, 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, 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. Methods of Treatment Indications Provided herein are methods for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα), 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). 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. 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. Potency of a PI3Kα inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 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). Potency of a PI3Kα inhibitor as provided herein can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 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). 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. 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. 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. In some embodiments, 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. In some embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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. In some embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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. 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). 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). In some embodiments, the subject is a pediatric subject. 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. In certain embodiments, 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. 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). 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. The phrase “dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kα that includes a deletion of at least one amino acid as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with one or more point mutations as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with at least one inserted amino acid as compared to a wild type PI3Kα, a gene duplication that results in an increased level of PI3Kα in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3Kα in a cell), an alternative spliced version of PI3Kα mRNA that results in PI3Kα having a deletion of at least one amino acid in the PI3Kα as compared to the wild type PI3Kα), or increased expression (e.g., increased levels) of a wild type PI3Kα in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non- cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or 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. 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. 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. 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). Provided herein 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 embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more a PI3Kα protein substitutions / point mutations / insertions. Non- limiting examples of PI3Kα protein substitutions / insertions / deletions are described in Table 1 and Table 2. In some embodiments, the PI3Kα protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid. In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments of any of the methods or uses 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. In some embodiments of any of the methods or uses 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. In some embodiments of any of the methods or uses 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. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is lung cancer. In some embodiments of any of the methods or uses 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 / DeletionsA

[0028] AUnless 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 20122; 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 / DeletionsA AUnless 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 20122; 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. 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. 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. Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)

[0029] In some embodiments, 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. Also provided herein are methods for treating a subject identified or diagnosed as having a PI3Kα-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a PI3Kα -associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Kα- associated cancer. 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). Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a PI3Kα-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a PI3Kα-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Kα-associated cancer. Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a 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 embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments of these methods, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a PI3Kα-associated cancer, a subject presenting with one or more symptoms of a PI3Kα-associated cancer, or a subject having an elevated risk of developing a PI3Kα-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. Also provided 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 embodiments of any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Also provided 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 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 embodiments, a subject is identified or diagnosed as having a PI3Kα-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a PI3Kα-associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses 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 methods or uses 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 methods or uses 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 methods or uses 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 methods or uses described herein, the subject is suspected of having a PI3Kα-associated cancer. In some embodiments, provided herein are methods for treating a PI3Kα-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more PI3Kα protein point mutations / insertions / deletions. Non-limiting examples of PI3Kα protein point mutations / insertions / deletions are described in Table 1 and Table 2. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Kα protein point mutations / insertions / deletions are selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, the cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments of any of the methods or uses 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 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. In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a 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 embodiments, the method includes determining that a subject has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation in a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same is one or more point mutation in the PIK3CA gene (e.g., any of the one or more of the PI3Kα point mutations described herein). The one or more point mutations in a PIK3CA gene can result, e.g., in the translation of a PI3Kα protein having one or more of the following amino acid substitutions, deletions, and insertions: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. The one or more mutations in a PIK3CA gene can result, e.g., in the translation of an PI3Kα protein having one or more of the following amino acids: 542, 545, 1043, and 1047 and 1049. In some embodiments, the dysregulation in a PIK3CA gene, a PI3Kα protein protein, or expression or activity or level of any of the same is one or more PI3Kα amino acid substitutions (e.g., any of the PI3Kα amino acid substitution described herein). Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments of any of the methods or uses described herein, an assay used to determine whether the subject has a dysregulation of a PIK3CA gene, or a PI3Kα protein, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a PI3Kα -associated cancer, a subject having one or more symptoms of a PI3Kα-associated cancer, and / or a subject that has an increased risk of developing a PI3Kα-associated cancer). In some embodiments, dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or the dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho- alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell- free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same. Also provided is a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Kα activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. The phrase "therapeutically effective amount" means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Kα protein- associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein. Combinations In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is PI3Kα inhibitor naïve. For example, the subject is naïve to treatment with a selective PI3Kα inhibitor. In some embodiments, a subject is not PI3Kα inhibitor naïve. In some embodiments, a subject is kinase inhibitor naïve. In some embodiments, a subject is not kinase inhibitor naïve. In some embodiments, a subject has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI) or another PI3K inhibitor, such as buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC- 0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK- 117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, or GSK2636771. In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents. Non-limiting examples of additional therapeutic agents include: other PI3Kα-targeted therapeutic agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (including mTOR inhibitors, as described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), farnesyl transferase inhibitors, signal transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERMs / SERDs), checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT- 414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors, as described herein), AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849. Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof. In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof. In some embodiments, the other PI3K inhibitor is another PI3Kα inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF- 04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN- 193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof. In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof. In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof. Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277. In some embodiments, a chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVENTM), or combinations thereof. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof. Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289. Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole. Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549. Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol.11: 39 (2018). In some embodiments, the additional therapy or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab- paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, buparlisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG 479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, amcenestrant, and combinations thereof. In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and / or as palliative therapy, for example, opioids and corticosteroids. In some embodiments, the additional therapy or therapeutic agent described herein is selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, a sodium-glucose transport protein 2 (SGLT-2) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, metformin, and combinations thereof. Non-limiting examples of GLP-1 receptor agonists include liraglutide (VICTOZA®, NN2211), dulaglutide (LY2189265, TRULICITY®), exenatide (BYETTA®, BYDUREON®, Exendin-4), taspoglutide, lixisenatide (LYXUMIA®), albiglutide (TANZEUM®), semaglutide (OZEMPIC®), ZP2929, NNC0113-0987, BPI-3016, and TT401. Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, serfliflozin, licofliglozin, sotagliflozin (ZYNQUISTATM), and tofogliflozin. Non-limiting examples of DPP-4 inhibitors include, sitagliptin (JANUVIA®), vildagliptin, saxagliptin (ONGLYZA®), linagliptin (TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (NESINA®), omarigliptin, evogliptin, and dutogliptin. In some embodiments, the subject is also instructed to maintain a particular diet and / or exercise regimen to control blood sugar levels. Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same. These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. Also provided herein is (i) a pharmaceutical combination for treating a cancer in a subject in need thereof, which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof. In some embodiments, the cancer is a PI3Kα-associated cancer. The term "pharmaceutical combination", as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a subject simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients Accordingly, also provided herein is a method of treating a cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I), or pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of Formula (I) and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittently dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. EMBODIMENTS Embodiment 1: A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl alkyl optionally substituted with hydroxyl,, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H; and wherein the compound is not a compound selected from the group consisting of: , , , , , , , , , , , , , ,

