Urea derivatives which can be used to treat cancer

Abstract

To achieve targeting PI3Kα, representing an approach for the treatment of proliferative disorders such as cancer.SOLUTION: 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, for example, for treating a condition, disease, or disorder in which increased (for example, excessive) PI3Ka activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (for example, cancer) in a subject (for example, a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application No. 63 / 210,370 filed June 14, 2021, U.S. Application No. 63 / 228,351 filed August 2, 2021, U.S. Application No. 63 / 288,909 filed December 13, 2021, U.S. Application No. 63 / 316,017 filed March 3, 2022, U.S. Application No. 63 / 319,236 filed March 11, 2022, and U.S. Application No. 63 / 348,261 filed June 2, 2022, the contents of which are incorporated herein by reference.

[0002] The present disclosure provides compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also provides compositions containing the same, as well as methods of using and making the same. [Background technology]

[0003] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene, is part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several researchers have demonstrated the role of PI3K / AKT signaling in physiological and pathophysiological functions that drive tumor progression, such as metabolism, cell growth, proliferation, angiogenesis, and metastasis (see Fruman, D.A. The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018, 15, 273-291). Inhibition of PI3K / AKT / TOR signaling (e.g., pharmacological or genetic) can lead to cancer cell death and tumor growth regression.

[0004] The PI3K pathway can be activated, for example, through point mutation(s) in the PIK3CA gene or through inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30–50% of human cancers and contributes to resistance to various anticancer therapies (see Martini, M. et al., PI3K / AKT signaling pathway and cancer: An updated review. Ann. Med. 2014, 46, 372–383 and Bauer, T. M. et al., Targeting PI3 kinase in cancer. Pharmacol. Ther. 2015, 146, 53–60). PI3K consists of three subunits: the p85 regulatory subunit, the p55 regulatory subunit, and the p110 catalytic subunit. According to their distinct structures and specific substrates, PI3Ks are classified into three classes: class I, class II, and class III. Class I PI3Ks include class IA and class IB PI3Ks. Class IA PI3Ks, heterodimers of the p85 regulatory subunit and the p110 catalytic subunit, are the type most clearly associated with human cancer. Class IA PI3Ks contain the p110α, p110β, and p110δ catalytic subunits, which are produced by distinct genes (PIK3CA, PIK3CB, and PIK3CD, respectively), whereas p110γ, produced by PIK3CG, represents the only catalytic subunit in class IB PI3Ks. PIK3CA, the gene encoding the p110α subunit, is frequently mutated or amplified in many human cancers, including breast, colon, gastric, cervical, prostate, and lung cancers (see Samuels Y, et al. High frequency of mutations of the PIK3CA gene in human cancers Science. 2004;304:554).

[0005] However, the development of PI3K inhibitors has been challenging for several reasons, including (i) adaptive molecular mechanisms during therapeutic inhibition of PI3K, (ii) the lack of ability to specifically inhibit signaling by PIK3CA mutations while sparing endogenous p110α, (iii) the limited use of these therapies in rational combinations, including those with strong reported 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 PI3Kα. However, the therapeutic benefit of alpelisib is limited by dose-limiting toxicities, including hyperglycemia, resulting from the inhibition of wild-type PI3Kα in normal tissues.

[0006] Additionally, there are other factors and compensatory pathways that affect PI3K signaling, such as HRAS and KRAS mutations that reduce sensitivity to PI3K inhibitors, derived from both clinical and in vitro basic studies (and knockdown of these has been shown to improve sensitivity to PI3K inhibitors) (see Misrha, R.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects Int. J. Mol. Sci. 2021, 22, 3464).

[0007] Domain deletions in PIK3CA can significantly activate PI3K signaling and can also enhance sensitivity to PI3K inhibitors (see Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426-1435). Thus, targeting PI3Kα represents a strategy for the treatment of proliferative disorders such as cancer. Summary of the Invention

[0008] Some embodiments include a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 became independent, (i) halogens, (ii) one or two hydroxyls or -NR A R B C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R G 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) Hydroxyl, -C(=O)NR B2 R C2 , a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, a C1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0009] Some embodiments include a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R 3is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 became independent, (i) halogens, (ii) one or two hydroxyls or -NR A R B C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R G 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected RG and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) Hydroxyl, -C(=O)NR B2 R C2 , a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, a C1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0010] Some embodiments include a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 became independent, (i) halogens, (ii) one or two hydroxyls or -NR A R B C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R G 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) Hydroxyl, -C(=O)NR B2 R C2, a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, a C1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H.

[0011] Some embodiments include a compound of formula (I) having the formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is a C-C cycloalkyl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 are independently a halogen, one or two hydroxyl, or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), —SO2(C1-C6 alkyl), —S(═O)(═NH)(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and each of one or two independently selected R G and selected from the group consisting of 3- to 6-membered heterocyclyl or 3- to 6-membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R Fare independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, —C(═O)(C1-C6 alkyl), —SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or hydroxyl, —C(═O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6 alkyl), -SO2(NH2), or C1-C6 alkyl optionally substituted by 1-2 substituents independently selected from R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0012] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0013] 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 provided herein.

[0014] Also provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0015] Provided herein is a method for treating a PI3Kα-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated disease or disorder a therapeutically effective amount of a compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0016] The present disclosure also provides a method for treating a PI3Kα-associated disease or disorder in a subject, the method comprising determining that a cancer in the subject is a PI3Kα-associated disease or disorder, and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0017] Further provided herein is a method for treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0018] The present disclosure also provides a method for treating a PI3Kα-associated cancer in a subject, the method comprising determining that the cancer in the subject is a PI3Kα-associated cancer, and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0019] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, to a subject having medical records indicating that the subject has a dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or level of any of them.

[0020] The present disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0021] Some embodiments of the methods and compositions described herein comprise a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 are independently one or two hydroxyl or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and RF are independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, —C(═O)(C1-C6 alkyl), C(═O)O(C1-C6 alkyl), —SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or hydroxyl, —C(═O)NR B2 R C2 , a 5-6 membered heteroaryl, a 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2), or R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H.

[0022] Also provided herein is a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0023] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

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

[0025] Provided herein is a method for treating a PI3Kα-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated disease or disorder a therapeutically effective amount of a compound of formula (II) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0026] The present disclosure also provides a method for treating a PI3Kα-associated disease or disorder in a subject, the method comprising: determining that a cancer in the subject is a PI3Kα-associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0027] Further provided herein is a method for treating a PI3Kα-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of formula (II) provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

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

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

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

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

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

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

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

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

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

[0037] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of a chemical substance being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to produce a clinically meaningful reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0038] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and 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.

[0039] 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 eliminate the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form a salt, for example, an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid such as arginine, lysine, etc., or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited, as long as it can be used in medicine. Examples of salts that the compounds described herein may form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, which are specifically exemplified by acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0040] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "pharmaceutically acceptable excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0041] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0042] As used herein, the term "treat" or "treatment" refers to therapeutic or preventative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, attenuation of the extent of the disease, a stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0043] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0044] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0045] The term "hydroxyl" refers to the --OH radical.

[0046] The term "cyano" refers to the -CN radical.

[0047] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0048] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with independently selected halo.

[0049] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0050] The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and 0, 1, 2, 3, or 4 atoms in each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0051] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms.

[0052] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and wherein at least one ring in the system is aromatic (although it need not be the ring containing the heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., in which the oxo group (i.e., "=O") is a component of the heteroaryl ring), and pyridones (e.g., [ka] Pyrimidones (e.g., [ka] Pyridazinones (e.g., [ka] Pyrazinones (e.g., [ka] and imidazolone (e.g., [ka] Also includes one or more of:

[0053] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms, having 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system), wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and or, if tricyclic, 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms, respectively, where, valences permitting, one or more ring atoms can be substituted by 1 to 3 oxo (e.g., to form a lactam), one or more N or S atoms can be substituted by 1 to 2 oxides (e.g., to form N-oxides, S-oxides, or S,S-dioxides), and 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyls can include multiple fused and bridged rings.Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[4.1.0]heptane ...4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]heptane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[4.1.0]hexane, 5-azabicyclo[2 Heterocyclyl includes 2-oxabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2 .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0054] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0055] As used herein, when a ring is described as being "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation due to the ring itself, e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0056] For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are defined as those in which the points of fusion are (i) located on adjacent ring atoms (e.g., [xx0] ring systems (where 0 represents zero atom bridges) (e.g., [ka] (ii) those located on a single ring atom (spiro-fused ring systems) (e.g., [ka] or (iii) located on a contiguous sequence of ring atoms (bridged ring systems where the total bridge length is >0) (e.g., [ka] It is understood that the term encompasses those having fused rings, including:

[0057] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopes of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 Contains C.

[0058] Additionally, the compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: [ka] Compounds containing the moiety: [ka] Similarly, a pyridinyl or pyrimidinyl moiety depicted as optionally substituted by hydroxyl includes the pyridone or pyrimidone tautomeric forms.

[0059] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass mixtures of enantiomers (e.g., R and S isomers), diastereomers, and individual enantiomers and diastereomers, including racemic and diastereomeric mixtures, resulting from structural asymmetry in a particular compound. Unless otherwise indicated, when a disclosed compound is designated or depicted by a structure without designating a stereochemical structure (e.g., a "flat" structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when a disclosed compound is designated or depicted by a structure with a designated stereochemical structure (e.g., a structure with "wedge" and / or "dashed" bonds) and has one or more chiral centers, it is understood to represent the depicted stereoisomer of the compound.

[0060] 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 disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0061] The present disclosure provides compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The disclosure also provides compositions containing the same, as well as methods of using and making the same.

[0062] Compounds of formula (I) Some embodiments include a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4became independent, (i) halogens, (ii) one or two hydroxyls or -NR A R B C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R G 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , RD1 , R E , and R F became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) Hydroxyl, -C(=O)NR B2 R C2 , a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, a C1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1, —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0063] In some embodiments, Z is NR x and R 3 is methyl, then ring A is not phenyl.

[0064] Some embodiments provide a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0065] Some embodiments provide a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0066] Some embodiments provide a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0067] Some embodiments include a compound of formula (I) having the formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected halogens; m is 0, 1, 2, or 3; R 2 is a C-C cycloalkyl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 are independently a halogen, one or two hydroxyl, or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F), —SO2(C1-C6 alkyl), —S(═O)(═NH)(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, and each of the 5- to 6-membered heteroaryls is optionally substituted with one or two independently selected R G and selected from the group consisting of 3- to 6-membered heterocyclyl or 3- to 6-membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, —C(═O)(C1-C6 alkyl), —SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or hydroxyl, —C(═O)NR B2 R C2 , 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6 alkyl), -SO2(NH2), or C1-C6 alkyl optionally substituted by 1-2 substituents independently selected from R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0068] Some embodiments provide a compound of formula (X) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0069] Some embodiments provide a compound of formula (X) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is not a compound selected from the group consisting of:

[0070] In some embodiments, the compounds described herein are not compounds selected from the groups described above (i.e., "excluded compounds"). In some embodiments, the excluded compounds are planar structures as shown 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.

[0071] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0072] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0073] In some embodiments, each R 1 is an independently selected halogen. In some embodiments, each R 1 is independently selected from fluoro and chloro. In some embodiments, each R 1 is independently selected from fluoro and bromo. In some embodiments, each R 1 is fluoro. In some embodiments, at least one R 1 are independently selected halogens. In some embodiments, at least one R 1 is independently selected from fluoro and chloro. In some embodiments, at least one R 1 is fluoro.

[0074] In some embodiments, at least one R 1 is cyano. In some embodiments, at least one R 1 is hydroxyl. In some embodiments, at least one R 1 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R 1is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R 1 is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R 1 is hydroxymethyl. In some embodiments, at least one R 1 is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 1 is methyl. In some embodiments, at least one R 1 is C-C cycloalkyl. In some embodiments, at least one R 1 is cyclopropyl.

[0075] In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 is C1-C6 alkyl. In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 is C3-C6 cycloalkyl. In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 In some embodiments, m is 2 and one R 1 is a halogen, and the other R 1 In some embodiments, m is 2 and one R 1 is fluoro and the other R 1 is fluoro.

[0076] In some embodiments, R 2 is hydroxyl. In some embodiments, R2 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R 2 is a C1-C6 alkyl substituted with hydroxyl. In some embodiments, R 2 is a C1-C3 alkyl substituted with hydroxyl. In some embodiments, R 2 is hydroxymethyl. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl. In some embodiments, R 2 is an unsubstituted C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0077] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.

[0078] In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro.

[0079] In some embodiments, R 2 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with two fluoro groups. In some embodiments, R 2is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 2 is a C-C cycloalkyl substituted with two fluoro. In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.

[0080] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is isopropyl.

[0081] In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is difluoromethyl. In some embodiments, R 3 is trifluoromethyl.

[0082] In some embodiments, R 3 is C-C cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C-C alkyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 3is a C-C cycloalkyl substituted with one fluoro. In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with one fluoro at the C3-C6 cycloalkyl position bonded to the methine in formula (I). In some embodiments, R 3 is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with one or two methyl. In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with one or two methyls. In some embodiments, R 3 is a C-C cycloalkyl substituted with one methyl. In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with one methyl at the C3-C6 cycloalkyl position bonded to the methine in formula (I). In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 3 In some embodiments, the C3-C6 cycloalkyl in R is cyclopropyl. 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is cyclohexyl.

[0083] 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.

[0084] In some embodiments, ring A is C3-C8 cycloalkyl. In some embodiments, ring A is C5-C6 cycloalkyl. In some embodiments, ring A is cyclohexyl.

[0085] 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 the 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 the 5 membered ring of ring A.

[0086] 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, [ka] In some embodiments, ring A is [ka] wherein the compound is selected from the group consisting of: * " indicates the point of attachment to the urea nitrogen atom in formula (I).

[0087] In some embodiments, ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, ring A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. In some embodiments, ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A is [ka] wherein the formula is selected from the group consisting of: * " indicates the point of attachment to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is 5-pyrimidinyl. In some embodiments, Ring A is [ka] In the formula, * " indicates the point of attachment to the urea nitrogen atom in Formula (I). In some embodiments, ring A is a 4-10 membered heterocyclyl. In some embodiments, ring A is a 6-9 membered heterocyclyl. In some embodiments, ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopyranyl-1,1-dioxide.

[0088] In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, [ka] In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, [ka] is.

[0089] In some embodiments, Ring A is 3-piperidinyl, [ka] is selected from the group consisting of:

[0090] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0091] In some embodiments, one R 4 is C1-C6 alkyl. In some embodiments, one R 4 is unsubstituted C1-C6 alkyl. In some embodiments, one R 4 is C1-C4 alkyl. In some embodiments, one R 4 is t-butyl. In some embodiments, one R 4 is methyl.

[0092] In some embodiments, one R 4 is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cyclopropyl. 4is a C1-C6 alkoxy substituted with hydroxyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with C3-C6 cycloalkyl. In some embodiments, one R 4 is C1-C6 alkoxy substituted with cyclopropyl. In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, one R 4 is methoxy.

[0093] In some embodiments, one R 4 is C1-C6 haloalkyl. In some embodiments, one R 4 is C1-C3 haloalkyl. In some embodiments, one R 4 is difluoromethyl. In some embodiments, one R 4 is trifluoromethyl.

[0094] In some embodiments, one R 4 is hydroxyl. In some embodiments, one R 4 is cyano. In some embodiments, one R 4 is —COH. In some embodiments, one R 4 is halogen. In some embodiments, one R 4 is fluoro. In some embodiments, one R 4 is chloro.

[0095] In some embodiments, one R 4 is a C1-C6 alkyl optionally substituted with 1 to 2 hydroxyl. In some embodiments, one R 4 is a C1-C6 alkyl substituted with 1 to 2 hydroxyl. In some embodiments, one R 4is a C1-C6 alkyl substituted with one hydroxyl. In some embodiments, one R 4 is a C1-C6 alkyl substituted with two hydroxyls. In some embodiments, one R 4 is a C1-C3 alkyl substituted with two hydroxyls. In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is -NR A R B In some embodiments, one R 4 is unsubstituted C1-C6 alkyl. In some embodiments, one R 4 is methyl.

