Methods for treating cancer

Abstract

This disclosure provides compounds of formula (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα), and their pharmaceutically acceptable salts. These chemical entities can be used, for example, to treat, conditions, diseases, or lesions (e.g., cancer) in individuals (e.g., humans) caused by increased (e.g., overactivation) of PI3Kα. This disclosure also provides compositions containing these chemical entities, as well as their use and methods of preparation.

Description

Technical field

[0001] Cross-reference of related applications

[0002] This application claims U.S. Application No. 63 / 210,370 filed on June 14, 2021, U.S. Application No. 63 / 228,351 filed on August 2, 2021, and U.S. Application No. 63 / 228,351 filed on December 13, 2021 Application No. 63 / 288,909, U.S. Application No. 63 / 316,017 filed on March 3, 2022, U.S. Application No. 63 / 319,236 filed on March 11, 2022, and U.S. Application No. 63 / 319,236 filed on June 2, 2022 Priority benefit from U.S. Application No. 63 / 348,261, the contents of which are incorporated herein by reference.

[0003] The present disclosure provides compounds of formula (I) and formula (II) that inhibit phosphatidyl inositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα) and their pharmaceutical applications. Take the salt of acceptance. Such chemical entities may be used, for example, to treat a condition, disease or disorder in which increased (eg excessive) activation of PI3Kα contributes to lesions and / or symptoms and / or progression of the condition, disease or disorder (eg, cancer) in an individual (eg, a human). The present disclosure also provides compositions containing these chemical entities and methods of their use and preparation.

Prior technology

[0004] Phosphatidyl inositol 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 involved in several human cancers. changes happened. Several researchers have demonstrated that the role of PI3K / AKT signaling involves physiological and pathophysiological functions that drive tumor progression, such as metabolism, cell growth, proliferation, angiogenesis, and cancer 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" "Targeting the PI3K pathway in cancer: Are we making headway?" "Nat. Rev. Clin. Oncol." 2018, 15, 273-291. Inhibition of / TOR signaling (e.g., pharmacological or genetic) can cause cancer cell death and regression of tumor growth.

[0005] The PI3K pathway can be activated, for example, through point mutations in the PIK3CA gene or through inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30%-50% of human cancers and contributes to resistance to various anti-cancer therapies. (See Martini, M. et al., "PI3K / AKT signaling pathway and cancer: An updated review." Ann. Med. 2014, 46, 372-383 and Bauer, T.M. et al., "Targeting PI3 kinase in cancer". "Pharmacol. Ther." 2015, 146, 53-60.) PI3K It consists of three subunits: p85 regulatory subunit, p55 regulatory subunit and p110 catalytic subunit. According to their different structures and specific receptors, PI3K is divided into three categories: I, II and III. Class I PI3K includes Class IA and Class IB PI3K. Class IA PI3K is a heterodimer of the p85 regulatory subunit and the p110 catalytic subunit and is the type most clearly implicated in human cancer. Class IA PI3Ks include p110α, p110β, and p110δ catalytic subunits produced by different genes (PIK3CA, PIK3CB, and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit among class IB PI3Ks. PIK3CA is a gene encoding the p110α subunit, which is frequently mutated or amplified in many human cancers such as breast, colorectal, gastric, cervical, prostate and lung cancers. (See Samuels Y et al., "High frequency of mutations of the PIK3CAgene in human cancers." Science. 2004;304:554.)

[0006] However, the development of PI3K inhibitors has been problematic for several reasons, including (i) the molecular mechanisms of fat adaptation following therapeutic inhibition of PI3K; (ii) the inability to specifically inhibit the development of PI3K inhibitors through PIK3CA mutations. signaling while circumventing endogenous p110α; (iii) limited use of these therapies in rational combinations, including those with strong mechanistic support; and (iv) dose-limiting toxicities that prevent sustained PI3K pathway inhibition. (See Hanker et al., "Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors", Cancer Discovery ( Cancer Discovery, Apr 2019;9: 482-491.) For example, alpelisib is an alpha-selective PI3K inhibitor that is equivalent to wild-type and mutant forms of PI3Kα. sex. However, the therapeutic benefit of apicoxib is limited by inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities, including hyperglycemia.

[0007] Additionally, there are other factors and compensatory pathways derived from clinical and in vitro laboratory studies that influence PI3K signaling, such as HRAS and KRAS mutations, which reduce sensitivity to PI3K inhibitors (and whose genetic expression has been blocked) Demonstrates increased sensitivity to PI3K inhibitors). (See Misrha, R.; "PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects". "International Journal of Molecular Sciences (Int. J. Mol. Sci.) 2021, 22, 3464"

[0008] Domain deletion in PIK3CA significantly activates PI3K signaling and also increases sensitivity to PI3K inhibitors. (See Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426-1435.) Therefore, targeting PI3Kα represents an approach to treat proliferative disorders such as cancer. [Content of the invention]

[0009] Some embodiments provide a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; Each R1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R2 is halogen, hydroxyl, optional C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl group, C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups optionally; R3 is C1-C6 alkyl, C1-C6 haloalkyl Or optionally, a C3-C6 cycloalkyl group substituted by 1 or 2 substituents independently selected from fluoro group and C1-C6 alkyl group; Ring A is a 6-10 membered aryl group, C3-C8 cycloalkyl group, 5 - 10-membered heteroaryl or 4-10-membered heterocyclyl; each R4 is independently selected from the group consisting of: (i) halogen, (ii) C1- substituted by 1 or 2 hydroxyl groups or -NRARB as appropriate C6 alkyl, (iii) optionally C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) )hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NREF), (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 by C1-C6 alkyl, (xvii) 3- optionally substituted by 1 or 2 independently selected RG 9-membered heterocyclyl, and (xviii) 3-6-membered cycloalkyl substituted by 1 or 2 independently selected RG as appropriate; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(= O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) optionally substituted with hydroxyl 3-6 membered cycloalkyl, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NRB2RC2, 5-6 membered hetero Aryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached are formed by 1-2 as appropriate 4-10 membered heterocyclyl groups independently selected from the following substituents: hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, optionally substituted with hydroxyl C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; each RA2, RB2 and RC2 is independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: Fluoro group, cyano group, hydroxyl group, optionally substituted C1-C6 alkyl group with hydroxyl group, C1-C6 alkoxy group, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl group) , C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H; and wherein the compound is not selected from the group consisting of Compound:.