[0030] Embodiment 2: The compound of embodiment 1, wherein m is 1. Embodiment 3: The compound of embodiment 1, wherein m is 2. Embodiment 4: The compound of embodiments 1 or 2, wherein . Embodiment 5: The compound of embodiments 1 or 2, wherein . Embodiment 6: The compound of embodiments 1 or 3, wherein . Embodiment 7: The compound of any one of embodiments 1-6, wherein each R1is halogen. Embodiment 8: The compound of any one of embodiments 1-7, wherein each R1is selected from fluoro and chloro. Embodiment 9: The compound of any one of embodiments 1-8, wherein each R1is fluoro. Embodiment 10: The compound of any one of embodiments 1-6, wherein one R1is cyano. Embodiment 11: The compound of any one of embodiments 1-6, wherein one R1is C1-C6alkyl. Embodiment 12: The compound of any one of embodiments 1-6, wherein one R1is C3- C6 cycloalkyl. Embodiment 13: The compound of embodiment 1, wherein m is 0. Embodiment 14: The compound of any one of embodiments 1-13, wherein R2is a C1-C6alkyl. Embodiment 15: The compound of embodiment 14, wherein R2is methyl. Embodiment 16: The compound of any one of embodiments 1-13, wherein R2is a C1-C6haloalkyl. Embodiment 17: The compound of embodiment 16, wherein R2is difluoromethyl. Embodiment 18: The compound of embodiment 16, wherein R2is trifluoromethyl. Embodiment 19: The compound of any one of embodiments 1-13, wherein R2is halogen. Embodiment 20: The compound of any one of embodiments 1-13, wherein R2is C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro. Embodiment 21: The compound of any one of embodiments 1-13 or 20, wherein R2is C3- C6 cycloalkyl substituted with 1 or 2 fluoro. Embodiment 22: The compound of any one of embodiments 1-13 or 21, wherein R2is an unsubstituted C3-C6cycloalkyl. Embodiment 23: The compound of any one of embodiments 1-22, wherein R3is a C1-C6alkyl. Embodiment 24: The compound of any one of embodiments 1-23, wherein R3is methyl, ethyl, or isopropyl. Embodiment 25: The compound of any one of embodiments 1-23, wherein R3is methyl. Embodiment 26: The compound of any one of embodiments 1-23, wherein R3is ethyl. Embodiment 27: The compound of any one of embodiments 1-23, wherein R3is isopropyl. Embodiment 28: The compound of any one of embodiments 1-22, wherein R3is a C1-C6haloalkyl. Embodiment 29: The compound of any one of embodiments 1-22 and 28, wherein R3is trifluoromethyl. Embodiment 30: The compound of any one of embodiments 1-22, wherein R3is C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl. Embodiment 31: The compound of any one of embodiments 1-22 and 30, wherein R3is C3-C6cycloalkyl substituted with 1 or 2 fluoro. Embodiment 32: The compound of any one of embodiments 1-22 and 30, wherein R3is an unsubstituted C3-C6cycloalkyl. Embodiment 33: The compound of any one of embodiments 1-22, 30, and 31, wherein the R3C3-C6cycloalkyl is cyclopropyl. Embodiment 34: The compound of any one of embodiments 1-33, wherein Ring A is a 6- 10 membered aryl. Embodiment 35: The compound of any one of embodiments 1-34, wherein Ring A is phenyl. Embodiment 36: The compound of any one of embodiments 1-33, wherein Ring A is a C3- C8 cycloalkyl. Embodiment 37: The compound of any one of embodiments 1-33 and 36, wherein Ring A is a C5-C6 cycloalkyl. Embodiment 38: The compound of any one of embodiments 1-33 and 36-37, wherein Ring A is a cyclohexyl. Embodiment 39: The compound of any one of embodiments 1-33, wherein Ring A is a 5- 10 membered heteroaryl. Embodiment 40: The compound of any one of embodiments 1-33 and 39, wherein Ring A is a 5-6 membered heteroaryl. Embodiment 41: The compound of any one of embodiments 1-33 and 39-40, wherein Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. Embodiment 42: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is pyrimidinyl. Embodiment 43: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is pyridyl. Embodiment 44: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is thiazolyl. Embodiment 45: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is thiophenyl. Embodiment 46: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is pyrazolyl. Embodiment 47: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. Embodiment 48: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 5-pyrimidinyl. Embodiment 49: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 3-pyridyl. Embodiment 50: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 4-pyrazolyl. Embodiment 51: The compound of any one of embodiments 1-33 and 39, wherein Ring A is a 9-10 membered heteroaryl. Embodiment 52: The compound of any one of embodiments 1-33, 39, and 51, wherein Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, or imidazo[1,2-a]pyridinyl. Embodiment 53: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is benzimidazolyl. Embodiment 54: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indazolyl. Embodiment 55: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indolyl. Embodiment 56: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indolyl. Embodiment 57: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is quinazolone. Embodiment 58: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is isobenzofuranonyl. Embodiment 59: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is isoindolinonyl. Embodiment 60: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is imidazo[1,2-a]pyridinyl. Embodiment 61: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, , or . Embodiment 62: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring A is 2-benzimidazolyl. Embodiment 63: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring A is 5-indazolyl. Embodiment 64: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring A is 2-indolyl. Embodiment 65: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring A is 7-imidazo[1,2-a]pyridinyl. Embodiment 66: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring . Embodiment 67: The compound of any one of embodiments 1-33, 39, and 61, wherein Ring . Embodiment 68: The compound of any one of embodiments 1-33, wherein Ring A is a 4- 10 membered heterocyclyl. Embodiment 69: The compound of any one of embodiments 1-33 and 68, wherein Ring A is a 6-9 membered heterocyclyl. Embodiment 70: The compound of any one of embodiments 1-33 and 68-69, wherein Ring A is piperidinyl or 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide. Embodiment 71: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is piperidinyl. Embodiment 72: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide. Embodiment 73: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 3-piperidinyl, 4-piperidinyl, or Embodiment 73: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 3-piperidinyl. Embodiment 74: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 4-piperidinyl. Embodiment 75: The compound of any one of embodiments 1-33 and 68-70, wherein Ring . Embodiment 76: The compound of any one of embodiments 1-75, wherein n is 1. Embodiment 77: The compound of any one of embodiments 1-75, wherein n is 2. Embodiment 78: The compound of any one of embodiments 1-77, wherein one R4is an unsubstituted C1-C6alkyl. Embodiment 79: The compound of any one of embodiments 1-78, wherein one