[0096] In some embodiments, one R 4 is -NR A R B is.

[0097] In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B The other of these is hydroxyl or -C(=O)NR B2 R C2 In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NH2. Aand R B is hydrogen, and R A and R B and the other of R is —C(═O)O(C1-C6 alkyl). A and R B is hydrogen, and R A and R B The other of R is —C(═O)OCH. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is a 4- to 6-membered heterocyclyl (e.g., oxetanyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R Band the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is a butyl substituted with a hydroxyl (e.g., 2-hydroxy-2-methyl-1-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R Bone of R A and R B and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0098] In some embodiments, R B2 and R C2 and R are hydrogen. B2 and R C2 is hydrogen, and R B2 and R C2 and the other of R is C1-C6 alkyl. B2 and R C2 is hydrogen, and R B2 and R C2 and the other of R is methyl. B2 and R C2 Both of the groups are methyl.

[0099] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 haloalkyl. A and R B Each is C1-C6 haloalkyl. In some embodiments, R A and R B are each C1-C3 haloalkyl.

[0100] In some embodiments, R A and R B one of which is C1-C6 alkyl, and R A and R B The other of one of the groups is C1-C6 haloalkyl.

[0101] In some embodiments, one R 4 is -C(=O)NR C R D is.

[0102] In some embodiments, R C and R D Each is hydrogen. In some embodiments, R C and R D is hydrogen, and R C and R D and the other of R is C1-C6 alkyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C3 alkyl. C and R D is hydrogen, and R C and R D and the other of R is methyl. C and R D are each C1-C6 alkyl. In some embodiments, R C and R D are each C1-C3 alkyl. In some embodiments, R C and R D Each R is methyl. C and R D one of which is C1-C6 alkyl, and R C and R D The other of these is a C1-C3 alkyl.

[0103] In some embodiments, R C and R D is hydrogen, and R C and R D and the other of R is C1-C6 haloalkyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C3 haloalkyl. C and R D Each is C1-C6 haloalkyl. In some embodiments, R C and R D one of which is C1-C6 alkyl, and R C and R D The other of these is C1-C6 haloalkyl.

[0104] In some embodiments, R C and R D together with the nitrogen atom attached to them, hydroxyl, halogen, -C(=O)NR B1 R C1 , —SO2(C1-C6 alkyl), —CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, to form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from —SO2(C1-C6 alkyl), —CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. C and R D together with the nitrogen atom attached to them, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl substituted by 1 to 2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0105] In some embodiments, R B1 and R C1Each is hydrogen. In some embodiments, R B1 and R C1 is hydrogen, and R B1 and R C1 and the other of R is C1-C6 alkyl. B1 and R C1 is hydrogen, and R B1 and R C1 and the other of R is methyl. B1 and R C1 are each independently selected C1-C6 alkyl. In some embodiments, R B1 and R C1 are each methyl.

[0106] In some embodiments, R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0107] In some embodiments, one R 4 is -SO2(NR E R F In some embodiments, R E and R F Each is hydrogen. In some embodiments, R E and R F is hydrogen, and R E and R F and the other of R is C1-C6 alkyl. E and R F is hydrogen, and R E and R F and the other of R is C1-C3 alkyl. E and R F is hydrogen, and R E and R Fand the other of R is methyl. E and R F are each C1-C6 alkyl. In some embodiments, R E and R F are each C1-C3 alkyl. In some embodiments, R E and R F are each methyl.

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

[0109] In some embodiments, one R 4 is —SO2(C1-C6 alkyl). In some embodiments, one R 4 is —SO2(C1-C3 alkyl). In some embodiments, one R 4 is -SO2Et. In some embodiments, one R 4 is -SO2Me.

[0110] In some embodiments, one R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, one R 4is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, one R 4 is -S(=O)(=NH)Me.

[0111] In some embodiments, one R 4 is —C(═O)(C1-C6 alkyl). In some embodiments, one R 4 is —C(═O)(C1-C3 alkyl). In some embodiments, one R 4 is -C(=O)Me.

[0112] In some embodiments, one R 4 is —CO2(C1-C6 alkyl). In some embodiments, one R 4 is —CO2(C1-C3 alkyl). In some embodiments, one R 4 is -CO2Me.

[0113] In some embodiments, one R 4 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl. In some embodiments, one R 4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. 4 is tetrazolyl substituted with methyl. In some embodiments, one R 4 is pyrazolyl. In some embodiments, one R 4 is unsubstituted pyrazolyl. In some embodiments, one R4 is 1-pyrazolyl.

[0114] In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R is a 3-membered heterocyclyl optionally substituted with 4 is one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, R is a 7-9 membered heterocyclyl optionally substituted with 4 The heterocyclyl is a spiro ring. In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one R G In some embodiments, one R 4 are two independently selected R G In some embodiments, one R 4 is an unsubstituted 3- to 6-membered heterocyclyl.

[0115] In some embodiments, one R 4is one or two independently selected R G In some embodiments, one R 4 is one or two independently selected R G In some embodiments, one R 4 is one R G In some embodiments, one R 4 are two independently selected R G In some embodiments, one R 4 is an unsubstituted 3- to 6-membered cycloalkyl.

[0116] In some embodiments, one or two independently selected R G is one R G In some embodiments, one or two independently selected R G are two independently selected R G In some embodiments, two R G When present, they are attached to the same atom, valence permitting. G When present, they are attached to adjacent atoms, valence permitting. G If there are two R G are different. In some embodiments, two R G If there are two R G are the same. In some embodiments, one R G is fluoro. In some embodiments, one R G is cyano. In some embodiments, one R G is hydroxyl. In some embodiments, one R G is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one R Gis 2-hydroxy-2-propyl. In some embodiments, one R G is C1-C6 alkyl. In some embodiments, one R G is C1-C3 alkyl. In some embodiments, one R G is methyl. In some embodiments, one R G is ethyl.

[0117] In some embodiments, one R G is C1-C6 alkoxy. In some embodiments, one R G is C1-C3 alkoxy. In some embodiments, one R G is methoxy.

[0118] In some embodiments, one R G is -NR A1 R B1 In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C3 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is methyl. A1 and R B1 are each C1-C6 alkyl. In some embodiments, R A1 and R B1 are each methyl.

[0119] In some embodiments, R A1and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 haloalkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C3 haloalkyl. A1 and R B1 Each is C1-C6 haloalkyl. In some embodiments, R A1 and R B1 one of which is C1-C6 alkyl, and R A1 and R B1 The other of these is C1-C6 haloalkyl.

[0120] In some embodiments, one R G is =NR A2 In some embodiments, one R G is ═NH. In some embodiments, R A2 is hydrogen. In some embodiments, R A2 is C1-C6 alkyl. In some embodiments, R A2 is methyl.

[0121] In some embodiments, one R G is -C(=O)NR C1 R D1 In some embodiments, one R G is —CO 2 NH 2 . In some embodiments, one R G is —CO 2 NHCH 3 . In some embodiments, R C1 and R D1 Each is hydrogen. In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 alkyl. C1 and R D1is hydrogen, and R C1 and R D1 and the other of R is C1-C3 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is methyl. C1 and R D1 are each C1-C6 alkyl. In some embodiments, R C1 and R D1 are each C1-C3 alkyl. In some embodiments, R C1 and R D1 are each methyl.

[0122] In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 haloalkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C3 haloalkyl. C1 and R D1 Each is C1-C6 haloalkyl. In some embodiments, R C1 and R D1 one of which is C1-C6 alkyl, and R C1 and R D1 The other of these is C1-C6 haloalkyl.

[0123] In some embodiments, one R G is —CO2(C1-C6 alkyl). In some embodiments, one R G is —CO2CH3. In some embodiments, one R G is C1-C6 haloalkyl. In some embodiments, one R Gis trifluoromethyl. In some embodiments, one R G is difluoromethyl. In some embodiments, one R G is C-C cycloalkyl. In some embodiments, one R G is cyclopropyl. In some embodiments, one R G is -CO2H.

[0124] In some embodiments, one R G is C1-C6 haloalkoxy. In some embodiments, one R G is C1-C3 haloalkoxy. In some embodiments, one R G is difluoromethoxy. In some embodiments, one R G is trifluoromethoxy.

[0125] In some embodiments, one R G is —SO2(C1-C6 alkyl). In some embodiments, one R G is -SO2CH3.

[0126] In some embodiments, R 4 In some embodiments, the 3- to 9-membered heterocyclyl is a 3- to 6-membered heterocyclyl. 4 In some embodiments, the 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4 The 3- to 6-membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. 4 The 3-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. 4 The 3- to 9-membered heterocyclyl is [ka] In some embodiments, R 4 3-9 membered heterocyclyl (e.g., R 4 3-6 membered heterocyclyl) is [ka] wherein Q is a C1-C3 alkylene in which one or more carbons are optionally replaced by -C(=O)-, NH, O, or S. In some embodiments, Q is a C1-C3 alkylene in which one or more carbons are optionally replaced by -C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene in which one or more carbons are optionally replaced by -C(=O)- or NH. In some embodiments, R 4 The 3- to 9-membered heterocyclyl is [ka] is selected from the group consisting of:

[0127] In some embodiments, one R 4 is an unsubstituted 3-6 membered heterocyclyl. In some embodiments, R 4 In some embodiments, the 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4 is azetidinyl, morpholinyl, or tetrahydropyranyl. In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0128] In some embodiments, [ka] teeth, [ka] wherein X is N and CR 4A2Selected from R 4A1 and R 4A2 are independently hydrogen, -NR A R B C1-C3 alkyl optionally substituted with methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), —SO2(C1-C6 alkyl), and one or two independently selected R G and one or two independently selected R G In some embodiments, X is selected from 3-6 membered cycloalkyl optionally substituted by CR 4A2 In some embodiments, R 4A1 and, if present, R 4A2 are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, —C(═O)NH, —C(═O)NHMe, —SONH, —SOMe, and azetidinyl optionally substituted with 1 to 2 independently selected fluoro, hydroxyl, or methyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, X is N and R 4A1 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl optionally substituted with C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0129] In some embodiments, X is N and R 4A1is selected from amino, or azetidinyl optionally substituted with one to two independently selected fluoro, hydroxyl, or methyl.

[0130] In some embodiments, [ka] teeth, [ka] where R 4B is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl. G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0131] In some embodiments, [ka] teeth, [ka] where R 4B is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, —C(O)Me, —C(O)NH, ═NH, difluoromethoxy, —S(O)Me, —COH, C-C haloalkyl, and C-C alkyl. In some embodiments, R G1is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, —C(O)Me, —C(O)NH, ═NH, difluoromethoxy, —S(O)Me, —COH, C-C haloalkyl, and C-C alkyl. G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0132] In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R Band the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxyl-1-propyl or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R Bare each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0133] In some embodiments, R 4B is an amino or has one nitrogen atom and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0134] In some embodiments, R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, each optionally containing 1-2 =O, and 1-2 R each independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. G In some embodiments, R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is selected from 1 to 2 R, each independently selected from fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, —COCH, and C-C alkyl. G In some embodiments, R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is selected from 1 to 2 R, each independently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. G In some embodiments, R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, and contains 1 to 2 R, each independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G In some embodiments, Ring B is azetidinyl.

[0135] In some embodiments, ring B is unsubstituted.

[0136] In some embodiments, ring B contains one R G In some embodiments, R G is fluoro. In some embodiments, R G is cyano. In some embodiments, R G is amino. In some embodiments, R G is hydroxyl. In some embodiments, R G is C1-C3 alkyl. In some embodiments, R G is methyl. In some embodiments, R G is ethyl. In some embodiments, R G is —CO2CH3. In some embodiments, R G is methoxy. In some embodiments, R G is methoxy.

[0137] In some embodiments, ring B is selected from two R G In some embodiments, each R Gis fluoro. In some embodiments, each R G is C1-C3 alkyl. In some embodiments, each R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is ethyl. In some embodiments, one R G is amino, and the other R G is methyl. In some embodiments, one R G is hydroxyl, and the other R G is cyclopropyl. In some embodiments, one R G is fluoro and the other R G1 is methyl. In some embodiments, one R G is hydroxyl, and the other R G is fluoro. In some embodiments, one R G is hydroxyl, and the other R G is trifluoromethyl. In some embodiments, each R G is attached to ring B in the para position relative to the nitrogen attached to ring A.

[0138] In some embodiments, [ka] teeth, [ka] wherein one or two independently selected R G is attached at the 3-position of the azetidine. [ka] teeth, [ka] In some embodiments, the compound is selected from the group consisting of: [ka] teeth, [ka] In some embodiments, the compound is selected from the group consisting of: [ka] teeth, [ka] is selected from the group consisting of:

[0139] In some embodiments, Z is O.

[0140] In some embodiments, Z is NR x is.

[0141] In some embodiments, R x is hydrogen.

[0142] In some embodiments, R x is C1-C6 alkyl. In some embodiments, R x is C1-C3 alkyl. In some embodiments, R x is methyl. In some embodiments, R x is ethyl. In some embodiments, R x is n-propyl. In some embodiments, R x is isopropyl.

[0143] In some embodiments, R x is C-C cycloalkyl. In some embodiments, R x is C-C cycloalkyl. In some embodiments, R xis cyclopropyl. In some embodiments, R x is cyclobutyl.

[0144] In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0145] In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 haloalkyl. In some embodiments, each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is trifluoromethyl.

[0146] In some embodiments, m is 2 and one R 4 is a halogen, and the other R 4 is —SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and the other R 4 is -SO2CH3.

[0147] In some embodiments, m is 2 and one R 4 is C1-C6 alkoxy, and the other R 4 is -C(=O)NR C R D is.

[0148] In some embodiments, m is 2 and one R 4is methoxy, and the other R 4 is —C(O)NHCH 3 . In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -COH, -NH, -C(=O)NH, -C(=O)NHMe, -SONH, -SONHMe, -SOMe, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0149] In some embodiments, each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0150] In some embodiments, each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4are independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0151] In some embodiments, each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0152] In some embodiments, each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 independently, -NHR B, and 1 to 2 R G and is selected from the group consisting of 4- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0153] In some embodiments, Z is O and each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, Z is O and each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0154] In some embodiments, Z is O and each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 haloalkyl. In some embodiments, Z is O and each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is trifluoromethyl.

[0155] In some embodiments, Z is O, m is 2, and one R 4 is a halogen, and the other R 4 is —SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and the other R 4 is -SO2CH3.

[0156] In some embodiments, Z is O, m is 2, and one R 4 is C1-C6 alkoxy, and the other R 4 is -C(=O)NR C R D is.

[0157] In some embodiments, Z is O, m is 2, and one R 4 is methoxy, and the other R 4 is —C(O)NHCH 3 . In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -COH, -NH, -C(=O)NH, -C(=O)NHMe, -SONH, -SONHMe, -SOMe, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0158] In some embodiments, Z is O, Each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0159] In some embodiments, Z is O, Each R 1 But it is fluoro, m is 1 or 2; R 2is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0160] In some embodiments, Z is O, Each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0161] In some embodiments, Z is O, Each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 independently, -NHR B , and 1 to 2 R G and is selected from the group consisting of 4- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0162] In some embodiments, Z is NR x and each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 alkyl. In some embodiments, Z is NR x and each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0163] In some embodiments, Z is NR x and each R 1 is fluoro, m is 1 or 2, and R 2 is a C1-C6 alkyl, and R 3 is C1-C6 haloalkyl. In some embodiments, Z is O and each R 1 is fluoro, m is 1 or 2, and R 2 is methyl and R 3 is trifluoromethyl.

[0164] In some embodiments, Z is NR x where m is 2 and one R 4 is a halogen, and the other R 4is —SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and the other R 4 is -SO2CH3.

[0165] In some embodiments, Z is NR x where m is 2 and one R 4 is C1-C6 alkoxy, and the other R 4 is -C(=O)NR C R D is.