R4is methyl. Embodiment 80: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl. Embodiment 81: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl. Embodiment 82: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkoxy substituted with hydroxyl or C3-C6cycloalkyl. Embodiment 83: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkoxy substituted with 2 substituents independently selected from hydroxyl and C3-C6cycloalkyl. Embodiment 84: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkoxy. Embodiment 85: The compound of any one of embodiments 1-77 and 84, wherein one R4is methoxy. Embodiment 86: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 haloalkyl. Embodiment 87: The compound of any one of embodiments 1-77 and 86, wherein one R4is trifluoromethyl. Embodiment 88: The compound of any one of embodiments 1-77, wherein one R4is hydroxyl. Embodiment 89: The compound of any one of embodiments 1-77, wherein one R4is cyano. Embodiment 90: The compound of any one of embodiments 1-77, wherein one R4is - CO2H. Embodiment 91: The compound of any one of embodiments 1-77, wherein one R4is halogen. Embodiment 92: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkyl substituted with 1-2 hydroxyl. Embodiment 93: The compound of any one of embodiments 1-77 and 92, wherein one R4is C1-C6alkyl substituted with hydroxyl. Embodiment 94: The compound of any one of embodiments 1-77 and 92, wherein one R4is C1-C6alkyl substituted with 2 hydroxyl. Embodiment 95: The compound of any one of embodiments 1-77, wherein one R4is C1- C6 alkyl substituted with -NRARB. Embodiment 96: The compound of any one of embodiments 1-77, wherein one R4is - NRARB. Embodiment 97: The compound of any one of embodiments 1-77 and 95-96, wherein RAand RBare each hydrogen. Embodiment 98: The compound of any one of embodiments 1-77 and 95-96, wherein RAand RBare each C1-C6alkyl. Embodiment 99: The compound of any one of embodiments 1-52, 95-96, and 98, wherein RAand RBare each methyl. Embodiment 100: The compound of any one of embodiments 1-77 and 95-96, wherein one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. Embodiment 101: The compound of any one of embodiments 1-77, wherein one R4is - C(=O)NRCRD. Embodiment 102: The compound of any one of embodimets 1-77 and 101, wherein RCand RDare each hydrogen. Embodiment 103: The compound of any one of embodiments 1-77 and 101, wherein RCand RDare each C1-C6alkyl. Embodiment 104: The compound of any one of embodiments 1-77 and 101, wherein RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy. Embodiment 105: The compound of any one of embodiments 1-77 and 101, wherein RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from hydroxyl, halogen, - C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy. Embodiment 106: The compound of any one of embodiments 1-77 and 101, wherein RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl. Embodiment 107: The compound of any one of embodiments 1-77, 101, and 76, wherein RCand RD, together with the nitrogen atom to which they are attached form azetidine or piperazine. Embodiment108: The compound of any one of embodiments 1-77, wherein one R4is - SO2(NRERF). Embodiment 109: The compound of any one of embodiments 1-77 and 108, wherein REand RFare each hydrogen. Embodiment 110: The compound of any one of embodiments 1-77 and 208, wherein REand RFare each is C1-C6alkyl. Embodiment 111: The compound of any one of embodiments 1-77, wherein one R4is - SO2(C1-C6alkyl). Embodiment 112: The compound of any one of embodiments 1-77 and 111, wherein one R4is -SO2Me. Embodiment 113: The compound of any one of embodiments 1-77 and 111, wherein one R4is -SO2Et. Embodiment 114: The compound of any one of embodiments 1-77, wherein one R4is - S(=O)(=NH)(C1-C6alkyl). Embodiment 115: The compound of any one of embodiments 1-77 and 84, wherein one R4is -S(=O)(=NH)Me. Embodiment 116: The compound of any one of embodiments 1-77, wherein one R4is - C(=O)(C1-C6alkyl). Embodiment 117: The compound of any one of embodiments 1-77 and 106, wherein one R4is -C(=O)Me. Embodiment 118: The compound of any one of embodiments 1-77, wherein one R4is - CO2(C1-C6alkyl). Embodiment 119: The compound of any one of embodiments 1-77 and 118, wherein one R4is -CO2Me. Embodiment 120: The compound of any one of embodiments 1-77, wherein one R4is 5-6 membered heteroaryl optionally substituted with C1-C6alkyl. Embodiment 121: The compound of any one of embodiments 1-77 and 120, wherein one R4is 5-6 membered heteroaryl substituted with C1-C6alkyl. Embodiment 122: The compound of any one of embodiments 1-77 and 120-121, wherein one R4is tetrazolyl substituted with methyl. Embodiment 123: The compound of any one of embodiments 1-77 and 90, wherein one R4is unsubstituted 5-6 membered heteroaryl. Embodiment 124: The compound of any one of embodiments 1-77, 90, and 93, wherein one R4is unsubstituted pyrazolyl. Embodiment 125: The compound of any one of embodiments 1-77, wherein one R4is 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. Embodiment 126: The compound of any one of embodiments 1-77, wherein one R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. Embodiment 127: The compound of any one of embodiments 1-77 and 96, wherein one R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. Embodiment 128: The compound of any one of embodiments 1-77 and 126-127, wherein one R4is 3-6 membered heterocyclyl substituted with 1 RG. Embodiment 129: The compound of any one of embodiments 1-77 and 126-127, wherein one R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. Embodiment 130: The compound of any one of embodiments 1-77, wherein one R4is 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG. Embodiment 131: The compound of any one of embodiments 1-77 and 130, wherein one R4is 3-6 membered cycloalkyl substituted with 1 or 2 independently selected RG. Embodiment 132: The compound of any one of embodiments 1-77 and 130-131, wherein one R4is 3-6 membered cycloalkyl substituted with 1 RG. Embodiment 133: The compound of any one of embodiments 1-77 and 130-131, wherein one R4is 3-6 membered cycloalkyl substituted with 2 independently selected RG. Embodiment 134: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis fluoro. Embodiment 135: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis cyano. Embodiment 136: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis hydroxyl. Embodiment 137: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis C1-C6alkyl. Embodiment 138: The compound of any one of embodiments 1-77, 125-133, and 137, wherein one RGis methyl. Embodiment 139: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis C1-C6alkoxy. Embodiment 140: The compound of any one of embodiments 1-77, 125-133, and 139, wherein one RGis methoxy. Embodiment 141: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis -NRA1RB1. Embodiment 142: The compound of any one of embodiments 1-77 and 125-133, wherein one RGis =NRA2. Embodiment 143: The compound of any one of embodiments 1-77, 125-133, and 142,wherein RA2is hydrogen. Embodiment 144: The compound of any one of embodiments 1-77, 125-133, and 142, wherein RA2is C1-C6alkyl. Embodiment 145: The compound of any one of embodiments 1-77 and 125-133, wherein RA1and RB1are each hydrogen. Embodiment 146: The compound of any one of embodiments 1-77, and 126-133, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6alkyl. Embodiment 147: The compound of any one of embodiments 1-77, 126-133, and 116, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. Embodiment 148: The compound of any one of embodiments 1-77 and 126-133, wherein RA1and RB1are each C1-C6alkyl. Embodiment 149: The compound of any one of embodiments 1-77, 126-133, and 118, wherein RA1and RB1are each methyl. Embodiment 150: The compound of any one of embodiments 1-77 and 126-133, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6haloalkyl. Embodiment 151: The compound of any one of embodiments 1-77 and 126-133, wherein RA1and RB1are each C1-C6haloalkyl. Embodiment 152: The compound of any one of embodiments 1-77 and 126-133, wherein one of RA1and RB1is C1-C6alkyl and the other of RA1and RB1is C1-C6haloalkyl. Embodiment 153: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis -C(=O)NRC1RD1. Embodiment 154: The compound of any one of embodiments 1-77, 126-133, and 123, wherein RC1and RD1are each is hydrogen. Embodiment 155: The compound of any one of embodiments 1-77, 126-133, and 123, wherein one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6alkyl. Embodiment 156: The compound of any one of embodiments 1-77, 126-133, 123, and 125, wherein one of RC1and RD1is hydrogen and the other of RC1and RD1is methyl. Embodiment 157: The compound of any one of embodiments 1-77, 126-133, and 123, wherein RC1and RD1are each is C1-C6alkyl. Embodiment 158: The compound of any one of embodiments 1-77, 126-133, 123, and 127, wherein RC1and RD1are each is methyl. Embodiment 159: The compound of any one of embodiments 1-77, 126-133, and 123, wherein one of RC1and RD1is hydrogen and the other of RC1and RD1is C1-C6haloalkyl. Embodiment 160: The compound of any one of embodiments 1-77, 126-133, and 123, wherein RC1and RD1are each is C1-C6haloalkyl. Embodiment 161: The compound of any one of embodiments 1-77, 126-133, and 123, wherein one of RC1and RD1is C1-C6alkyl and the other of RC1and RD1is C1-C6haloalkyl. Embodiment 162: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis -CO2(C1-C6alkyl). Embodiment 163: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis -CO2CH3. Embodiment 164: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis C1-C6haloalkyl. Embodiment 165: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis trifluoromethyl. Embodiment 166: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis C1-C6haloalkoxy. Embodiment 167: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis - SO2(C1-C6alkyl). Embodiment 168: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis C3-C6cycloalkyl. Embodiment 169: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis cyclopropyl. Embodiment 170: The compound of any one of embodiments 1-77 and 126-133, wherein one RGis -CO2H. Embodiment 171: The compound of any one of embodiments 1-77 and 125, wherein one R4is unsubstituted 3-6 membered heterocyclyl. Embodiment 172: The compound of any one of embodiments 125-129, wherein the R43- 6 membered heterocyclyl is a 5-6 membered heterocyclyl. Embodiment 173: The compound of any one of embodiments 125-129, wherein the R43- 6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. Embodiment 174: The compound of any one of embodiments 125-129, wherein the R43- 6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4- tetrahydropyranyl. Embodiment 175: The compound of any one of embodiments 1-77 and 130, wherein one R4is unsubstituted 3-6 membered cycloalkyl. Embodiment 176: The compound of any one of embodiments 130-170 and 175, wherein the R43-6 membered cycloalkyl is a 3-4 membered cycloalkyl. Embodiment 177: The compound of any one of embodiments 130-170 and 175-176, wherein the R43-6 membered cycloalkyl is cyclobutyl. Embodiment 178: The compound of any one of embodiments 1-77, wherein n is 0. Embodiment 179: The compound of any one of embodiments 1-33, wherein , wherein: X is selected from N and CR4A2; R4A1and R4A2are independently selected from hydrogen, C1-C3alkyl optionally substituted with -NRARB, methoxy, C1-C3haloalkyl, hydroxyl, cyano, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), 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. Embodiment 180: The compound of embodiment 179, wherein X is N. Embodiment 181: The compound of embodiment 179, wherein X is CR4A2. Embodiment 182: The compound of any one of embodiments 179-181, wherein R4A1and, when present, R4A2are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, -C(=O)NH2, -C(=O)NHMe, - SO2NH2, -SO2Me, and azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. Embodiment 183: The compound of embodiment 179, wherein X is N and R4A1is selected from amino and azetidinyl optionally substituted with 1-2 independently selected fluoro, hydroxyl, or methyl. Embodiment 184: The compound of any one of embodiments 1-33, wherein wherein: R4Bis selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, C1-C6haloalkyl, and C1-C6alkyl. Embodiment 185: The compound of embodiment 184, wherein RAand RBare both hydrogen. Embodiment 186: The compound of embodiment 184, wherein one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. Embodiment 187: The compound of any one of embodiments 184 and 186, wherein one of RAand RBis hydrogen and the other of RAand RBis methyl. Embodiment 188: The compound of embodiment 184, wherein R4Bis 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. Embodiment 189: The compound of embodiment 184, wherein R4B wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6alkyl. Embodiment 190: The compound of embodiment 189, wherein Ring B is azetidinyl. Embodiment 191: The compound of any one of embodiments 189-190, wherein Ring B is unsubstituted. Embodiment 192: The compound of any one of embodiments 189-190, wherein Ring B is substituted with 1 RG. Embodiment 193: The compound of embodiment 192, wherein RGis fluoro. Embodiment 194: The compound of embodiment 192, wherein RGis hydroxyl. Embodiment 195: The compound of embodiment 192, wherein RGis methyl. Embodiment 196: The compound of any one of embodiments 189-190, wherein Ring B is substituted with 2 RG. Embodiment 197: The compound of embodiment 196, wherein each RGis fluoro. Embodiment 198: The compound of embodiment 196, wherein each RGis methyl. Embodiment 199: The compound of embodiment 196, wherein one RGis hydroxyl and the other RGis methyl. Embodiment 200: The compound of embodiment 196, wherein one RGis fluoro and the other RGis methyl. Embodiment 201: The compound of embodiment 196, wherein one RGis hydroxyl and the other RGis fluoro. Embodiment 202: The compound of any one of embodiments 189-201, wherein each RGis bonded to the position of Ring B para to the nitrogen that is bonded to Ring A. Embodiment 203: The compound of embodiment 1, wherein each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6alkyl. Embodiment 204: The compound of embodiment 1, wherein each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; and R3is a C1-C6haloalkyl. Embodiment 205: The compound of