[0166] In some embodiments, Z is NR x where m is 2 and one R 4 is methoxy, and the other R 4 is —C(O)NHCH 3 . In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -COH, -NH, -C(=O)NH, -C(=O)NHMe, -SONH, -SONHMe, -SOMe, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0167] In some embodiments, Z is NR x and Each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0168] In some embodiments, Z is NR x and Each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0169] In some embodiments, Z is NR x and Each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; n is 1 or 2.

[0170] In some embodiments, Z is NR x and Each R 1 is fluoro, cyano, or methyl; m is 1 or 2; R 2 is C1-C3 alkyl, R 3 is C1-C3 alkyl or C1-C3 haloalkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 independently, -NHR B , and 1 to 2 R G and is selected from the group consisting of 4- to 6-membered heterocyclyl optionally substituted by n is 1 or 2.

[0171] In some embodiments, the compound of formula (I) has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl; R 4 independently, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G and one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by where R 4 is attached to the ring A1 position, which is para to the N atom of the urea moiety, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, 4- to 6-membered heterocyclyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl, 3- to 6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); RC and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0172] 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.

[0173] 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.

[0174] In some embodiments of formula (IA), [ka] teeth, [ka] where R 4B is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0175] In some embodiments of Formula (IA), R A and R B are each hydrogen.

[0176] In some embodiments of Formula (IA), R A and R B Each is a 4- to 6-membered heterocyclyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is 1,1-dioxidetetrahydrothiophen-3-yl. A and R B is hydrogen, and R A and R B The other of is a 6-membered heterocyclyl.

[0177] In some embodiments of Formula (IA), R A and R B are each C1-C6 haloalkyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R Band the other of R is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 haloalkyl. A and R B one of which is C1-C6 alkyl, and R A and R B The other of these is C1-C6 haloalkyl.

[0178] In some embodiments of Formula (IA), R A and R B Each is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is an unsubstituted 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R Band the other of R is a 4-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is cis- or trans-3-hydroxycyclobutyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 6-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B one of which is C1-C6 alkyl, and R A and R B The other of is a 3- to 6-membered cycloalkyl substituted with hydroxyl.

[0179] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and RA and R B and the other of R is a C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxy 1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B The other of these is methyl.

[0180] In some embodiments of Formula (IA), R A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (IA), R A and R B are each C1-C6 alkyl. In some embodiments of Formula (IA), R A and R B are each C1-C3 alkyl. In some embodiments of Formula (IA), R A and R B are each methyl.

[0181] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R Aand R B and the other of R is a C1-C3 alkyl substituted with a 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with a 3-4 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-4 membered cycloalkyl and a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (IA), R A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B are both C1-C6 alkyl substituted with 3- to 6-membered cycloalkyl.

[0182] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R Band the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2CH3, for example, 1-(methylsulfonyl)propan-2-yl. A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B are both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0183] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R Band the other of R is C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl. In some embodiments of Formula (IA), R A and R B one of which is a C1-C6 alkyl hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formula (IA), R A and R B are both C1-C6 alkyl substituted with -SO2(NH2).

[0184] In some embodiments of Formula (IA), R 4B contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0185] In some embodiments of Formula (IA), R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, and contains 1 to 2 R, each independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G In some embodiments of Formula (IA), Ring B is azetidinyl.

[0186] In some embodiments of formula (IA), ring B is unsubstituted.

[0187] In some embodiments of formula (IA), ring B contains one R G In some embodiments of formula (IA), R G is fluoro. In some embodiments of Formula (IA), R Gis cyano. In some embodiments of Formula (IA), R G is hydroxyl. In some embodiments of Formula (IA), R G is C1-C3 alkyl. In some embodiments of Formula (IA), R G is methyl. In some embodiments of Formula (IA), R G is -CO2CH3.

[0188] In some embodiments of Formula (IA), ring B is selected from two independently selected R G In some embodiments of Formula (IA), each R G In some embodiments of Formula (IA), each R G is C1-C3 alkyl. In some embodiments of Formula (IA), each R G is methyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G is C1-C3 alkyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G is methyl. In some embodiments of Formula (IA), one R G is fluoro and the other R G is C1-C3 alkyl. In some embodiments of Formula (IA), one R G is fluoro and the other R G is methyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G is trifluoromethyl.

[0189] In some embodiments of formula (IA), [ka] teeth, [ka] wherein one or two independently selected R G is at the 3-position of the azetidine. In some embodiments of Formula (IA), [ka] teeth, [ka] In some embodiments of formula (IA), [ka] teeth, [ka] is selected from the group consisting of:

[0190] In some embodiments, the compound of formula (I) has formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R 4 independently, -NR A R BC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G and one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, 4- to 6-membered heterocyclyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl, 3- to 6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1, —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0191] In some embodiments, R 1A and R 1B are each fluoro.

[0192] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0193] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is trifluoromethyl.

[0194] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is isopropyl.

[0195] In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is trifluoromethyl.

[0196] In some embodiments, R 3is C-C cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C-C alkyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 3 In some embodiments, the C3-C6 cycloalkyl in R is cyclopropyl. 3 is cyclopropyl.

[0197] In some embodiments, R 4 is -NR A R B In some embodiments, R 4 is -NR A R B In some embodiments, R 4 is -NR A R B In some embodiments, R 4 is C1-C4 alkyl. In some embodiments, R 4 is methyl.

[0198] In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, R 4 is methoxy.

[0199] In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R4 is trifluoromethyl.

[0200] In some embodiments, R 4 is hydroxyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is —COH. In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R Bis hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxyl-1-propyl or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and RB are each methyl.

[0201] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 haloalkyl. A and R B Each is C1-C6 haloalkyl. In some embodiments, R A and R B one of which is C1-C6 alkyl, and R A and R B and one of the other is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 haloalkyl. A and R B one of which is C1-C6 alkyl, and R A and R B The other of these is C1-C6 haloalkyl.

[0202] In some embodiments, R A and R B Each R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4-membered heterocyclyl. A and R B is hydrogen, and R A and R Band the other of R is a 5-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is 1,1-dioxidetetrahydrothiophen-3-yl. A and R B is hydrogen, and R A and R B The other of is a 6-membered heterocyclyl.

[0203] In some embodiments, R A and R B Each R is a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is an unsubstituted 3- to 6-membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R Band the other of R is a 4-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is cis- or trans-3-hydroxycyclobutyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 6-membered cycloalkyl optionally substituted with hydroxyl. A and R B one of which is C1-C6 alkyl, and R A and R B The other of is a 3- to 6-membered cycloalkyl substituted with hydroxyl.

[0204] In some embodiments, R A and R B is hydrogen, and R A and R B The other of is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2).

[0205] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R Aand R B and the other of R is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-4 membered cycloalkyl and a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B are both C1-C6 alkyl substituted with 3- to 6-membered cycloalkyl.

[0206] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). A and R Bis hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). A and R B is hydrogen, and R A and R B and the other of R is C-C alkyl substituted with -SOCH, e.g., 1-(methylsulfonyl)propan-2-yl. A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). A and R B are both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl. A and R B one of which is a C1-C6 alkyl hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). Aand R B are both C1-C6 alkyl substituted with -SO2(NH2).

[0207] In some embodiments, one R 4 is -C(=O)NR C R D In some embodiments, R C and R D Each is hydrogen. In some embodiments, R C and R D is hydrogen, and R C and R D and the other of R is C1-C6 alkyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C3 alkyl. C and R D is hydrogen, and R C and R D and the other of R is methyl. C and R D are each C1-C6 alkyl. In some embodiments, R C and R D are each C1-C3 alkyl. In some embodiments, R C and R D Each R is methyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C6 haloalkyl. C and R D Each is C1-C6 haloalkyl. In some embodiments, R C and R D one of which is C1-C6 alkyl, and R C and R D and the other of R is C1-C6 haloalkyl.C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0208] In some embodiments, one R 4 is -SO2(NR E R F In some embodiments, R E and R F Each is hydrogen. In some embodiments, R E and R F is hydrogen, and R E and R F and the other of R is C1-C6 alkyl. E and R F is hydrogen, and R E and R F and the other of R is methyl. E and R F are each C1-C6 alkyl. In some embodiments, R E and R F are each C1-C3 alkyl. In some embodiments, R E and R F Each R is methyl. E and R F is hydrogen, and R E and R F and the other of R is C1-C6 haloalkyl. E and R F Each is C1-C6 haloalkyl. In some embodiments, R E and R F one of which is C1-C6 alkyl, and R E and R F The other of these is C1-C6 haloalkyl.

[0209] In some embodiments, R 4 is —SO2(C1-C6 alkyl). In some embodiments, R 4 is —SO2(C1-C3 alkyl). In some embodiments, R 4 is -SOMe. In some embodiments, R 4 is -SO2Et.

[0210] In some embodiments, R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 is -S(=O)(=NH)Me.

[0211] In some embodiments, R 4 is —C(═O)(C1-C6 alkyl). In some embodiments, R 4 is —C(═O)(C1-C3 alkyl). In some embodiments, R 4 is -C(=O)Me.

[0212] In some embodiments, R 4 is —CO2(C1-C6 alkyl). In some embodiments, R 4 is —CO2(C1-C3 alkyl). In some embodiments, R 4 is -CO2Me.

[0213] In some embodiments, one R 4 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R 4 is a 5-6 membered heteroaryl. In some embodiments, R 4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. 4 is pyrazolyl. In some embodiments, one R 4 is tetrazolyl substituted with methyl. In some embodiments, one R 4 is pyrazolyl. In some embodiments, one R 4 is unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolyl.

[0214] In some embodiments, R 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl optionally substituted with 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 is one R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 are two independently selected R G is a 3- to 6-membered heterocyclyl substituted with

[0215] In some embodiments, R G is fluoro. In some embodiments, R G is cyano. In some embodiments, R G is hydroxyl. In some embodiments, R G is C1-C6 alkyl. In some embodiments, R G is C1-C3 alkyl. In some embodiments, R G is methyl.

[0216] In some embodiments, R G is C1-C6 alkoxy. In some embodiments, R G is C1-C3 alkoxy. In some embodiments, R G is methoxy.

[0217] In some embodiments, one R G is -NR A1 R B1 In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C3 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is methyl. A1 and R B1 are each C1-C6 alkyl. In some embodiments, R A1 and R B1 are each C1-C3 alkyl. In some embodiments, R A1 and R B1 are each methyl.

[0218] In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 haloalkyl. A1 and R B1Each is C1-C6 haloalkyl. In some embodiments, R A1 and R B1 one of which is C1-C6 alkyl, and R A1 and R B1 The other of these is C1-C6 haloalkyl.

[0219] In some embodiments, one R G is -C(=O)NR C1 R D1 In some embodiments, R C1 and R D1 Each is hydrogen. In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C3 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is methyl. C1 and R D1 are each C1-C6 alkyl. In some embodiments, R C1 and R D1 Each R is methyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 haloalkyl. C1 and R D1 Each is C1-C6 haloalkyl. In some embodiments, R C1 and R D1 one of which is C1-C6 alkyl, and R C1 and R D1The other of these is C1-C6 haloalkyl.

[0220] In some embodiments, one R G is —CO2(C1-C6 alkyl). In some embodiments, one R G is -CO2CH3.

[0221] In some embodiments, one R G is C1-C6 haloalkyl. In some embodiments, one R G is trifluoromethyl.

[0222] In some embodiments, one R G is C-C cycloalkyl. In some embodiments, one R G is cyclopropyl.

[0223] In some embodiments, R G is -CO2H.

[0224] In some embodiments, R 4 In some embodiments, the 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4 The 3- to 6-membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. 4 The 3- to 6-membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0225] In some embodiments, R 4 is an unsubstituted 3-6 membered heterocyclyl. In some embodiments, R 4 is a 5- to 6-membered heterocyclyl. In some embodiments, R 4 is azetidinyl, morpholinyl, or tetrahydropyranyl.

[0226] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0227] In some embodiments, R 4 is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0228] In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R Band the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxyl-1-propyl or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and RB and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0229] In some embodiments, R 4 contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0230] In some embodiments, the compound of formula (I) has the formula (IC): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NRE R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and —COH.

[0231] In some embodiments, the compound of formula (I) has the formula (ID): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0232] In some embodiments, the compound of formula (I) has the formula (IE): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R Gare independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0233] In some embodiments, the compound of formula (I) has the formula (IF): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , RB1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H, wherein the compound is [ka] isn't it.

[0234] Some embodiments provide a compound of formula (IF), wherein the compound is [ka] is not a compound selected from the group consisting of:

[0235] In some embodiments, the compound of formula (I) has the formula (IG): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0236] In some embodiments, the compound of Formula (I) has the formula (IH): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen, cyano, cyclopropyl, or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl or C1-C6 haloalkyl, R 4 are independently selected from C1-C6 alkyl, hydroxyl, and C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR A R B and one or two independently selected R G and 3- to 9-membered heterocyclyl optionally substituted by Each R A , R B , R C1 , and R D1 are independently hydrogen, 4- to 6-membered heterocyclyl, hydroxyl, or —C(═O)NR B2 R C2 C1-C6 alkyl, —C(═O)O(C1-C6 alkyl), or C1-C6 haloalkyl optionally substituted by Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, ═NR A2 , -C(=O)NR C1 RD1 , C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H.

[0237] In some embodiments, the compound of formula (I) has formula (IJ): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl; R 4 independently, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R Gand one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by where R 4 is attached to the ring A1 position, which is para to the N atom of the urea moiety, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, 4- to 6-membered heterocyclyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl, 3- to 6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0238] 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.

[0239] 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.

[0240] In some embodiments of formula (IA), [ka] teeth, [ka] where R 4B is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0241] In some embodiments of Formula (IA), R A and R B are each hydrogen.

[0242] In some embodiments of Formula (IA), R A and R B Each is a 4- to 6-membered heterocyclyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4-membered heterocyclyl. A and R Bis hydrogen, and R A and R B and the other of R is a 5-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is 1,1-dioxidetetrahydrothiophen-3-yl. A and R B is hydrogen, and R A and R B The other of is a 6-membered heterocyclyl.

[0243] In some embodiments of Formula (IA), R A and R B are each C1-C6 haloalkyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 haloalkyl. A and R B one of which is C1-C6 alkyl, and R A and R B The other of these is C1-C6 haloalkyl.

[0244] In some embodiments of Formula (IA), R A and R B Each is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R Band the other of R is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is an unsubstituted 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 4-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is cis- or trans-3-hydroxycyclobutyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a 6-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R Bone of which is C1-C6 alkyl, and R A and R B The other of is a 3- to 6-membered cycloalkyl substituted with hydroxyl.

[0245] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R Bis hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxy 1-propyl or 1-hydroxy-2-propyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B The other of these is methyl.

[0246] In some embodiments of Formula (IA), R A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (IA), R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of RA and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments of Formula (IA), R A and R B are each C1-C6 alkyl. In some embodiments of Formula (IA), R A and R B are each C1-C3 alkyl. In some embodiments of Formula (IA), R A and R B are each methyl.

[0247] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with a 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with a 3-4 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-4 membered cycloalkyl and a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with cyclopropyl and hydroxyl.A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments of Formula (IA), R A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B are both C1-C6 alkyl substituted with 3- to 6-membered cycloalkyl.

[0248] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2CH3, for example, 1-(methylsulfonyl)propan-2-yl. A and R Bone of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (IA), R A and R B are both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0249] In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formula (IA), R A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl. In some embodiments of Formula (IA), R A and R B one of which is a C1-C6 alkyl hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of Formula (IA), R A and R B are both C1-C6 alkyl substituted with -SO2(NH2).

[0250] In some embodiments of Formula (IA), R 4B contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0251] In some embodiments of Formula (IA), R 4B teeth, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, and contains 1 to 2 R, each independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G In some embodiments of Formula (IA), Ring B is azetidinyl.

[0252] In some embodiments of formula (IA), ring B is unsubstituted.

[0253] In some embodiments of formula (IA), ring B contains one R G In some embodiments of formula (IA), R G is fluoro. In some embodiments of Formula (IA), R G is cyano. In some embodiments of Formula (IA), R G is hydroxyl. In some embodiments of Formula (IA), R G is C1-C3 alkyl. In some embodiments of Formula (IA), R G is methyl. In some embodiments of Formula (IA), R G is -CO2CH3.