embodiment 1, wherein: Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl, and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2. Embodiment 206: The compound of embodiment 1, wherein: each R1is fluoro; m is 1 or 2; R2is a C1-C6alkyl; R3is a C1-C6alkyl; Ring A is a phenyl or a 5-6 membered heteroaryl; each R4is independently selected from the group consisting of: C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, - SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O) Me, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG; and n is 1 or 2. Embodiment 207: A compound of Formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent; R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A1 is a 6 membered heteroaryl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; wherein R4is bonded to the position of Ring A1 that is para to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. Embodiment 208: The compound of embodiment 207, wherein Ring A1 is pyrimidinyl. Embodiment 209: The compound of embodiment 207, wherein Ring A1 is pyridyl. Embodiment 210: The compound of embodiment 207, wherein Ring A1 is pyrazolyl. Embodiment 211: The compound of embodiment 207, wherein Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. Embodiment 212: The compound of embodiment 207, wherein is , wherein: R4Bis selected from -NRARBand 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1is selected from fluoro, hydroxyl, and C1-C6alkyl. Embodiment 213: The compound of embodiment 212, wherein RAand RBare both hydrogen. Embodiment 214: The compound of embodiment 212, wherein one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1- C6 alkyl), and -SO2(NH2). Embodiment 215: The compound of any one of embodiments 212 and 214, wherein one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. Embodiment 216: The compound of any one of embodiments 212 and 214-215, wherein one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. Embodiment 217: The compound of any one of embodiments 212 and 214, wherein one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. Embodiment 218: The compound of any one of embodiments 212 and 214, wherein RAand RBare both C1-C6haloalkyl. Embodiment 219: The compound of any one of embodiments 212 and 214, wherein one of RAand RBis C1-C6alkyl and the other of RAand RBis C1-C6haloalkyl. Embodiment 220: The compound of any one of embodiments 212 and 214, wherein one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. Embodiment 221: The compound of any one of embodiments 212, 214, and 220, wherein one of RAand RBis hydrogen and the other of RAand RBis cyclobutanyl optionally substituted with hydroxyl. Embodiment 222: The compound of any one of embodiments 212, 214, and 220-221, wherein one of RAand RBis hydrogen and the other of RAand RBis 3-hydroxycyclobutyl. Embodiment 223: The compound of any one of embodiments 212 and 214, wherein one of RAand RBis hydrogen and the other of RAand RBC1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2). Embodiment 224: The compound of any one of embodiments 212,214, and 223, wherein one of RAand RBis hydrogen and the other of RAand RBis methyl. Embodiment 225: The compound of any one of embodiments 212,214, and 223, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with hydroxyl. Embodiment 226: The compound of any one of embodiments 212, 214, and 223, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with 3-6 membered cycloalkyl and hydroxyl. Embodiment 227: The compound of any one of embodiments 212, 214, 223, and 226, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with 3-4 membered cycloalkyl and hydroxyl. Embodiment 228: The compound of any one of embodiments 212, 214, and 223, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with - SO2(C1-C6alkyl). Embodiment 229: The compound of any one of embodiments 212, 214, 223, and 228, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with -SO2CH3. Embodiment 230: The compound of any one of embodiments 212, 214, and 223, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with - SO2(NH2). Embodiment 231: The compound of embodiment 212, wherein R4Bis 4-6 membered heterocyclyl comprising one nitrogen ring member and optionally substituted with 1-2 independently selected RG; wherein RGis selected from fluoro, hydroxyl, and C1-C6alkyl. Embodiment 232: The compound of embodiment 212 or 231, wherein R4Bis ; wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, each optionally substituted with 1-2 RGindependently selected from fluoro, hydroxyl, and C1-C6alkyl. Embodiment 233: The compound of embodiment 232, wherein Ring B is azetidinyl. Embodiment 234: The compound of any one of embodiments 232-233, wherein Ring B is unsubstituted. Embodiment 235: The compound of any one of embodiments 232-233, wherein Ring B is substituted with 1 RG. Embodiment 236: The compound of embodiment 235, wherein RGis fluoro. Embodiment 237: The compound of embodiment 235, wherein RGis cyano. Embodiment 238: The compound of embodiment 235, wherein RGis hydroxyl. Embodiment 239: The compound of embodiment 235, wherein RGis methyl. Embodiment 240: The compound of embodiment 235, wherein RGis -CO2CH3. Embodiment 241: The compound of any one of embodiments 232-233, wherein Ring B is substituted with 2 independently selected RG. Embodiment 242: The compound of embodiment 241, wherein each RGis fluoro. Embodiment 243: The compound of embodiment 241, wherein each RGis methyl. Embodiment 244: The compound of embodiment 241, wherein one RGis hydroxyl and the other RGis methyl. Embodiment 245: The compound of embodiment 241, wherein one RGis fluoro and the other RG1is methyl. Embodiment 246: The compound of embodiment 241, wherein one RGis hydroxyl and the other RG1is fluoro. Embodiment 247: The compound of any one of embodiments 232-233 and 235-246, wherein each RGis bonded to the position of Ring B para to the nitrogen. Embodiment 248: A compound of Formula (I-B): or a pharmaceutically acceptable salt thereof, wherein: R1Ais halogen; R1Bis halogen or absent (the phenyl ring is monosubstituted with R1A); R2is a C1-C6alkyl or a C1-C6haloalkyl; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; R4is independently selected from the group consisting of: C1-C6alkyl optionally substituted with -NRARB, C1-C6alkoxy, C1-C6haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), -CO2(C1-C6alkyl), 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently hydrogen, 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, and -CO2H. Embodiment 249: The compound of any one of embodiments 207-248, wherein R1Aand R1Bare each fluoro. Embodiment 250: The compound of any one of embodiments 207-249, wherein R2is a C1- C6 alkyl. Embodiment 251: The compound of any one of embodiments 207-250, wherein R2is methyl. Embodiment 252: The compound of any one of embodiments 207-249, wherein R2is a C1- C6 haloalkyl. Embodiment 253: The compound of any one of embodiments 207-249 and 242, wherein R2is a trifluoromethyl. Embodiment254: The compound of any one of embodiments 207-253, wherein R3is a C1- C6 alkyl. Embodiment 255: The compound of any one of embodiments 207-254, wherein R3is a C1- C3 alkyl. Embodiment 256: The compound