[0254] In some embodiments of Formula (IA), ring B is selected from two independently selected R G In some embodiments of Formula (IA), each R G In some embodiments of Formula (IA), each R G is C1-C3 alkyl. In some embodiments of Formula (IA), each R G is methyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G is C1-C3 alkyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other RG is methyl. In some embodiments of Formula (IA), one R G is fluoro and the other R G is C1-C3 alkyl. In some embodiments of Formula (IA), one R G is fluoro and the other R G is methyl. In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G In some embodiments of Formula (IA), one R G is hydroxyl, and the other R G is trifluoromethyl.

[0255] In some embodiments of formula (IA), [ka] teeth, [ka] wherein one or two independently selected R G is at the 3-position of the azetidine. In some embodiments of Formula (IA), [ka] teeth, [ka] In some embodiments of formula (IA), [ka] teeth, [ka] is selected from the group consisting of:

[0256] In some embodiments, the compound of Formula (I) has the formula (IK): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R 4 independently, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G and one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , RD , R D1 , R E , and R F are independently hydrogen, 4- to 6-membered heterocyclyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl, 3- to 6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0257] In some embodiments, R 1A and R 1B are each fluoro.

[0258] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0259] In some embodiments, R 2 is C1-C6 haloalkyl. In some embodiments, R 2 is C1-C3 haloalkyl. In some embodiments, R 2 is trifluoromethyl.

[0260] In some embodiments, R 3is C1-C6 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is isopropyl.

[0261] In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C1-C3 haloalkyl. In some embodiments, R 3 is trifluoromethyl.

[0262] In some embodiments, R 3 is C-C cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C-C alkyl. In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with one or two fluoro. In some embodiments, R 3 is a C-C cycloalkyl substituted with one or two fluoro. In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 3 In some embodiments, the C3-C6 cycloalkyl in R is cyclopropyl. 3 is cyclopropyl.

[0263] In some embodiments, R 4 is -NR A R B In some embodiments, R 4 is -NR A R B In some embodiments, R4 is -NR A R B In some embodiments, R 4 is C1-C4 alkyl. In some embodiments, R 4 is methyl.

[0264] In some embodiments, R 4 is C1-C6 alkoxy. In some embodiments, R 4 is C1-C3 alkoxy. In some embodiments, R 4 is methoxy.

[0265] In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is trifluoromethyl.

[0266] In some embodiments, R 4 is hydroxyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is —COH. In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R Band the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxyl-1-propyl or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R A and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R Band the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0267] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 haloalkyl. A and R B Each is C1-C6 haloalkyl. In some embodiments, R A and R B one of which is C1-C6 alkyl, and R A and R B and one of the other is C1-C6 haloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 haloalkyl. A and R B one of which is C1-C6 alkyl, and R A and R BThe other of these is C1-C6 haloalkyl.

[0268] In some embodiments, R A and R B Each R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4- to 6-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 4-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered heterocyclyl. A and R B is hydrogen, and R A and R B and the other of R is 1,1-dioxidetetrahydrothiophen-3-yl. A and R B is hydrogen, and R A and R B The other of is a 6-membered heterocyclyl.

[0269] In some embodiments, R A and R B Each R is a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R Aand R B and the other of R is a 3-6 membered cycloalkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is an unsubstituted 3- to 6-membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 4-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is cis- or trans-3-hydroxycyclobutyl. A and R B is hydrogen, and R A and R B and the other of R is a 5-membered cycloalkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a 6-membered cycloalkyl optionally substituted with hydroxyl. A and R B one of which is C1-C6 alkyl, and R A and R B The other of is a 3- to 6-membered cycloalkyl substituted with hydroxyl.

[0270] In some embodiments, R A and R Bis hydrogen, and R A and R B The other of is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2).

[0271] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. A and R B is hydrogen, and R A and R B and the other of R is a 3-4 membered cycloalkyl and a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. A and R Bone of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. A and R B are both C1-C6 alkyl substituted with 3- to 6-membered cycloalkyl.

[0272] In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). A and R B is hydrogen, and R A and R B and the other of R is C-C alkyl substituted with -SOCH, e.g., 1-(methylsulfonyl)propan-2-yl. A and R B one of which is C1-C6 alkyl, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). A and R B are both C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R Bis hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropan-2-yl. A and R B one of which is a C1-C6 alkyl hydrogen, and R A and R B and the other of R is C1-C6 alkyl substituted with -SO2(NH2). A and R B are both C1-C6 alkyl substituted with -SO2(NH2).

[0273] In some embodiments, one R 4 is -C(=O)NR C R D In some embodiments, R C and R D Each is hydrogen. In some embodiments, R C and R D is hydrogen, and R C and R D and the other of R is C1-C6 alkyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C3 alkyl. C and R D is hydrogen, and R C and R D and the other of R is methyl. C and R D are each C1-C6 alkyl. In some embodiments, R C and RD are each C1-C3 alkyl. In some embodiments, R C and R D Each R is methyl. C and R D is hydrogen, and R C and R D and the other of R is C1-C6 haloalkyl. C and R D Each is C1-C6 haloalkyl. In some embodiments, R C and R D one of which is C1-C6 alkyl, and R C and R D and the other of R is C1-C6 haloalkyl. C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0274] In some embodiments, one R 4 is -SO2(NR E R F In some embodiments, R E and R F Each is hydrogen. In some embodiments, R E and R F is hydrogen, and R E and R F and the other of R is C1-C6 alkyl. E and R F is hydrogen, and R E and R F and the other of R is methyl. E and R F are each C1-C6 alkyl. In some embodiments, R E and R Fare each C1-C3 alkyl. In some embodiments, R E and R F Each R is methyl. E and R F is hydrogen, and R E and R F and the other of R is C1-C6 haloalkyl. E and R F Each is C1-C6 haloalkyl. In some embodiments, R E and R F one of which is C1-C6 alkyl, and R E and R F The other of these is C1-C6 haloalkyl.

[0275] In some embodiments, R 4 is —SO2(C1-C6 alkyl). In some embodiments, R 4 is —SO2(C1-C3 alkyl). In some embodiments, R 4 is -SOMe. In some embodiments, R 4 is -SO2Et.

[0276] In some embodiments, R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 is -S(=O)(=NH)Me.

[0277] In some embodiments, R 4 is —C(═O)(C1-C6 alkyl). In some embodiments, R 4 is —C(═O)(C1-C3 alkyl). In some embodiments, R 4 is -C(=O)Me.

[0278] In some embodiments, R 4is —CO2(C1-C6 alkyl). In some embodiments, R 4 is —CO2(C1-C3 alkyl). In some embodiments, R 4 is -CO2Me.

[0279] In some embodiments, one R 4 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R 4 is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R 4 is a 5-6 membered heteroaryl. In some embodiments, R 4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. 4 is pyrazolyl. In some embodiments, one R 4 is tetrazolyl substituted with methyl. In some embodiments, one R 4 is pyrazolyl. In some embodiments, one R 4 is unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolyl.

[0280] In some embodiments, R 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl optionally substituted with 4 is one or two independently selected R G In some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 is one R GIn some embodiments, R is a 3- to 6-membered heterocyclyl substituted with 4 are two independently selected R G is a 3- to 6-membered heterocyclyl substituted with

[0281] In some embodiments, R G is fluoro. In some embodiments, R G is cyano. In some embodiments, R G is hydroxyl. In some embodiments, R G is C1-C6 alkyl. In some embodiments, R G is C1-C3 alkyl. In some embodiments, R G is methyl.

[0282] In some embodiments, R G is C1-C6 alkoxy. In some embodiments, R G is C1-C3 alkoxy. In some embodiments, R G is methoxy.

[0283] In some embodiments, one R G is -NR A1 R B1 In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C3 alkyl. A1 and R B1 is hydrogen, and R A1 and R B1and the other of R is methyl. A1 and R B1 are each C1-C6 alkyl. In some embodiments, R A1 and R B1 are each C1-C3 alkyl. In some embodiments, R A1 and R B1 are each methyl.

[0284] In some embodiments, R A1 and R B1 is hydrogen, and R A1 and R B1 and the other of R is C1-C6 haloalkyl. A1 and R B1 Each is C1-C6 haloalkyl. In some embodiments, R A1 and R B1 one of which is C1-C6 alkyl, and R A1 and R B1 The other of these is C1-C6 haloalkyl.

[0285] In some embodiments, one R G is -C(=O)NR C1 R D1 In some embodiments, R C1 and R D1 Each is hydrogen. In some embodiments, R C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C3 alkyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is methyl.C1 and R D1 are each C1-C6 alkyl. In some embodiments, R C1 and R D1 Each R is methyl. C1 and R D1 is hydrogen, and R C1 and R D1 and the other of R is C1-C6 haloalkyl. C1 and R D1 Each is C1-C6 haloalkyl. In some embodiments, R C1 and R D1 one of which is C1-C6 alkyl, and R C1 and R D1 The other of these is C1-C6 haloalkyl.

[0286] In some embodiments, one R G is —CO2(C1-C6 alkyl). In some embodiments, one R G is -CO2CH3.

[0287] In some embodiments, one R G is C1-C6 haloalkyl. In some embodiments, one R G is trifluoromethyl.

[0288] In some embodiments, one R G is C-C cycloalkyl. In some embodiments, one R G is cyclopropyl.

[0289] In some embodiments, R G is -CO2H.

[0290] In some embodiments, R 4 In some embodiments, the 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl. 4The 3- to 6-membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. 4 The 3- to 6-membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0291] In some embodiments, R 4 is an unsubstituted 3-6 membered heterocyclyl. In some embodiments, R 4 is a 5- to 6-membered heterocyclyl. In some embodiments, R 4 is azetidinyl, morpholinyl, or tetrahydropyranyl.

[0292] In some embodiments, R 4 teeth, [ka] is selected from the group consisting of:

[0293] In some embodiments, R 4 is -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0294] In some embodiments, R A and R B Each is hydrogen. In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and RA and R B and the other of R is C1-C6 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C6 alkyl. A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl optionally substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B is hydrogen, and R A and R B and the other of R is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B is hydrogen, and R A and R B and the other of R is a propyl substituted with a hydroxyl (e.g., 2-hydroxyl-1-propyl or 1-hydroxy-2-propyl). A and R B is hydrogen, and R A and R B and the other of R is C1-C3 alkyl. A and R B is hydrogen, and R A and R B and the other of R is methyl. A and R B Each is a C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and R B are each C1-C6 alkyl substituted with hydroxyl. In some embodiments, R A and R B one of which is C1-C3 alkyl, and R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is a C1-C3 alkyl substituted with hydroxyl. A and R B one of R A and R B and the other of R is ethyl substituted with a hydroxyl (e.g., 2-hydroxy-1-propyl). A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each C1-C3 alkyl. In some embodiments, R A and R B are each methyl.

[0295] In some embodiments, R 4 contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0296] In some embodiments, the compound of formula (I) has the formula (IL): [ka] or a pharmaceutically acceptable salt thereof, wherein: R xis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R Gare independently fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 and —COH.

[0297] In some embodiments, the compound of formula (I) has the formula (IM): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , RB , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0298] In some embodiments, the compound of formula (I) has the formula (IN): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0299] In some embodiments, the compound of formula (I) has the formula (IO): [ka] or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R Gare independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0300] In some embodiments, the compound of formula (I) has the formula (IP): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 4 are independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -COH, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F are independently hydrogen, or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with hydroxyl; R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and —CO2H.

[0301] In some embodiments, the compound of Formula (I) has the formula (IQ): [ka] or a pharmaceutically acceptable salt thereof, wherein: R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A is a halogen, R 1B is halogen, cyano, cyclopropyl, or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl or C1-C6 haloalkyl, R 4are independently selected from C1-C6 alkyl, hydroxyl, and C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR A R B and one or two independently selected R G and 3- to 9-membered heterocyclyl optionally substituted by Each R A , R B , R C1 , and R D1 are independently hydrogen, 4- to 6-membered heterocyclyl, hydroxyl, or —C(═O)NR B2 R C2 C1-C6 alkyl, —C(═O)O(C1-C6 alkyl), or C1-C6 haloalkyl optionally substituted by Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, ═NR A2 , -C(=O)NR C1 R D1 , C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H.

[0302] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein, wherein the compound is [ka] is not a compound selected from the group consisting of:

[0303] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein, wherein the compound is [ka] is not a compound selected from the group consisting of:

[0304] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein, wherein the compound is [ka] is not a compound selected from the group consisting of:

[0305] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein.

[0306] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein.

[0307] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and ring A are as described herein.

[0308] Non-limiting exemplary compounds In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-195 (eg, compounds 1-276), or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table A, or a pharmaceutically acceptable salt thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] [Table 4-17] [Table 4-18] [Table 4-19] [Table 4-20] [Table 4-21]

[0310] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table B, or a pharmaceutically acceptable salt thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

Table 5-20

Table 5-21

[0311] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table C, or a pharmaceutically acceptable salt thereof. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19] [Table 6-20] [Table 6-21]

[0312] In some embodiments, the compound is selected from the group consisting of the compounds depicted in Table D, or a pharmaceutically acceptable salt thereof. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7]

[0313] Pharmaceutical Compositions and Administration General Provisions In some embodiments, the chemical entity (e.g., a compound that inhibits PI3Kα, or a pharmaceutically acceptable salt thereof) is administered as a pharmaceutical composition comprising a chemical entity described herein and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents.

[0314] In some embodiments, the chemical substance can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamer, or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, and wool fat. Cyclodextrins, e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives, e.g., hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared containing 0.005% to 100% of the chemical entities described herein, with the remainder consisting of pharmaceutically acceptable excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of the chemical entities provided herein. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd Edition (Pharmaceutical Press, London, UK. 2012).

[0315] Route of Administration and Composition Components In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, intrainterstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraintestinal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0316] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal route.Typically, such compositions can be prepared as injections, either as solution or suspension, and solid forms suitable for preparing solution or suspension by adding liquid before injection can also be prepared, and the preparation can also be emulsified.The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[0317] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions; formulations containing 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 fluid to the extent that it can be easily injected. It must also be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

[0318] The carrier can also 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. 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 dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the composition of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0319] Sterile injection solution is prepared by incorporating the required amount of active compound into suitable solvent, which contains various other components as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active components into a sterile vehicle that contains basic dispersion medium and other components as listed above that are required.For the preparation of sterile powder for sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying technology, which can obtain the powder of active component that contains any additional desired components from the solution that has been previously sterilized and filtered.

[0320] Intratumoral injection is discussed, for example, in Lammers, et al., "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems," Neoplasia. 2006, 10, 788-795.

[0321] Pharmaceutically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, a mixture of polyethylene glycols of various molecular weights and a fatty acid ester of polyethylene glycol called Vaseline, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, edetate sodium, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0322] In certain embodiments, suppositories may 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 will melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[0323] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract using oral administration (eg, solid or liquid dosage form).

[0324] 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, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using pharmaceutically acceptable excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0325] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, etc., a lubricant such as magnesium stearate, etc., and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, spherical granules, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated, such as capsules (or tablets within capsules) containing granules of each drug, bilayer tablets, bicompartment gel capsules, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0326] 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.

[0327] In certain embodiments, the pharmaceutically acceptable excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage forms, such as tablets and capsules, the pharmaceutically acceptable excipients do not require sterility. USP / NF standards are usually sufficient.

[0328] In certain embodiments, the solid oral dosage form may further comprise one or more components that chemically and / or structurally direct the composition to facilitate delivery of the chemical to the stomach or lower GI, for example, the ascending colon and / or the transverse colon and / or the distal colon and / or the small intestine. Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0329] Examples include upper GI targeting techniques such as accordion pills (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0330] Other examples include lower GI targeting techniques. Several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available for targeting various regions of the intestinal tract. These materials are typically polymers designed to dissolve or erode at a specific pH range, selected based on the GI region where drug release is desired. These materials also function to protect acid-labile drugs from gastric fluids or limit exposure if the active ingredient may be irritating to the upper GI tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer), and Marcoat). Other techniques include dosage forms that respond to local bacterial flora in the GI tract, pressure-controlled colonic delivery capsules, and Pulsincap.