of any one of embodiments 207-255, wherein R3is methyl, ethyl, or isopropyl. Embodiment 257: The compound of any one of embodiments 207-256, wherein R3is methyl. Embodiment 258: The compound of any one of embodiments 207-256, wherein R3is ethyl. Embodiment 259: The compound of any one of embodiments 207-256, wherein R3is isopropyl. Embodiment 260: The compound of any one of embodiments 207-253, wherein R3is a C1- C6 haloalkyl. Embodiment 261: The compound of any one of embodiments 207-253 and 260, wherein R3is a trifluoromethyl. Embodiment 262: The compound of any one of embodiments 207-253, wherein R3is C3- C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl. Embodiment 263: The compound of any one of embodiments 207-253 and 262, wherein R3is C3-C6cycloalkyl substituted with 1 or 2 fluoro. Embodiment 264: The compound of any one of embodiments 207-253 and 262, wherein R3is unsubstituted C3-C6cycloalkyl. Embodiment 265: The compound of any one of embodiments 207-253, wherein the R3C3- C6 cycloalkyl is cyclopropyl. Embodiment 266: The compound of any one of embodiments 207-211 and 248-265, wherein, R4is C1-C6alkyl optionally substituted with -NRARB. Embodiment 267: The compound of any one of embodiments 207-211 and 248-266, wherein R4is C1-C3alkyl optionally substituted with -NRARB. Embodiment 268: The compound of any one of embodiments 207-211 and 248-267, wherein R4is methyl optionally substituted with -NRARB. Embodiment 269: The compound of any one of embodiments 207-211 and 248-265, wherein R4is C1-C6alkyl. Embodiment 270: The compound of any one of embodiments 207-211 and 248-265, wherein R4is methyl. Embodiment 271: The compound of any one of embodiments 207-211 and 248-265, wherein R4is C1-C6alkoxy. Embodiment 272: The compound of any one of embodiments 207-211, 248-265, and 271, wherein R4is methoxy. Embodiment 273: The compound of any one of embodiments 207-211 and 248-265, wherein R4is C1-C6haloalkyl. Embodiment 274: The compound of any one of embodiments 207-211, 248-265, and 273, wherein R4is trifluoromethyl. Embodiment 275: The compound of any one of embodiments 207-211 and 248-265, wherein R4is hydroxyl. Embodiment 276: The compound of any one of embodiments 207-211 and 248-265, wherein R4is cyano or -CO2H. Embodiment 277: The compound of any one of embodiments 207-211 and 248-265, wherein R4is -NRARB. Embodiment 278: The compound of any one of embodiments 207-211, 248-265, and 277, wherein RAand RBare each hydrogen. Embodiment 279: The compound of any one of embodiments 207-211, 248-265, and 277, wherein one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. Embodiment 280: The compound of any one of embodiments 207-211, 248-265, 277, and 249, wherein one of RAand RBis hydrogen and the other of RAand RBis methyl. Embodiment 281: The compound of any one of embodiments 207-265, and 277, wherein RAand RBare each C1-C6alkyl. Embodiment 282: The compound of any one of embodiments 207-211, 248-265, 277, and 251, wherein RAand RBare each methyl. Embodiment 283: The compound of any one of embodiments 207-211, 248-265, and 277, wherein one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl, C1-C6haloalkyl, 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2). Embodiment 284: The compound of any one of embodiments 207-211, 248-265, 277 and 283, wherein one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl. Embodiment 285: The compound of any one of embodiments 207-211, 248-265, 277 and 283-284, wherein one of RAand RBis hydrogen and the other of RAand RBis 5 membered heterocyclyl. Embodiment 286: The compound of any one of embodiments 207-211, 248-265, 277 and 283, wherein one of RAand RBis hydrogen and the other of RAand RBis 3-6 membered cycloalkyl optionally substituted with hydroxyl. Embodiment 287: The compound of any one of embodiments 207-211, 248-265, 277, 283 and 286, wherein one of RAand RBis hydrogen and the other of RAand RBis cyclobutanyl optionally substituted with hydroxyl. Embodiment 288: The compound of any one of embodiments 207-211, 248-265, 277, 283 and 286-287, wherein one of RAand RBis hydrogen and the other of RAand RBis 3- hydroxycyclobutyl. Embodiment 289: The compound of any one of embodiments 207-211, 248-265, 277, and 283, wherein one of RAand RBis hydrogen and the other of RAand RBis C1-C6haloalkyl. Embodiment 290: The compound of any one of embodiments 207-211, 248-265, and 277, wherein RAand RBare each C1-C6haloalkyl. Embodiment 291: The compound of any one of embodiments 207-211, 248-265, and 277, wherein one of RAand RBis C1-C6alkyl and the other of one of RAand RBis C1-C6haloalkyl. Embodiment 292: The compound of any one of embodiments 207-211, 248-265, 277, and 283, wherein one of RAand RBis hydrogen and the other of RAand RBC1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), and -SO2(NH2). Embodiment 293: The compound of any one of embodiments 207-211, 248-265, 277, 283, and 292, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with hydroxyl. Embodiment 294: The compound of any one of embodiments 207-211, 248-265, 277, 283, and 292, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with 3-6 membered cycloalkyl and hydroxyl. Embodiment 295: The compound of any one of embodiments 207-211, 248-265, 277, 283, 292 and 294, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl substituted with 3-4 membered cycloalkyl and hydroxyl. Embodiment 296: The compound of any one of embodiments 207-211, 248-265, 277, 283, and 292, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with -SO2(C1-C6alkyl). Embodiment 297: The compound of any one of embodiments 207-211, 248-265, 277, 283, 292, and 296, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with -SO2CH3. Embodiment 298: The compound of any one of embodiments 207-211, 248-265, 277, 283, and 292, wherein one of RAand RBis hydrogen and the other of RAand RBis ethyl or propyl substituted with -SO2(NH2) Embodiment 299: The compound of any one of embodiments 207-211 and 248-265, wherein one R4is -C(=O)NRCRD. Embodiment 300: The compound of any one of embodiments 207-211, 248-265, and 299, wherein RCand RDare each hydrogen. Embodiment 301: The compound of any one of embodiments 207-211, 248-265, and 299, wherein one of RCand RDis hydrogen and the other of RCand RDis C1-C6alkyl. Embodiment 302: The compound of any one of embodiments 207-211, 248-265, and 299, wherein one of RCand RDis hydrogen and the other of RCand RDis methyl. Embodiment 303: The compound of any one of embodiments 207-211, 248-265, and 299, wherein RCand RDare each C1-C6alkyl. Embodiment 304: The compound of any one of embodiments 207-211, 248-265, and 299, wherein RCand RDare each methyl. Embodiment 305: The compound of any one of embodiments 207-211, 248-265, and 299, wherein one of RCand RDis hydrogen and the other of RCand RDis C1-C6haloalkyl. Embodiment 306: The compound of any one of embodiments 207-211, 248-265, and 299, wherein RCand RDare each is C1-C6haloalkyl. Embodiment 307: The compound of any one of embodiments 207-211, 248-265, and 299, wherein one of RCand RDis C1-C6alkyl and the other of RCand RDis C1-C6haloalkyl. Embodiment 308: The compound of any one of embodiments 207-211 and 