[0331] The intraocular compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin), preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0332] Topical compositions can include ointments and creams. Ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol, while the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a moisturizer. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0333] In any of the above-described embodiments, the pharmaceutical compositions described herein may include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0334] Dosage Dosage amounts may vary depending on the needs of the patient, the severity of the condition being treated, and the particular compound being used. Determination of the proper dosage for a particular situation can be determined by a medical professional. The total daily dosage may be divided and administered in smaller amounts throughout the day, or by means providing continuous delivery.

[0335] In some embodiments, the compounds described herein are administered in a dose range of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg, about 0.01 mg / Kg to about 200 mg / Kg, about 0.01 mg / Kg to about 150 mg / Kg, about 0.01 mg / Kg to about 100 mg / Kg, about 0.01 mg / Kg to about 50 mg / Kg, about 0.01 mg / Kg to about 10 mg / Kg, about 0.01 mg / Kg to about 5 mg / Kg, about 0.01 mg / Kg to about 1 mg / Kg, about 0.01mg / Kg to about 0.5mg / Kg, about 0.01mg / Kg to about 0.1mg / Kg, about 0.1mg / Kg to about 200mg / Kg, about 0.1mg / Kg to about 150mg / Kg, about 0.1mg / Kg to about 100mg / Kg, about 0.1mg / Kg to about 50mg / Kg, about 0.1mg / Kg to about 10mg / Kg, about 0.1mg / Kg to about 5mg / Kg, about 0.1mg / Kg to about 1mg / Kg, about 0.1mg / Kg to about 0.5mg / Kg).

[0336] Regimen The dosages described above can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0337] In some embodiments, the administration period of the compounds described herein ranges from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In further embodiments, the period of time during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, a therapeutic compound is administered to an individual for a period of time, followed by a separate period of time. In other embodiments, a therapeutic compound is administered for a first period of time, followed by a second period of time during which administration is suspended, followed by a third period of time during which administration of the therapeutic compound is initiated, and then followed by a fourth period of time during which administration is suspended. In some aspects of this embodiment, the period of administration of the therapeutic compound followed by a period during which administration is stopped is repeated for a determined or undetermined period of time. In further embodiments, the administration period spans 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.In further embodiments, the period of time during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0338] Treatment method Indications Provided herein is a method for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα), encoded by the PIK3CA gene. For example, provided herein are inhibitors of PI3Kα useful for treating or preventing diseases or disorders associated with the PIK3CA gene, the PI3Kα protein, or dysregulation of the expression, activity, or level of any of them (i.e., PI3Kα-related diseases or disorders), such as PIK3CA-associated overgrowth syndrome (PROS), see, e.g., Venot, et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., megalencephaly-capillary malformation syndrome (MCAP) and hemimegalencephaly), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-associated cancer).

[0339] As used herein, a "PI3K alpha inhibitor" includes any compound that exhibits (e.g., inhibits or reduces) PI3K alpha inactivation activity. In some embodiments, the PI3K alpha inhibitor may be selective for PI3K alphas with one or more mutations.

[0340] The ability of a test compound to act as an inhibitor of PI3K alpha can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3K alpha inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. An alternative in vitro assay quantifies the ability of an inhibitor to bind to the protein kinase, which can be measured either by radiolabeling the compound before binding, isolating the compound / kinase complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which a new compound is incubated with a kinase bound to a known radioligand.

[0341] The efficacy of the PI3Kα inhibitors provided herein is measured by EC 50 A lower EC value when determined under substantially similar conditions can be determined by the 50 Compounds with higher EC 50 In some embodiments, the substantially similar conditions include determining the level of PI3K α-dependent phosphorylation in vitro or in vivo (e.g., in tumor cells, A594 cells, U2OS cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing wild-type PI3K α, mutant PI3K α, or a fragment of either thereof).

[0342] The efficacy of the PI3Kα inhibitors provided herein also measured by IC 50 A lower IC value when determined under substantially similar conditions may also be determined. 50 Compounds with higher IC 50In some embodiments, the substantially similar conditions include determining the level of PI3K alpha-dependent phosphorylation in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3K alpha, mutant PI3K alpha, or a fragment of any thereof, SKOV3, T47D, CAL33, BT20, HSC2, OAW42, NCI, HCC1954, NCIH1048, Detroit562, A594 cells, U2OS cells, A431 cells, A594 cells, U2OS cells, Ba / F3 cells, or 3T3 cells).

[0343] Selectivity between wild-type PI3Kα and PI3Kα containing one or more mutations described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorescence-based binding assays, as well as cellular assays such as levels of pAKT, a biomarker of PI3Kα activity, or proliferation assays in which cell proliferation is dependent on mutant PI3Kα kinase activity.

[0344] In some embodiments, compounds provided herein may exhibit potent and selective inhibition of PI3K α. For example, compounds provided herein may bind to the catalytic domain of the helical phosphatidylinositol kinase homology domain of PI3K α. In some embodiments, compounds provided herein may exhibit nanomolar potency against PI3K α kinases containing one or more mutations, e.g., those in Tables 1 and 2.

[0345] In some embodiments, compounds provided herein may exhibit potent and selective inhibition of mutant PI3K α. For example, compounds provided herein may bind to an allosteric site in the kinase domain. In some embodiments, compounds provided herein may exhibit nanomolar potency against PI3K α proteins containing activating mutations, with minimal activity against related kinases (e.g., wild-type PI3K α). Inhibition of wild-type PI3K α can cause undesirable side effects (e.g., hyperglycemia and skin rash) that can affect quality of life and compliance. In some cases, inhibition of wild-type PI3K α can also 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 PI3K α.

[0346] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3K alpha, for example, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3K alpha over another kinase or non-kinase target.

[0347] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit greater inhibition of a PI3K α containing one or more mutations described herein (e.g., one or more mutations described in Table 1 or Table 2) compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of a PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit up to 1,000-fold greater inhibition of a PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit up to 10,000-fold greater inhibition of a PI3K α having a combination of mutations described herein compared to wild-type PI3K α.

[0348] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 2-fold to about 10-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 10-fold to about 100-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 100-fold to about 1000-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 1000-fold to about 10,000-fold greater inhibition of PI3K α containing one or more mutations described herein compared to wild-type PI3K α.

[0349] The compounds of formula (I), or pharmaceutically acceptable salts thereof, are useful for treating PI3Kα-associated diseases and disorders, e.g., diseases and disorders that can be treated with PI3Kα inhibitors, such as proliferative disorders such as PIK3CA-associated overgrowth syndrome (PROS) and cancer, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0350] In some embodiments, the subject has been identified or diagnosed with cancer involving dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels (PI3K alpha-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 dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay, or kit). For example, the subject has a tumor that is positive for a mutation listed in Table 1 or Table 2. The subject may be a subject with tumor(s) that are positive for dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay, or kit). The subject may be one whose tumor has a dysregulated PIK3CA gene, PI3K alpha protein, or expression or activity or levels thereof (e.g., the tumor has been identified as such using a kit or assay approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject is suspected of having a PI3K alpha-associated cancer. In some embodiments, the subject has medical records indicating that the subject has a tumor with a dysregulated PIK3CA gene, PI3K alpha protein, or expression or activity or levels of any of them (and optionally, the medical records indicate that the subject should be treated with any of the compositions provided herein).

[0351] In some embodiments, the subject is a pediatric subject.

[0352] The term "pediatric subject" as used herein refers to a subject who is under 21 years old at the time of diagnosis or treatment. The term "child" can be further divided into various subgroups, including neonates (birth to 1 month), infants (1 month to 2 years); children (2 to 12 years), and adolescents (12 to 21 years (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 2 years of age, from 2 years of age to less than 12 years of age, or from 12 years of age to 21 years of age (up to but not including their 22nd birthday). In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 1 year of age, from 1 month of age to less than 4 months of age, from 3 months of age to less than 7 months of age, from 6 months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than 7 years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0353] In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for preventing diseases and disorders defined herein (e.g., PIK3CA-associated overgrowth syndrome (PROS) and cancer). As used herein, the term "prevent" means delaying the onset, recurrence, or spread, in whole or in part, of a disease or condition described herein, or a symptom thereof.

[0354] As used herein, the term "PI3K alpha-associated disease or disorder" refers to a disease or disorder associated with or involving dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or level of the PIK3CA gene, or the PI3K alpha protein, or any of them described herein). Non-limiting examples of PI3K alpha-associated diseases or disorders include, for example, PIK3CA-associated overgrowth syndrome (PROS), encephalopathy (e.g., megalencephaly-capillary malformation syndrome (MCAP) and hemimegalencephaly), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibroadipose hyperplasia (FH), or cancer (e.g., PI3K alpha-associated cancer).

[0355] As used herein, the term "PI3K alpha-associated cancer" refers to cancers associated with or having dysregulation of the PIK3CA gene, the PI3K alpha protein, or the expression or activity or levels of any of them. Non-limiting examples of PI3K alpha-associated cancers are described herein.

[0356] The phrase "dysregulated expression or activity or levels of the PIK3CA gene, the PI3K α protein, or any of them" refers to a genetic mutation (e.g., a mutation in the PIK3CA gene that results in the expression of PI3K α containing at least one amino acid deletion compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in the expression of PI3K α with one or more point mutations compared to wild-type PI3K α, a mutation in the PIK3CA gene that results in the expression of PI3K α with at least one inserted amino acid compared to wild-type PI3K α, a gene duplication that results in increased PI3K α levels in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in increased PI3K α levels in a cell), an alternatively spliced ​​version of PI3K α mRNA that results in PI3K α with at least one amino acid deletion in PI3K α compared to wild-type PI3K α), or increased expression (e.g., increased levels) of wild-type PI3K α in mammalian cells due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to non-cancerous control cells). As another example, dysregulation of the expression, activity, or levels of the PIK3CA gene, the PI3K alpha protein, or any of them may be a mutation in the PIK3CA gene that encodes a PI3K alpha that is constitutively active or has increased activity compared to a protein encoded by a PIK3CA gene that does not contain the mutation. Non-limiting examples of point mutations / substitutions / insertions / deletions in PI3K alpha are listed in Tables 1 and 2.

[0357] The term "activating mutation" with reference to PI3K α describes a mutation in the PIK3CA gene that results in the expression of PI3K α with increased kinase activity, e.g., compared to wild-type PI3K α, when assayed under the same conditions. For example, an activating mutation can be a mutation in the PIK3CA gene that results in the expression of PI3K α with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that have increased kinase activity, e.g., compared to wild-type PI3K α, when assayed under the same conditions. In another example, an activating mutation can be a mutation in PIK3CA that results in the expression of PI3K α with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid deletions, e.g., compared to wild-type PI3K α, when assayed under the same conditions. In another example, an activating mutation can be a mutation in the PIK3CA gene that results in expression of a PI3K α with at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid insertion compared to wild-type PI3K α, e.g., an exemplary wild-type PI3K α described herein, when assayed under identical conditions. Additional examples of activating mutations are known in the art.

[0358] The term "wild type" or "wild-type" describes a nucleic acid (e.g., PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) sequence that is typically found in a subject that does not have a disease or disorder associated with the referenced nucleic acid or protein.

[0359] The term "wild-type PI3K α" or "wild-type PI3K α" describes a normal PI3K α nucleic acid (e.g., PIK3CA or PI3K α mRNA) or protein found in a subject who does not have a PI3K α-related disease, e.g., a PI3K α-related cancer (and optionally does not have an increased risk of developing a PI3K α-related disease and / or is not suspected of having a PI3K α-related disease), or found in cells or tissues from a subject who does not have a PI3K α-related disease, e.g., a PI3K α-related cancer (and optionally does not have an increased risk of developing a PI3K α-related disease and / or is not suspected of having a PI3K α-related disease).

[0360] Provided herein are methods for treating cancer (e.g., PI3K alpha-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3K alpha-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them comprises one or more substitutions / point mutations / insertions in the PI3K alpha protein. Non-limiting examples of substitutions / insertions / deletions in the PI3K alpha protein are listed in Tables 1 and 2.

[0361] In some embodiments, the substitution / insertion / deletion in the PI3K alpha protein is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the substitution / insertion / deletion in the PI3K alpha protein is H1047X (wherein X is any amino acid).

[0362] In some embodiments of any of the methods or uses described herein, the cancer (eg, PI3K alpha-associated cancer) is selected from a hematological cancer and a solid tumor.

[0363] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Both breast cancer and ER + breast cancer, and triple-negative breast cancer), endometrial cancer, lung cancer (including adenocarcinoma of the lung and lung squamous cell carcinoma), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagogastric junction adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell carcinoma such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumor (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0364] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Both breast cancer and ER +breast cancer, and triple-negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumors (pNETs), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma of the lung and squamous cell carcinoma of the lung), and endometrial cancer.

[0365] In some embodiments of any of the methods or uses described herein, the cancer (e.g., a PI3Kα-associated cancer) is selected from breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, gastroesophageal junction adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0366] In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3K alpha-associated cancer is lung cancer.

[0367] In some embodiments of any of the methods or uses described herein, the PI3K alpha associated cancer is selected from the cancers listed in Tables 1 and 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 2-1

Table 2-2

Table 2-3

[0368] In some embodiments, the dysregulation of the expression or activity or level of the PIK3CA gene, the PI3K α protein, or any of them comprises a splice variation in the PI3K α mRNA that results in the expressed protein being an alternative splice variant of PI3K α, in which at least one residue is deleted (compared to the wild-type PI3K α protein), thereby resulting in constitutive activity of the PI3K α protein domain.

[0369] In some embodiments, the dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K α protein, or any of them comprises at least one point mutation in the PIK3CA gene, which results in the production of a PI3K α protein with one or more amino acid substitutions or insertions compared to the wild-type PI3K α protein, or a deletion in the PIK3CA gene, which results in the production of a PI3K α protein with one or more amino acid insertions or deletions.In some cases, the resulting mutant PI3K α protein has increased activity compared to the wild-type PI3K α protein or a PI3K α protein that does not contain the same mutation.In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3K α protein compared to the wild-type PI3K α protein or a PI3K α protein that does not contain the same mutation.

[0370] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) [ka]

[0371] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating cancers identified as having one or more PI3K alpha mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0372] Also provided herein are methods for treating a subject identified or diagnosed with a PI3K alpha-associated cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is identified or diagnosed with a PI3K alpha-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the PIK3CA gene, PI3K alpha protein, or expression, activity, or level of any of them in the subject or in 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 a PI3K alpha-associated cancer.

[0373] The term "regulatory authority" refers to a national authority for approval of the medical use of a drug in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0374] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting a PI3K alpha-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have a PI3K alpha-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them in the subject or in a biopsy sample from the subject, or by 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 a PI3K alpha-associated cancer.

[0375] Also provided are methods for treating a subject, the methods comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, such as at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having a PI3K alpha-associated cancer, a subject exhibiting one or more symptoms of a PI3K alpha-associated cancer, or a subject at high risk of developing a PI3K alpha-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0376] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a PI3K alpha-associated cancer in a subject who has been identified or diagnosed as having a PI3K alpha-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them (wherein the presence of a dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them identifies the subject as having a PI3K alpha-associated cancer). Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a PI3K α-associated cancer in a subject identified or diagnosed as having a PI3K α-associated cancer through the step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the PIK3CA gene, PI3K α protein, or any of them (wherein the presence of dysregulated expression, activity, or level of the PIK3CA gene, PI3K α protein, or any of them identifies the subject as having a PI3K α-associated cancer). Some embodiments of any of the methods or uses described herein further include recording in the subject's medical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the PIK3CA gene, PI3K α protein, or any of them through the performance of the assay and should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory approved assay, e.g., an FDA approved kit, hi some embodiments, the assay is a liquid biopsy.

[0377] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need of cancer treatment or a subject identified or diagnosed with a PI3K alpha-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in a subject identified or diagnosed with a PI3K alpha-associated cancer. In some embodiments, a subject is identified or diagnosed with a PI3K alpha-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of the PIK3CA gene, PI3K alpha protein, or the expression, activity, or level of any of them in a subject or a biopsy sample from the subject. As defined herein, PI3K alpha-associated cancers include those described herein and known in the art.

[0378] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having cancer involving dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a PI3K alpha-associated cancer. In some embodiments, provided herein are methods for treating a PI3K alpha-associated cancer in a subject in need thereof, the methods comprising: a) detecting dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3K alpha protein, or any of them comprises one or more point mutations / insertions / deletions in the PI3K alpha protein. Non-limiting examples of point mutations / insertions / deletions in the PI3K alpha protein are listed in Tables 1 and 2. In some embodiments, the point mutation / insertion / deletion in the PI3K alpha protein is H1047X (wherein X is any amino acid).In some embodiments, the point mutation / insertion / deletion in the PI3K alpha protein is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, cancers associated with dysregulation of the PIK3CA gene, the PI3K alpha protein, or expression or activity or levels of any of them are determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA. In some embodiments, tumors associated with dysregulation of the PIK3CA gene, the PI3K alpha protein, or expression or activity or levels of any of them are determined using an assay or kit approved by a regulatory agency, e.g., approved by the FDA.

[0379] In some embodiments of any of the methods or uses described herein, the subject has medical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them. Also provided is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject with medical records indicating that the subject has dysregulated expression or activity or levels of the PIK3CA gene, PI3K alpha protein, or any of them.

[0380] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the PIK3CA gene, PI3K alpha protein, or any of them. In some such embodiments, the method also includes administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to have dysregulated expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments, the method includes determining that the subject has dysregulated expression or levels of the PIK3CA gene, PI3K alpha protein, or any of them through an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the dysregulation in the expression, activity, or levels of the PIK3CA gene, PI3K alpha protein, or any of them is one or more point mutations in the PIK3CA gene (e.g., any one or more of the PI3K alpha point mutations described herein). One or more point mutations in the PIK3CA gene can result in the translation of a PI3K alpha protein having, for example, one or more of the following amino acid substitutions, deletions, and insertions: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. One or more mutations in the PIK3CA gene can result in the translation of a PI3K alpha protein having, for example, one or more of the following amino acids: 542, 545, 1043, 1047, and 1049.In some embodiments, the dysregulation in the expression or activity or level of the PIK3CA gene, the PI3K alpha protein, or any of them is one or more PI3K alpha amino acid substitutions (e.g., any of the PI3K alpha amino acid substitutions described herein). Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., immunotherapy).

[0381] In some embodiments of any of the methods or uses described herein, the assay used to determine whether a subject has a dysregulated expression, activity, or level of the PIK3CA gene, or the PI3K α protein, using a sample from the subject, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and real-time quantitative RT-PCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art for detecting dysregulated expression, activity, or level of the PIK3CA gene, the PI3K α protein, or any of them (see, for example, the references cited herein). In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a PI3Kα-associated cancer, a subject with one or more symptoms of a PI3Kα-associated cancer, and / or a subject at increased risk of developing a PI3Kα-associated cancer.

[0382] In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid-phase biopsy). See, e.g., Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment," Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of the expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them. Liquid biopsies can be performed on biological samples that are relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of the expression, activity, or level of the PIK3CA gene, PI3K alpha protein, or any of them. In some embodiments, liquid biopsy can be used to detect the presence of dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels at an earlier stage than conventional methods. In some embodiments, biological samples used in liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of the PIK3CA gene, PI3K alpha protein, or any of their expression, activity, or levels.

[0383] Also provided are methods for inhibiting PI3K alpha activity in cells, the methods comprising contacting the cells with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vivo and the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having cells with aberrant PI3K alpha activity. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer described herein. In some embodiments, the cancer cells are PI3K alpha-associated cancer cells. As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" a PI3K alpha protein with a compound provided herein includes administering a compound provided herein to an individual or subject, such as a human, having a PI3K alpha protein, as well as, for example, introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing a PI3K alpha protein.

[0384] Also provided herein are methods for inhibiting cell proliferation in vitro or in vivo, the methods 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.

[0385] Further provided herein is a method for increasing 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 for increasing tumor cell death in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0386] The phrase "therapeutically effective amount" means an amount of a compound sufficient, when administered to a subject in need of such treatment, to (i) treat a PI3Kα protein-associated disease or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that would correspond to such an amount will vary depending on factors such as the particular compound, the condition and its severity, and the identity (e.g., body weight) of the subject requiring treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0387] When employed as pharmaceuticals, the compounds of formula (I) (including pharmaceutically acceptable salts thereof) can be administered in the form of pharmaceutical compositions described herein.

[0388] combination In the field of medical oncology, it is common practice to treat each subject with cancer using a combination of different forms of treatment. In medical oncology, such co-treatment or other component(s) of the therapy in addition to the compositions provided herein can be, for example, surgery, radiation therapy, and chemotherapeutic agents such as other kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery can be open surgery or minimally invasive surgery. Therefore, the compounds of formula (I) or pharmaceutically acceptable salts thereof can also be useful as adjuvants for cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents acting by the same or different mechanisms of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used before the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof can be administered one or more doses of the compound of formula (I) or pharmaceutically acceptable salts thereof for a certain period of time, and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, over a period of time, followed by one or more radiation therapy sessions. In some embodiments, treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to one or more radiation therapy sessions.

[0389] In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a standard of care (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to a previous treatment (e.g., administration of a chemotherapeutic agent such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) for which there is no standard of care. In some embodiments, the subject is PI3K alpha inhibitor naive. For example, the subject is naive to treatment with a selective PI3K alpha inhibitor. In some embodiments, the subject is not PI3K alpha inhibitor naive. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive. In some embodiments, the subject has received a previous treatment.For example, a multikinase inhibitor (MKI) or another PI3K inhibitor, such as bupallisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolic acid sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587 ), ceravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK10 Treatment with 59615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, or GSK2636771.

[0390] In some embodiments of any of the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[0391] Non-limiting examples of additional therapeutic agents include other PI3Kα targeted therapeutic agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (including the mTOR inhibitors described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutic agents (e.g., Trk inhibitors or multikinase inhibitors)), farnesyltransferase inhibitors, signal transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERMs / SERDs), checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapy, angiogenesis targeted therapy, immune targeted agents including immunotherapy, and radiation therapy.

[0392] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), bande Tanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylarkannin), 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, vallitinib (ASLAN001, ARRY -334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, avatinib, Disruptin, CL-387785, EGFR Bi-arm autologous T cells, and EGFR 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.

[0393] 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®), and HER2 inhibitors. (R), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-222611, and AEE-788.

[0394] As used herein, "RAS pathway-targeted therapeutic agent" includes any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any one of proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, the RAS pathway modulator may be selective for a protein in the RAS pathway, e.g., the RAS pathway modulator may be selective for RAS (also known as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway-targeted therapeutic agent is a "KRAS pathway modulator." KRAS pathway modulators include any compound that exhibits inactivation activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors described herein), AKT, and mTOR. In some embodiments, the KRAS pathway modulator may be selective for a protein in the RAS pathway, for example, the KRAS pathway modulator may be selective for KRAS (also known as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0395] Non-limiting examples of KRAS targeted therapeutics (e.g., KRAS inhibitors) include BI1701963, AMG510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0396] Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

[0397] 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.

[0398] 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.

[0399] In some embodiments, the other PI3K inhibitor is another PI3K alpha inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is bupallisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolicib (PX-86 6), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), ceravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK1059615, GDC-0084 (RG76 66), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

[0400] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphosphocholine, erufosin e), SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (triciribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY1125976, 3-oxo-tirucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0401] In some embodiments, the mTOR inhibitor is selected from MLN0128, bistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

[0402] Non-limiting examples of farnesyltransferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0403] In some embodiments, the chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVEN™), or a combination thereof.

[0404] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0405] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0406] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0407] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0408] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0409] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amsenestrant (SAR439859), AZD9833, lindestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0410] Non-limiting examples of immunotherapies include immune checkpoint therapy, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapy include inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or a combination thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, e.g., Marin-Acevedo, et al., J Hematol Oncol. 11:39 (2018).

[0411] In some embodiments, the additional treatment or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab-paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, bupallisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, amsenestrant, and combinations thereof.

[0412] In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of certain anti-cancer therapies and / or as palliative therapy (e.g., opioids and corticosteroids). In some embodiments, the additional therapy or therapeutic agent described herein is selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, metformin, and combinations thereof.

[0413] 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.

[0414] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, sergliflozin, licofliglozin, sotagliflozin (ZYNQUISTA™), and tofogliflozin.

[0415] 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.

[0416] In some embodiments, the subject is also instructed to maintain a particular diet and / or exercise regimen to control blood sugar levels.

[0417] Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer comprising (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective to treat cancer.

[0418] In some embodiments, the additional therapeutic agent(s) include any one of the therapies or therapeutic agents listed above that are standard of care in cancer, wherein the cancer has dysregulation of the expression or activity or levels of the PIK3CA gene, the PI3K alpha protein, or any of them.

[0419] These additional therapeutic agents may be administered as part of the same or separate dosage form, via the same or different route of administration, and / or on the same or different dosing schedules along with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in accordance with standard pharmaceutical practice known to those skilled in the art.

[0420] Also provided herein are (i) pharmaceutical combinations for treating cancer in a subject in need thereof, comprising (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are combined to be effective in treating cancer; (ii) pharmaceutical compositions comprising such combinations; (iii) uses of such combinations for the preparation of medicaments for the treatment of cancer; and (iv) commercial packages or articles of manufacture comprising such combinations as combined preparations for simultaneous, separate, or sequential use, as well as methods of treating cancer in a subject in need thereof. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0421] As used herein, the term "pharmaceutical combination" refers to a drug therapy resulting from the mixing or combination of multiple active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are 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., a chemotherapeutic agent) are formulated as separate compositions or dosages that can be administered to a subject in need thereof simultaneously, in parallel, or sequentially with variable intervening time limits, such that such administration results in effective levels of the two or more compounds in the subject's body. This also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0422] Thus, also provided herein are methods for treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer, comprising (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, for simultaneous, separate, or sequential use for the treatment of cancer, wherein the compound of Formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, and the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are jointly effective to treat cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially in any order as separate dosages, in jointly therapeutically effective amounts, for example, in a daily dosage or intermittent dosages. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously in a combined dosage.

[0423] Embodiment Embodiment 1: A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR x and R x is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R 2 is halogen, hydroxyl, C1-C6 alkylalkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R 4 became independent, (i) halogens, (ii) one or two hydroxyls or -NR A R B C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano; (vii) -CO2H, (viii)-NR A R B , (ix)=NR A2 , (x)-C(=O)NR C R D , (xi)-SO2(NR E R F ), (xii) -SO2(C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R G 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) Hydroxyl, -C(=O)NR B2 R C2 , a 5- to 6-membered heteroaryl, a 3- to 6-membered cycloalkyl, a C1-C6 alkyl optionally substituted by 1 to 2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R A2 , R B2 , and R C2 are independently hydrogen or C1-C6 alkyl, Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 , —CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO2(C1-C6 alkyl), and —CO2H; wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, which is not a compound selected from the group consisting of:

[0424] Embodiment 2: The compound of embodiment 1, wherein m is 1.

[0425] Embodiment 3: The compound of embodiment 1, wherein m is 2.

[0426] Embodiment 4: [ka] but, [ka] 3. The compound of embodiment 1 or 2, wherein

[0427] Embodiment 5: [ka] but, [ka] 3. The compound of embodiment 1 or 2, wherein

[0428] Embodiment 6: [ka] but, [ka] 4. The compound of embodiment 1 or 3, wherein

[0429] Embodiment 7: Each R 1 The compound of any one of embodiments 1-6, wherein is halogen.

[0430] Embodiment 8: Each R 1 The compound of any one of embodiments 1-7, wherein is selected from fluoro and chloro.

[0431] Embodiment 9: Each R 1 The compound of any one of embodiments 1-8, wherein is fluoro.

[0432] Embodiment 10: One R 1 The compound of any one of embodiments 1-6, wherein is cyano.

[0433] Embodiment 11: One R 1 The compound of any one of embodiments 1-6, wherein is C1-C6 alkyl.

[0434] Embodiment 12: One R 1 The compound of any one of embodiments 1-6, wherein is C3-C6 cycloalkyl.

[0435] Embodiment 13: The compound of embodiment 1, wherein m is 0.

[0436] Embodiment 14:R 2 The compound of any one of embodiments 1-13, wherein is C1-C6 alkyl.

[0437] Embodiment 15:R 2is methyl.

[0438] Embodiment 16:R 2 The compound of any one of embodiments 1-13, wherein is C1-C6 haloalkyl.

[0439] Embodiment 17:R 2 is difluoromethyl.

[0440] Embodiment 18:R 2 is trifluoromethyl.

[0441] Embodiment 19:R 2 The compound of any one of embodiments 1-13, wherein is halogen.

[0442] Embodiment 20:R 2 The compound of any one of embodiments 1-13, wherein is C3-C6 cycloalkyl optionally substituted with one or two fluoro.

[0443] Embodiment 21:R 2 The compound of any one of embodiments 1-13 or 20, wherein is C3-C6 cycloalkyl substituted with one or two fluoro.

[0444] Embodiment 22:R 2 The compound of any one of embodiments 1-13 or 21, wherein is unsubstituted C3-C6 cycloalkyl.

[0445] Embodiment 23:R 3 The compound of any one of embodiments 1-22, wherein is C1-C6 alkyl.

[0446] Embodiment 24:R 3 The compound of any one of embodiments 1-23, wherein is methyl, ethyl, or isopropyl.

[0447] Embodiment 25:R 3 The compound of any one of embodiments 1-23, wherein is methyl.

[0448] Embodiment 26:R 3 The compound of any one of embodiments 1-23, wherein is ethyl.

[0449] Embodiment 27:R 3 The compound of any one of embodiments 1-23, wherein is isopropyl.

[0450] Embodiment 28:R 3 The compound of any one of embodiments 1-22, wherein is C1-C6 haloalkyl.

[0451] Embodiment 29:R 3 The compound of any one of embodiments 1-22 and 28, wherein is trifluoromethyl.

[0452] Embodiment 30:R 3 The compound of any one of embodiments 1-22, wherein is C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl.

[0453] Embodiment 31:R 3 The compound of any one of embodiments 1-22 and 30, wherein is C3-C6 cycloalkyl substituted with one or two fluoro.

[0454] Embodiment 32:R 3 The compound of any one of embodiments 1-22 and 30, wherein is unsubstituted C3-C6 cycloalkyl.

[0455] Embodiment 33: The R 3 The compound of any one of embodiments 1 to 22, 30, and 31, wherein the C3-C6 cycloalkyl is cyclopropyl.

[0456] Embodiment 34: A compound of any one of embodiments 1 to 33, wherein ring A is a 6- to 10-membered aryl.

[0457] Embodiment 35: The compound of any one of embodiments 1 to 34, wherein Ring A is phenyl.

[0458] Embodiment 36: A compound of any one of embodiments 1 to 33, wherein Ring A is C3-C8 cycloalkyl.

[0459] Embodiment 37: The compound of any one of embodiments 1 to 33 and 36, wherein Ring A is C5-C6 cycloalkyl.

[0460] Embodiment 38: The compound of any one of embodiments 1-33 and 36-37, wherein Ring A is cyclohexyl.

[0461] Embodiment 39: A compound of any one of embodiments 1 to 33, wherein Ring A is a 5-10 membered heteroaryl.

[0462] Embodiment 40: The compound of any one of embodiments 1 to 33 and 39, wherein Ring A is a 5-6 membered heteroaryl.

[0463] Embodiment 41: The compound of any one of embodiments 1-33 and 39-40, wherein Ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl.

[0464] Embodiment 42: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is pyrimidinyl.

[0465] Embodiment 43: The compound of any one of embodiments 1 to 33 and 39 to 41, wherein Ring A is pyridyl.

[0466] Embodiment 44: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is thiazolyl.