248-265, wherein one R4is -SO2(NRERF). Embodiment 309: The compound of any one of embodiments 207-211, 248-265, and 308, wherein REand RFare each hydrogen. Embodiment 310: The compound of any one of embodiments 207-211, 248-265, and 308, wherein one of REand RFis hydrogen and the other of REand RFis C1-C6alkyl. Embodiment 311: The compound of any one of embodiments 207-211, 248-265, and 308, wherein one of REand RFis hydrogen and the other of REand RFis methyl. Embodiment 312: The compound of any one of embodiments 207-211, 248-265, and 308, wherein REand RFare each is C1-C6alkyl. Embodiment 313: The compound of any one of embodiments 207-211, 248-235, and 308, wherein REand RFare each methyl. Embodiment 314: The compound of any one of embodiments 207-211, 248-265, and 308, wherein one of REand RFis hydrogen and the other of REand RFis C1-C6haloalkyl. Embodiment 315: The compound of any one of embodiments 207-211, 248-265, and 308, wherein REand RFare each C1-C6haloalkyl. Embodiment 316: The compound of any one of embodiments 207-211, 248-265, and 308, wherein one of REand RFis C1-C6alkyl and the other of REand RFis C1-C6haloalkyl. Embodiment 317: The compound of any one of embodiments 207-211 and 248-265, wherein R4is -SO2(C1-C6alkyl). Embodiment 318: The compound of any one of embodiments 207-211, 248-265, and 317, wherein R4is -SO2Me. Embodiment 319: The compound of any one of embodiments 207-211, 248-265, and 317, wherein R4is -SO2Et. Embodiment 320: The compound of any one of embodiments 207-211 and 248-265, wherein R4is -S(=O)(=NH)(C1-C6alkyl). Embodiment 321: The compound of any one of embodiments 207-211, 248-265, and 320, wherein R4is -S(=O)(=NH)Me. Embodiment 322: The compound of any one of embodiments 207-211 and 248-265, wherein R4is -C(=O)(C1-C6alkyl). Embodiment 323: The compound of any one of embodiments 207-211, 248-265, and 322, wherein R4is -C(=O)Me. Embodiment 324: The compound of any one of embodiments 207-211 and 248-265, wherein R4is -CO2(C1-C6alkyl). Embodiment 325: The compound of any one of embodiments 207-211, 248-265, and 324, wherein R4is -CO2Me. Embodiment 326: The compound of any one of embodiments 207-211 and 248-265, wherein R4is 5-6 membered heteroaryl optionally substituted with C1-C6alkyl. Embodiment 327: The compound of any one of embodiments 207-211, 248-265, and 326, wherein one R4is 5-6 membered heteroaryl substituted with C1-C6alkyl. Embodiment 328: The compound of any one of embodiments 207-211, 248-265, and 326- 327, wherein one R4is tetrazolyl substituted with methyl. Embodiment 329: The compound of any one of embodiments 207-211, 248-265, and 326, wherein one R4is unsubstituted 5-6 membered heteroaryl. Embodiment 330: The compound of any one of embodiments 207-211, 248-265, 326, and 329, wherein R4is unsubstituted pyrazolyl. Embodiment 331: The compound of any one of embodiments 207-211 and 248-265, wherein R4is 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG. Embodiment 332: The compound of any one of embodiments 207-211, 248-265, and 331, wherein R4is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RG. Embodiment 333: The compound of any one of embodiments 207-211, 248-265, and 332, wherein R4is 3-6 membered heterocyclyl substituted with 1 RG. Embodiment 334: The compound of any one of embodiments 207-211, 248-265, and 332, wherein R4is 3-6 membered heterocyclyl substituted with 2 independently selected RG. Embodiment 335: The compound of any one of embodiments 207-211, 248-265, wherein R4is 3-6 membered cycloalkyl substituted with 1 or 2 independently selected RG. Embodiment 336: The compound of any one of embodiments 207-211, 248-265, and 335, wherein R4is 3-6 membered cycloalkyl substituted with 1 RG. Embodiment 337: The compound of any one of embodiments 207-211, 248-265, and 335, wherein R4is 3-6 membered cycloalkyl substituted with 2 independently selected RG. Embodiment 338: The compound of any one of embodiments 207-211, 248-265, and 336, wherein R4is cyclobutanyl substituted with 1 RG. Embodiment 339: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis halogen. Embodiment 340: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis fluoro. Embodiment 341: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis cyano. Embodiment 342: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis hydroxyl. Embodiment 343: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis C1-C6alkyl. Embodiment 344: The compound of any one of embodiments 207-211, 248-265, 331-338, and 343, wherein one RGis methyl. Embodiment 345: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis C1-C6alkoxy. Embodiment 346: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 345, wherein one RGis methoxy. Embodiment 347: The compound of any one of embodiments 207-211, 248-265, and 331- 338, wherein one RGis -NRA1RB1. Embodiment 348: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein RA1and RB1are each hydrogen. Embodiment 349: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6alkyl. Embodiment 350: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is methyl. Embodiment 351: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein RA1and RB1are each C1-C6alkyl. Embodiment 352: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein RA1and RB1are each methyl. Embodiment 353: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein one of RA1and RB1is hydrogen and the other of RA1and RB1is C1-C6haloalkyl. Embodiment 354: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein RA1and RB1are each C1-C6haloalkyl. Embodiment 355: The compound of any one of embodiments 207-211, 248-265, and 331- 338, and 347, wherein one of RA1and RB1is C1-C6alkyl and t...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, and C3-C6cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6alkyl, a C1-C6haloalkyl, or a C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl; Ring A is a 6-10 membered aryl, a C3-C8cycloalkyl, a 5-10 membered heteroaryl, or a 4- 10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6alkyl optionally substituted with 1 or 2 hydroxyl or -NRARB, (iii) C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl, (iv) C1-C6haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB,(ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6alkyl), (xiii) -S(=O)(=NH)(C1-C6alkyl), (xiv) -C(=O)(C1-C6alkyl), (xv) -CO2(C1-C6alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6haloalkyl, (v) -C(=O)(C1-C6alkyl), (vi) -C(=O)O(C1-C6alkyl), (vii) -SO2(C1-C6alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, –C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6alkyl), -CO2H, and -SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6alkyl), -CO2H, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, and C1-C6haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6alkyl;each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6alkyl optionally substituted with hydroxyl, C1-C6alkoxy, -NRA1RB1, =NRA2, - C(=O)NRC1RD1, -CO2(C1-C6alkyl), C1-C6haloalkyl, C3-C6cycloalkyl, C1-C6haloalkoxy, - SO2(C1-C6alkyl), and -CO2H; and wherein the compound is not a compound selected from the group consisting of:, , ,,, , , , ,,,2. The compound of claim 1, wherein m is 1.