[0467] Embodiment 45: The compound of any one of embodiments 1-33 and 39-41, wherein ring A is thiophenyl.

[0468] Embodiment 46: The compound of any one of embodiments 1-33 and 39-41, wherein Ring A is pyrazolyl.

[0469] 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.

[0470] Embodiment 48: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 5-pyrimidinyl.

[0471] Embodiment 49: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 3-pyridyl.

[0472] Embodiment 50: The compound of any one of embodiments 1-33, 39-41, and 47, wherein Ring A is 4-pyrazolyl.

[0473] Embodiment 51: The compound of any one of embodiments 1 to 33 and 39, wherein Ring A is a 9-10 membered heteroaryl.

[0474] 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.

[0475] Embodiment 53: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is benzimidazolyl.

[0476] Embodiment 54: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indazolyl.

[0477] Embodiment 55: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indolyl.

[0478] Embodiment 56: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is indolyl.

[0479] Embodiment 57: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is a quinazolone.

[0480] Embodiment 58: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is isobenzofuranonyl.

[0481] Embodiment 59: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is isoindolinonyl.

[0482] Embodiment 60: The compound of any one of embodiments 1-33, 39, and 51-52, wherein Ring A is imidazo[1,2-a]pyridinyl.

[0483] Embodiment 61: Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, [ka] The compound of any one of embodiments 1-33, 39, and 51-52, wherein

[0484] Embodiment 62: The compound of any one of embodiments 1 to 33, 39, and 61, wherein Ring A is 2-benzimidazolyl.

[0485] Embodiment 63: The compound of any one of embodiments 1 to 33, 39, and 61, wherein Ring A is 5-indazolyl.

[0486] Embodiment 64: The compound of any one of embodiments 1 to 33, 39, and 61, wherein Ring A is 2-indolyl.

[0487] Embodiment 65: The compound of any one of embodiments 1 to 33, 39, and 61, wherein Ring A is 7-imidazo[1,2-a]pyridinyl.

[0488] Embodiment 66: Ring A is [ka] The compound of any one of embodiments 1-33, 39, and 61, wherein

[0489] Embodiment 67: Ring A is [ka] The compound of any one of embodiments 1-33, 39, and 61, wherein

[0490] Embodiment 68: A compound of any one of embodiments 1 to 33, wherein ring A is a 4- to 10-membered heterocyclyl.

[0491] Embodiment 69: A compound of any one of embodiments 1 to 33 and 68, wherein ring A is a 6- to 9-membered heterocyclyl.

[0492] 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.

[0493] Embodiment 71: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is piperidinyl.

[0494] 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.

[0495] Embodiment 73: Ring A is 3-piperidinyl, 4-piperidinyl, or [ka] The compound of any one of embodiments 1-33 and 68-70, wherein

[0496] Embodiment 73: A compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 3-piperidinyl.

[0497] Embodiment 74: The compound of any one of embodiments 1-33 and 68-70, wherein Ring A is 4-piperidinyl.

[0498] Embodiment 75: Ring A is: [ka] The compound of any one of embodiments 1-33 and 68-70, wherein

[0499] Embodiment 76: A compound of any one of embodiments 1 to 75, wherein n is 1.

[0500] Embodiment 77: The compound of any one of embodiments 1 to 75, wherein n is 2.

[0501] Embodiment 78: One R 4 The compound of any one of embodiments 1-77, wherein is unsubstituted C1-C6 alkyl.

[0502] Embodiment 79: One R 4 The compound of any one of embodiments 1-78, wherein is methyl.

[0503] Embodiment 80: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[0504] Embodiment 81: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[0505] Embodiment 82: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkoxy substituted with hydroxyl or C3-C6 cycloalkyl.

[0506] Embodiment 83: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkoxy substituted with two substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[0507] Embodiment 84: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkoxy.

[0508] Embodiment 85: One R 4 The compound of any one of embodiments 1-77 and 84, wherein is methoxy.

[0509] Embodiment 86: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 haloalkyl.

[0510] Embodiment 87: One R 4 The compound of any one of embodiments 1-77 and 86, wherein is trifluoromethyl.

[0511] Embodiment 88: One R 4 The compound of any one of embodiments 1-77, wherein is hydroxyl.

[0512] Embodiment 89: One R 4The compound of any one of embodiments 1-77, wherein is cyano.

[0513] Embodiment 90: One R 4 The compound of any one of embodiments 1-77, wherein is —CO 2 H.

[0514] Embodiment 91: One R 4 The compound of any one of embodiments 1-77, wherein is halogen.

[0515] Embodiment 92: One R 4 The compound of any one of embodiments 1-77, wherein is C1-C6 alkyl substituted with 1 to 2 hydroxyl.

[0516] Embodiment 93: One R 4 The compound of any one of embodiments 1-77 and 92, wherein is C1-C6 alkyl substituted with hydroxyl.

[0517] Embodiment 94: One R 4 The compound of any one of embodiments 1-77 and 92, wherein is C1-C6 alkyl substituted with two hydroxyls.

[0518] Embodiment 95: One R 4 But, -NR A R B The compound of any one of embodiments 1-77, wherein the R is C1-C6 alkyl substituted with R.

[0519] Embodiment 96: One R 4 But, -NR A R B The compound of any one of embodiments 1-77, wherein

[0520] Embodiment 97:R A and R B The compound of any one of embodiments 1-77 and 95-96, wherein each is hydrogen.

[0521] Embodiment 98:R A and R B The compound of any one of embodiments 1-77 and 95-96, wherein each is C1-C6 alkyl.

[0522] Embodiment 99:R A and R B The compound of any one of embodiments 1-52, 95-96, and 98, wherein each is methyl.

[0523] Embodiment 100:R A and R B is hydrogen, and R A and R B The compound of any one of embodiments 1-77 and 95-96, wherein the other of is C1-C6 haloalkyl.

[0524] Embodiment 101: One R 4 But -C(=O)NR C R D The compound of any one of embodiments 1-77, wherein

[0525] Embodiment 102:R C and R D The compound of any one of embodiments 1-77 and 101, wherein each is hydrogen.

[0526] Embodiment 103:R C and R D The compound of any one of embodiments 1-77 and 101, wherein each is C1-C6 alkyl.

[0527] Embodiment 104:R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0528] Embodiment 105:R C and R D together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, forming a 4-10 membered heterocyclyl.

[0529] Embodiment 106:R C and R D together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

[0530] Embodiment 107:R C and R D together with the nitrogen atom to which they are attached form an azetidine or piperazine.

[0531] Embodiment 108: One R 4 But -SO2(NR E R F 78. The compound of any one of embodiments 1-77, wherein

[0532] Embodiment 109:R E and R F The compound of any one of embodiments 1-77 and 108, wherein each is hydrogen.

[0533] Embodiment 110:R E and R F The compound of any one of embodiments 1-77 and 208, wherein each is C1-C6 alkyl.

[0534] Embodiment 111: One R 4 The compound of any one of embodiments 1-77, wherein is —SO 2 (C 1 -C 6 alkyl).

[0535] Embodiment 112: One R 4 The compound of any one of embodiments 1-77 and 111, wherein is —SO 2 Me.

[0536] Embodiment 113: One R 4 The compound of any one of embodiments 1-77 and 111, wherein is -SO2Et.

[0537] Embodiment 114: One R 4 The compound of any one of embodiments 1-77, wherein is -S(=O)(=NH)(C1-C6 alkyl).

[0538] Embodiment 115: One R 4 The compound of any one of embodiments 1-77 and 84, wherein is —S(═O)(═NH)Me.

[0539] Embodiment 116: One R 4 The compound of any one of embodiments 1-77, wherein is —C(═O)(C1-C6 alkyl).

[0540] Embodiment 117: One R 4 The compound of any one of embodiments 1-77 and 106, wherein is —C(═O)Me.

[0541] Embodiment 118: One R 4 The compound of any one of embodiments 1-77, wherein is -CO2(C1-C6 alkyl).

[0542] Embodiment 119: One R 4 The compound of any one of embodiments 1-77 and 118, wherein is —CO 2 Me.

[0543] Embodiment 120: One R 4 The compound of any one of embodiments 1-77, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0544] Embodiment 121: One R 4 The compound of any one of embodiments 1-77 and 120, wherein is 5-6 membered heteroaryl substituted with C1-C6 alkyl.

[0545] Embodiment 122: One R 4 The compound of any one of embodiments 1-77 and 120-121, wherein is tetrazolyl substituted with methyl.

[0546] Embodiment 123: One R 4 The compound of any one of embodiments 1-77 and 90, wherein is unsubstituted 5-6 membered heteroaryl.

[0547] Embodiment 124: One R 4 The compound of any one of embodiments 1-77, 90, and 93, wherein is unsubstituted pyrazolyl.

[0548] Embodiment 125: One R 4 where one or two independently selected R G The compound according to any one of embodiments 1 to 77, wherein R is 3-9 membered heterocyclyl optionally substituted by:

[0549] Embodiment 126: One R 4 where one or two independently selected R G The compound according to any one of embodiments 1 to 77, wherein R is 3-6 membered heterocyclyl optionally substituted by:

[0550] Embodiment 127: One R 4 is one or two independently selected R G The compound of any one of embodiments 1-77 and 96, wherein the compound is 3-6 membered heterocyclyl substituted with

[0551] Embodiment 128: One R 4 But one R G The compound according to any one of embodiments 1-77 and 126-127, wherein the compound is 3-6 membered heterocyclyl substituted with

[0552] Embodiment 129: One R 4 are two independently selected R G The compound according to any one of embodiments 1-77 and 126-127, wherein the compound is 3-6 membered heterocyclyl substituted with

[0553] Embodiment 130: One R 4 is one or two independently selected R G The compound of any one of embodiments 1 to 77, wherein R is 3-6 membered cycloalkyl optionally substituted by:

[0554] Embodiment 131: One R 4 is one or two independently selected R G The compound of any one of embodiments 1-77 and 130, wherein the cycloalkyl is 3-6 membered substituted with

[0555] Embodiment 132: One R 4 But one R G The compound of any one of embodiments 1-77 and 130-131, wherein the cycloalkyl is 3-6 membered substituted with

[0556] Embodiment 133: One R 4 are two independently selected R G The compound of any one of embodiments 1-77 and 130-131, wherein the cycloalkyl is 3-6 membered substituted with

[0557] Embodiment 134: One R G The compound according to any one of embodiments 1-77 and 125-133, wherein is fluoro.

[0558] Embodiment 135: One R G The compound of any one of embodiments 1-77 and 125-133, wherein is cyano.

[0559] Embodiment 136: One R G The compound according to any one of embodiments 1-77 and 125-133, wherein is hydroxyl.

[0560] Embodiment 137: One R G The compound according to any one of embodiments 1-77 and 125-133, wherein is C1-C6 alkyl.

[0561] Embodiment 138: One R G The compound of any one of embodiments 1-77, 125-133, and 137, wherein is methyl.

[0562] Embodiment 139: One R G The compound of any one of embodiments 1-77 and 125-133, wherein is C1-C6 alkoxy.

[0563] Embodiment 140: One R G The compound of any one of embodiments 1-77, 125-133, and 139, wherein is methoxy.

[0564] Embodiment 141: One R G But, -NR A1 R B1 The compound of any one of embodiments 1-77 and 125-133, wherein

[0565] Embodiment 142: One R G But, =NR A2 The compound of any one of embodiments 1-77 and 125-133, wherein

[0566] Embodiment 143:R A2 The compound of any one of embodiments 1-77, 125-133, and 142, wherein is hydrogen.

[0567] Embodiment 144:R A2 The compound of any one of embodiments 1-77, 125-133, and 142, wherein is C1-C6 alkyl.

[0568] Embodiment 145:R A1 and R B1 The compound of any one of embodiments 1-77 and 125-133, wherein each is hydrogen.

[0569] Embodiment 146:R A1 and R B1 is hydrogen, and R A1 and R B1 The compound according to any one of embodiments 1-77 and 126-133, wherein the other of is C1-C6 alkyl.

[0570] Embodiment 147:R A1 and R B1 is hydrogen, and R A1 and R B1 The compound of any one of embodiments 1-77, 126-133, and 116, wherein the other of is methyl.

[0571] Embodiment 148:R A1 and R B1 The compound of any one of embodiments 1-77 and 126-133, wherein each is C1-C6 alkyl.

[0572] Embodiment 149:R A1 and R B1 The compound of any one of embodiments 1-77, 126-133, and 118, wherein each is methyl.

[0573] Embodiment 150:R A1 and R B1 is hydrogen, and RA1 and R B1 The compound according to any one of embodiments 1-77 and 126-133, wherein the other of is C1-C6 haloalkyl.

[0574] Embodiment 151:R A1 and R B1 The compound of any one of embodiments 1-77 and 126-133, wherein each is C1-C6 haloalkyl.

[0575] Embodiment 152:R A1 and R B1 one of which is C1-C6 alkyl, and R A1 and R B1 The compound according to any one of embodiments 1-77 and 126-133, wherein the other of is C1-C6 haloalkyl.

[0576] Embodiment 153: One R G But -C(=O)NR C1 R D1 The compound of any one of embodiments 1-77 and 126-133, wherein

[0577] Embodiment 154:R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein each is hydrogen.

[0578] Embodiment 155:R C1 and R D1 is hydrogen, and R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein the other of is C1-C6 alkyl.

[0579] Embodiment 156:R C1 and R D1 is hydrogen, and R C1 and R D1The compound of any one of embodiments 1-77, 126-133, 123, and 125, wherein the other of is methyl.

[0580] Embodiment 157:R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein each is C1-C6 alkyl.

[0581] Embodiment 158:R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, 123, and 127, wherein each is methyl.

[0582] Embodiment 159:R C1 and R D1 is hydrogen, and R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein the other of is C1-C6 haloalkyl.

[0583] Embodiment 160:R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein each is C1-C6 haloalkyl.

[0584] Embodiment 161:R C1 and R D1 one of which is C1-C6 alkyl, and R C1 and R D1 The compound of any one of embodiments 1-77, 126-133, and 123, wherein the other of is C1-C6 haloalkyl.

[0585] Embodiment 162: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is -CO2(C1-C6 alkyl).

[0586] Embodiment 163: One R GThe compound of any one of embodiments 1-77 and 126-133, wherein is —CO 2 CH 3 .

[0587] Embodiment 164: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is C1-C6 haloalkyl.

[0588] Embodiment 165: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is trifluoromethyl.

[0589] Embodiment 166: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is C1-C6 haloalkoxy.

[0590] Embodiment 167: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is -SO2(C1-C6 alkyl).

[0591] Embodiment 168: One R G The compound of any one of embodiments 1-77 and 126-133, wherein is C3-C6 cycloalkyl.

[0592] Embodiment 169: One R G The compound according to any one of embodiments 1-77 and 126-133, wherein is cyclopropyl.

[0593] Embodiment 170: One R G The compound of any one of embodiments 1-77 and 126-133, wherein is —CO 2 H.

[0594] Embodiment 171: One R 4 The compound according to any one of embodiments 1 to 77 and 125, wherein is unsubstituted 3-6 membered heterocyclyl.

[0595] Embodiment 172: The R4 The compound according to any one of embodiments 125 to 129, wherein said 3- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl.

[0596] Embodiment 173: The R 4 The compound according to any one of embodiments 125-129, wherein the 3-6 membered heterocyclyl is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl.

[0597] Embodiment 174: The R 4 The compound according to any one of embodiments 125-129, wherein the 3-6 membered heterocyclyl is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl.

[0598] Embodiment 175: One R 4 The compound of any one of embodiments 1-77 and 130, wherein is unsubstituted 3-6 membered cycloalkyl.

[0599] Embodiment 176: The R 4 The compound according to any one of embodiments 130-170 and 175, wherein the 3-6 membered cycloalkyl is a 3-4 membered cycloalkyl.

[0600] Embodiment 177: The R 4 The compound according to any one of embodiments 130-170 and 175-176, wherein said 3-6 membered cycloalkyl is cyclobutyl.

[0601] Embodiment 178: A compound according to any one of embodiments 1 to 77, wherein n is 0.