3. The compound of claim 1, wherein m is 2.

4. The compound of any one of claims 1-3, whereinis5. The compound of any one of claims 1-4, wherein each R1is halogen.

6. The compound of any one of claims 1-5, wherein each R1is selected from fluoro and chloro.

7. The compound of any one of claims 1-6, wherein each R1is fluoro.

8. The compound of any one of claims 1-4, wherein one R1is cyano.

9. The compound of any one of claims 1-4, wherein one R1is C1-C6alkyl or C3-C6cycloalkyl.

10. The compound of claim 1, wherein m is 0.

11. The compound of any one of claims 1-10, wherein R2is a C1-C6alkyl.

12. The compound of claim 11, wherein R2is methyl.

13. The compound of any one of claims 1-10, wherein R2is a C1-C6haloalkyl.

14. The compound of claim 13, wherein R2is difluoromethyl.

15. The compound of claim 13, wherein R2is trifluoromethyl.

16. The compound of any one of claims 1-10, wherein R2is halogen.

17. The compound of any one of claims 1-10, wherein R2is C3-C6cycloalkyl optionally substituted with 1 or 2 fluoro.

18. The compound of any one of claims 1-17, wherein R3is a C1-C6haloalkyl.

19. The compound of any one of claims 1-18, wherein R2is difluoromethyl.

20. The compound of any one of claims 1-18, wherein R2is trifluoromethyl.

21. The compound of any one of claims 1-17, wherein R3is a C1-C6alkyl.

22. The compound of any one of claims 1-17, wherein R3is C3-C6cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6alkyl.

23. The compound of any one of claims 1-22, wherein Ring A is a 5-10 membered heteroaryl.

24. The compound of any one of claims 1-23, wherein Ring A is a 5-6 membered heteroaryl.

25. The compound of any one of claims 1-24, wherein Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl.

26. The compound of any one of claims 1-25, wherein Ring A is pyrimidinyl.

27. The compound of any one of claims 1-25, wherein Ring A is pyridyl.

28. The compound of any one of claims 1-25, wherein Ring A is thiazolyl.

29. The compound of any one of claims 1-25, wherein Ring A is thiophenyl.

30. The compound of any one of claims 1-25, wherein Ring A is pyrazolyl.

31. The compound of any one of claims 1-23, wherein Ring A is a 9-10 membered heteroaryl.

32. The compound of any one of claims 1-23 and 31, wherein Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, or imidazo[1,2-a]pyridinyl.

33. The compound of any one of claims 1-23 and 31-32, wherein Ring A is benzimidazolyl.

34. The compound of any one of claims 1-23 and 31-32, wherein Ring A is indazolyl.

35. The compound of any one of claims 1-23 and 31-32, wherein Ring A is indolyl.

36. The compound of any one of claims 1-23 and 31-32, wherein Ring A is quinazolone.

37. The compound of any one of claims 1-23 and 31-32, wherein Ring A is isobenzofuranonyl.

38. The compound of any one of claims 1-23 and 31-32, wherein Ring A is isoindolinonyl.

39. The compound of any one of claims 1-23 and 31-32, wherein Ring A is imidazo[1,2-a]pyridinyl.

40. The compound of any one of claims 1-22, wherein Ring A is phenyl.

41. The compound of any one of claims 1-22, wherein Ring A is a C3-C8cycloalkyl.

42. The compound of any one of claims 1-22, wherein Ring A is a 4-10 membered heterocyclyl.

43. The compound of any one of claims 1-22 or 42, wherein Ring A is a 4-6 membered heterocyclyl.

44. The compound of any one of claims 1-43, wherein n is 1.

45. The compound of any one of claims 1-43, wherein n is 2.

46. The compound of any one of claims 1-45, wherein one R4is an unsubstituted C1- C6 alkyl.

47. The compound of any one of claims 1-45, wherein one R4is C1-C6alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6cycloalkyl.

48. The compound of any one of claims 1-45, wherein one R4is C1-C6haloalkyl.

49. The compound of any one of claims 1-45, wherein one R4is hydroxyl, cyano, - CO2H, halogen, or C1-C6alkyl substituted with 1-2 hydroxyl or -NRARB.

50. The compound of any one of claims 1-45, wherein one R4is -NRARB, - C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6alkyl), -S(=O)(=NH)(C1-C6alkyl), -C(=O)(C1-C6alkyl), or -CO2(C1-C6alkyl).

51. The compound of any one of claims 1-45, wherein one R4is 5-6 membered heteroaryl optionally substituted with C1-C6alkyl.

52. The compound of any one of claims 1-45, wherein one R4is 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG.

53. The compound of any one of claims 1-52, wherein Z is O.

54. The compound of any one of claims 1-52, wherein Z is NRx.

55. A compound selected from the group consisting of the compounds in Table A, Table B, and Table C, Table D, or a pharmaceutically acceptable salt thereof.

56. A pharmaceutical composition comprising a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

57. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 56.

58. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 56.

59. A method of treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 56.

60. A method for modulating PI3Kα in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1- 55, or a pharmaceutically acceptable salt thereof.