[0602] Embodiment 179: [ka] but, [ka] wherein X is N and CR 4A2 Selected from R 4A1 and R 4A2 are independently hydrogen, -NR A R B C1-C3 alkyl optionally substituted with methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), one or two independently selected R G and one or two independently selected R G The compound of any one of embodiments 1 to 33, wherein the cycloalkyl is selected from 3- to 6-membered cycloalkyl optionally substituted by:

[0603] Embodiment 180: The compound of embodiment 179, wherein X is N.

[0604] Embodiment 181: X is CR 4A2 180. The compound of embodiment 179, wherein

[0605] Embodiment 182:R 4A1 and, if present, R 4A2 are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, —C(═O)NH, —C(═O)NHMe, —SONH, —SOMe, and azetidinyl optionally substituted with 1 to 2 independently selected fluoro, hydroxyl, or methyl.

[0606] Embodiment 183: X is N and R 4A1 is selected from amino, and azetidinyl optionally substituted with one to two independently selected fluoro, hydroxyl, or methyl.

[0607] Embodiment 184: [ka] but, [ka] where R 4B But, -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 The compound of any one of embodiments 1-33, wherein is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl.

[0608] Embodiment 185:R A and R B The compound of embodiment 184, wherein both are hydrogen.

[0609] Embodiment 186:R A and R B is hydrogen, and R A and R B and the other of is C1-C6 alkyl.

[0610] Embodiment 187:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 184 and 186, wherein the other of is methyl.

[0611] Embodiment 188:R 4B contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by Gis selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0612] Embodiment 189:R 4B but, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is selected from 1 to 2 R, each independently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. G The compound of embodiment 184, optionally substituted by:

[0613] Embodiment 190: A compound of embodiment 189, wherein Ring B is azetidinyl.

[0614] Embodiment 191: A compound according to any one of embodiments 189-190, wherein Ring B is unsubstituted.

[0615] Embodiment 192: Ring B is one R G The compound of any one of embodiments 189-190, substituted with:

[0616] Embodiment 193:R G The compound of embodiment 192, wherein is fluoro.

[0617] Embodiment 194:R G is hydroxyl.

[0618] Embodiment 195:R G The compound of embodiment 192, wherein is methyl.

[0619] Embodiment 196: Ring B is a ring having two R G The compound of any one of embodiments 189-190, substituted with:

[0620] Embodiment 197: Each RG The compound of embodiment 196, wherein is fluoro.

[0621] Embodiment 198: Each R G The compound of embodiment 196, wherein is methyl.

[0622] Embodiment 199: One R G is hydroxyl, and the other R G The compound of embodiment 196, wherein is methyl.

[0623] Embodiment 200: One R G is fluoro and the other R G The compound of embodiment 196, wherein is methyl.

[0624] Embodiment 201: One R G is hydroxyl, and the other R G The compound of embodiment 196, wherein is fluoro.

[0625] Embodiment 202: Each R G is attached to ring B at a position para to the nitrogen attached to ring A.

[0626] Embodiment 203: Each R 1 is fluoro, m is 1 or 2, and R 2 is C1-C6 alkyl, and R 3 is C1-C6 alkyl.

[0627] Embodiment 204: Each R 1 is fluoro, m is 1 or 2, and R 2 is C1-C6 alkyl, and R 3 is C1-C6 haloalkyl.

[0628] Embodiment 205: Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and unsubstituted 3- to 6-membered heterocyclyl; The compound of embodiment 1, wherein n is 1 or 2.

[0629] Embodiment 206: Each R 1 But it is fluoro, m is 1 or 2; R 2 is C1-C6 alkyl, R 3 is C1-C6 alkyl, Ring A is phenyl or 5- to 6-membered heteroaryl; Each R 4 are independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SON2NH2, -SON2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5- to 6-membered heteroaryl, and one or two independently selected R G and is selected from the group consisting of 3- to 6-membered heterocyclyl optionally substituted by The compound of embodiment 1, wherein n is 1 or 2.

[0630] Embodiment 207: A compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is a halogen or is absent, R 2is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl; R 4 independently, -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G and one or two independently selected R G and is selected from the group consisting of 3 to 6 membered cycloalkyl optionally substituted by where R 4 is attached to the ring A1 position, which is para to the N atom of the urea moiety, Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R Fare independently hydrogen, 4- to 6-membered heterocyclyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from hydroxyl, 3- to 6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); R C and R D together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R G are independently fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H, or a pharmaceutically acceptable salt thereof.

[0631] Embodiment 208: A compound according to embodiment 207, wherein Ring A1 is pyrimidinyl.

[0632] Embodiment 209: A compound according to embodiment 207, wherein Ring A1 is pyridyl.

[0633] Embodiment 210: A compound of embodiment 207, wherein Ring A1 is pyrazolyl.

[0634] Embodiment 211: A compound according to embodiment 207, wherein Ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl.

[0635] Embodiment 212: [ka] but, [ka] where R 4BBut, -NR A R B and one to two independently selected R G1 and 4-6 membered heterocyclyl optionally substituted by G1 The compound according to embodiment 207, wherein is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0636] Embodiment 213:R A and R B and R are both hydrogen.

[0637] Embodiment 214:R A and R B is hydrogen, and R A and R B and the other of is a 4-6 membered heterocyclyl, a C1-C6 haloalkyl, a 3-6 membered cycloalkyl optionally substituted with hydroxyl, or a C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 membered cycloalkyl, —SO2(C1-C6 alkyl), and —SO2(NH2).

[0638] Embodiment 215:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212 and 214, wherein the other of is 4-6 membered heterocyclyl.

[0639] Embodiment 216:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212 and 214-215, wherein the other of is 5-membered heterocyclyl.

[0640] Embodiment 217:R A and R Bis hydrogen, and R A and R B The compound according to any one of embodiments 212 and 214, wherein the other of is C1-C6 haloalkyl.

[0641] Embodiment 218:R A and R B The compound according to any one of embodiments 212 and 214, wherein both are C1-C6 haloalkyl.

[0642] Embodiment 219:R A and R B one of which is C1-C6 alkyl, and R A and R B The compound according to any one of embodiments 212 and 214, wherein the other of is C1-C6 haloalkyl.

[0643] Embodiment 220:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212 and 214, wherein the other of is a 3-6 membered cycloalkyl optionally substituted with hydroxyl.

[0644] Embodiment 221:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 220, wherein the other of is cyclobutanyl optionally substituted with hydroxyl.

[0645] Embodiment 222:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 220-221, wherein the other of is 3-hydroxycyclobutyl.

[0646] Embodiment 223:R A and R B is hydrogen, and R A and R B and the other is C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2).

[0647] Embodiment 224:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 223, wherein the other of is methyl.

[0648] Embodiment 225:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 223, wherein the other of is ethyl or propyl substituted with hydroxyl.

[0649] Embodiment 226:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 223, wherein the other of is ethyl or propyl substituted with 3-6 membered cycloalkyl and hydroxyl.

[0650] Embodiment 227:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, 223, and 226, wherein the other of is ethyl substituted with 3-4 membered cycloalkyl and hydroxyl.

[0651] Embodiment 228:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 223, wherein the other of is ethyl or propyl substituted with -SO2(C1-C6 alkyl).

[0652] Embodiment 229:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, 223, and 228, wherein the other of is ethyl or propyl substituted with -SO2CH3.

[0653] Embodiment 230:R A and R B is hydrogen, and R A and R B The compound according to any one of embodiments 212, 214, and 223, wherein the other of is ethyl or propyl substituted with -SO2(NH2).

[0654] Embodiment 231:R 4B contains one nitrogen ring member and one to two independently selected R G and 4-6 membered heterocyclyl optionally substituted by G 213. The compound of embodiment 212, wherein is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0655] Embodiment 232:R 4B but, [ka] wherein Ring B is azetidinyl, pyrrolidinyl, or piperidinyl, and is selected from 1 to 2 R, each independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G 232. The compound of embodiment 212 or 231, optionally substituted by:

[0656] Embodiment 233: A compound according to embodiment 232, wherein Ring B is azetidinyl.

[0657] Embodiment 234: A compound according to any one of embodiments 232-233, wherein Ring B is unsubstituted.

[0658] Embodiment 235: Ring B is one R G The compound according to any one of embodiments 232-233, substituted with:

[0659] Embodiment 236:R G The compound of embodiment 235, wherein is fluoro.

[0660] Embodiment 237:R G The compound of embodiment 235, wherein is cyano.

[0661] Embodiment 238:R G The compound of embodiment 235, wherein is hydroxyl.

[0662] Embodiment 239:R G The compound of embodiment 235, wherein is methyl.

[0663] Embodiment 240:R G The compound of embodiment 235, wherein is —CO 2 CH 3 .

[0664] Embodiment 241: Ring B is selected from two independently selected R G The compound according to any one of embodiments 232-233, substituted with:

[0665] Embodiment 242: Each R G The compound of embodiment 241, wherein is fluoro.

[0666] Embodiment 243: Each R G The compound according to embodiment 241, wherein is methyl.

[0667] Embodiment 244: One R G is hydroxyl, and the other R G The compound according to embodiment 241, wherein is methyl.

[0668] Embodiment 245: One R G is fluoro and the other R G1 The compound according to embodiment 241, wherein is methyl.

[0669] Embodiment 246: One R G is hydroxyl, and the other R G1 The compound of embodiment 241, wherein is fluoro.

[0670] Embodiment 247: Each R G is attached to a position on Ring B para to said nitrogen.

[0671] Embodiment 248: A compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1A is a halogen, R 1B is halogen or absent (the phenyl ring is 1A monosubstituted with R 2 is C1-C6 alkyl or C1-C6 haloalkyl, R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R 4 independently, -NR A R BC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 a...

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: Z is O or NR ｘ and R ｘ is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R １ are independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R ２ is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with one or two fluoro; R ３ is C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl; Ring A is a 6- to 10-membered aryl, C3-C8 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl; Each R ４ became independent, (i) halogen, (ii) one or two hydroxyl or -NR Ａ R Ｂ C1-C6 alkyl optionally substituted by (iii) C1-C6 alkoxy optionally substituted with 1 to 2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl; (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii)-CO ２ H、 ())) Ａ ( Ｂ 、 (i8)=NR Ａ２ 、 (x)-C(=O)NR Ｃ R Ｄ 、 (xi)-SO ２ (NR Ｅ R Ｆ )、 (xii) -SO ２ (C1-C6 alkyl), (xiii) —S(═O)(═NH)(C1-C6 alkyl), (xiv) —C(═O)(C1-C6 alkyl), (xv) —CO ２ (C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xvii) one or two independently selected R Ｇ 3- to 9-membered heterocyclyl optionally substituted by (xviii) one or two independently selected R Ｇ and is selected from the group consisting of 3- to 6-membered cycloalkyl optionally substituted by n is 0, 1, or 2; Each R Ａ , R Ａ１ , R Ｂ , R Ｂ１ , R Ｃ , R Ｃ１ , R Ｄ , R Ｄ１ , R Ｅ , and R Ｆ became independent, (i) hydrogen, (ii) hydroxyl, (iii) 4- to 6-membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) —C(═O)(C1-C6 alkyl), (vi) —C(═O)O(C1-C6 alkyl), (vii) -SO ２ (C1-C6 alkyl), (viii) a 3- to 6-membered cycloalkyl optionally substituted with hydroxyl, or (ix) hydroxyl, —C(═O)NR Ｂ２ R Ｃ２ , 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, —SO ２ (C1-C6 alkyl), —CO ２ H, and -SO ２ (NH ２ or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from R Ｃ and R Ｄ together with the nitrogen atom to which they are bonded, hydroxyl, halogen, -C(=O)NR Ｂ１ R Ｃ１ , -SO ２ (C1-C6 alkyl), —CO ２ forming a 4-10 membered heterocyclyl optionally substituted by 1-2 substituents independently selected from H, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; Each R Ａ２ , R Ｂ２ , and R Ｃ２ are independently hydrogen or C1-C6 alkyl; Each R Ｇ are independently fluoro, cyano, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, —NR Ａ１ R Ｂ１ , =NR Ａ２ , —C(═O)NR Ｃ１ R Ｄ１ , -CO ２ (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, —SO ２ (C1-C6 alkyl), and —CO ２ H; wherein the compound is 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 【Chemistry 2-5】 【Chemistry 2-6】 【Chemistry 2-7】 【Chemistry 2-8】 【Chemistry 2-9】 【Chemistry 2-10】 【Chemistry 2-11】 or a pharmaceutically acceptable salt thereof, which is not a compound selected from the group consisting of:

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

3. 2. The compound of claim 1, wherein m is 2. 【Request 4】 【Chemical 3】 but, 【Chemistry 4】 The compound according to any one of claims 1 to 3,

5. Each R １ The compound according to any one of claims 1 to 4, wherein is halogen.

6. Each R １ A compound according to any one of claims 1 to 5, wherein is selected from fluoro and chloro.

7. Each R １ The compound of any one of claims 1 to 6, wherein is fluoro.

8. One R １ The compound according to any one of claims 1 to 4, wherein is cyano.

9. One R １ The compound according to any one of claims 1 to 4, wherein is C1 to C6 alkyl or C3 to C6 cycloalkyl.

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

11. R ２ The compound according to any one of claims 1 to 10, wherein is C1 to C6 alkyl.

12. R ２ The compound of claim 11 , wherein is methyl.

13. R ２ The compound according to any one of claims 1 to 10, wherein is C1-C6 haloalkyl.

14. R ２ The compound of claim 13, wherein is difluoromethyl.

15. R ２ The compound of claim 13, wherein is trifluoromethyl.

16. R ２ The compound according to any one of claims 1 to 10, wherein is halogen.

17. R ２ The compound of any one of claims 1 to 10, wherein is a C3-C6 cycloalkyl optionally substituted with one or two fluoro.

18. R ３ The compound of any one of claims 1 to 17, wherein is C1-C6 haloalkyl.

19. R ２ The compound according to any one of claims 1 to 18, wherein is difluoromethyl.

20. R ２ The compound of any one of claims 1 to 18, wherein is trifluoromethyl.

21. R ３ The compound according to any one of claims 1 to 17, wherein is C1 to C6 alkyl.

22. R ３ is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl.

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

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

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

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

27. The compound of any one of claims 1 to 25, wherein ring A is pyridyl.

28. The compound of any one of claims 1 to 25, wherein ring A is thiazolyl.

29. The compound of any one of claims 1 to 25, wherein ring A is thiophenyl.

30. The compound of any one of claims 1 to 25, wherein ring A is pyrazolyl.

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

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

33. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is benzimidazolyl.

34. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is indazolyl.

35. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is indolyl.

36. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is quinazolone.

37. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is isobenzofuranonyl.

38. The compound according to any one of claims 1 to 23 and 31 to 32, wherein ring A is isoindolinonyl.

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

40. The compound of any one of claims 1 to 22, wherein ring A is phenyl.

41. The compound according to any one of claims 1 to 22, wherein ring A is C3 to C8 cycloalkyl.

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

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

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

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

46. One R ４ The compound of any one of claims 1 to 45, wherein is unsubstituted C1-C6 alkyl.

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

48. One R ４ The compound of any one of claims 1 to 45, wherein is C1-C6 haloalkyl.

49. One R ４ is hydroxyl, cyano, -CO ２ H, halogen, or 1-2 hydroxyl or -NR Ａ R Ｂ 46. ​​The compound of any one of claims 1 to 45, wherein the compound is C1-C6 alkyl substituted with

50. One R ４ But, -NR Ａ R Ｂ , —C(═O)NR Ｃ R Ｄ , -SO ２ (NR Ｅ R Ｆ ), -SO ２ (C1-C6 alkyl), —S(═O)(═NH)(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), or —CO ２ (C1-C6 alkyl).

51. One R ４ 46. ​​The compound of any one of claims 1 to 45, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

52. One R ４ is one or two independently selected R Ｇ 46. ​​The compound of any one of claims 1 to 45, which is a 3- to 9-membered heterocyclyl optionally substituted by:

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

54. Z is NR ｘ The compound according to any one of claims 1 to 52,

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

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

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

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

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

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