[0010] Some embodiments provide a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from halogen, hydroxyl, cyano, optionally a C1-C6 alkane substituted by hydroxyl base, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 haloalkyl, optionally substituted by 1 or 2 fluoro-substituted C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or optionally 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl Substituted C3-C6 cycloalkyl; Ring A is 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; each R4 is independently selected from the following The group of: (i) halogen, (ii) C1-C6 alkyl optionally substituted by 1 or 2 hydroxyl groups or -NRARB, (iii) optionally substituted by 1-2 hydroxyl groups and C3-C6 C1-C6 alkoxy substituted by the substituent of cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix ) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH) (C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) optionally substituted by C1-C6 alkyl 5-6 membered heteroaryl, (xvii) 3-9 membered heterocyclyl optionally substituted by 1 or 2 independently selected RG, and (xviii) optionally substituted by 1 or 2 independently selected RG 3-6 membered cycloalkyl; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently (i) hydrogen, (ii) hydroxyl, ( iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1- C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) optionally 1-2 independently selected from C1-C6 alkyl substituted by the following substituents: hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl group optionally substituted with 1-2 substituents independently selected from: hydroxyl, halogen, - C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; each RA2 , RB2 and RC2 are independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group substituted by hydroxyl group as appropriate, C1-C6 Alkoxy, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2 (C1-C6 alkyl) and -CO2H; and wherein the compound is not a compound selected from the group consisting of:.

[0011] Some embodiments provide a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: each R1 is independently selected from halogen, hydroxyl, cyano, optionally a C1-C6 alkane substituted by hydroxyl base, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R2 is halogen, hydroxyl, C1-C6 alkyl optionally substituted by hydroxyl, C1-C6 haloalkyl, optionally substituted by 1 or 2 fluoro-substituted C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or optionally 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl Substituted C3-C6 cycloalkyl; Ring A is 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; each R4 is independently selected from the following The group of: (i) halogen, (ii) C1-C6 alkyl optionally substituted by 1 or 2 hydroxyl groups or -NRARB, (iii) optionally substituted by 1-2 hydroxyl groups and C3-C6 C1-C6 alkoxy substituted by the substituent of cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix ) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (xii) -SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH) (C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv) -CO2(C1-C6 alkyl), (xvi) optionally substituted by C1-C6 alkyl 5-6 membered heteroaryl, (xvii) 3-9 membered heterocyclyl optionally substituted by 1 or 2 independently selected RG, and (xviii) optionally substituted by 1 or 2 independently selected RG 3-6 membered cycloalkyl; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently (i) hydrogen, (ii) hydroxyl, ( iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1- C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) optionally 1-2 independently selected from C1-C6 alkyl substituted by the following substituents: hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl group optionally substituted with 1-2 substituents independently selected from: hydroxyl, halogen, - C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; each RA2 , RB2 and RC2 are independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group substituted by hydroxyl group as appropriate, C1-C6 Alkoxy, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, - SO2 (C1-C6 alkyl) and -CO2H.

[0012] Some embodiments provide compounds of formula (I) having formula (X): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl or C3-C6 Cycloalkyl; each R1 is an independently selected halogen; m is 0, 1, 2 or 3; R2 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted by 1 or 2 fluoro groups C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; Ring A is 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; each R4 is independently selected from the group consisting of: halogen, optionally substituted by 1 or 2 hydroxyl groups or -NRARB C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NREF), -SO2(C1- C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 3-6-membered heteroaryl and 3-6-membered heterocyclyl or 3-6-membered cycloalkyl substituted by 1 or 2 independently selected RG as appropriate; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF 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 by hydroxyl, or C1-C6 alkyl optionally substituted by 1-2 substituents independently selected from the following: hydroxyl, -C(= O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6 alkyl), -SO2(NH2; or RC and RD together with the nitrogen atom to which they are attached form 4- 6-membered heterocyclic group; each RG is independently selected from the group consisting of: fluorine group, hydroxyl group, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, -C(=O)NRC1RD1, -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H; and wherein the compound is not a compound selected from the group consisting of:.

[0013] This article also provides a pharmaceutical composition, which includes a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0014] Provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or as provided herein. Pharmaceutical compositions.

[0015] Also provided herein is a method for treating cancer in an individual in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof; and (b) administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0016] This article provides a method for treating a PI3Kα-related disease or disorder in an individual, which method includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical thereof to an individual identified or diagnosed as suffering from a PI3Kα-related disease or disorder. acceptable salts or pharmaceutical compositions as provided herein.

[0017] The present disclosure also provides a method of treating a PI3Kα-related disease or disorder in an individual, the method comprising: determining that the individual's cancer is a PI3Kα-related disease or disorder; and administering a therapeutically effective amount of Formula (I) to the individual. compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0018] This article further provides a method of treating PI3Kα-related cancer in an individual, the method comprising administering to an individual identified or diagnosed as suffering from PI3Kα-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable version thereof. Salts or pharmaceutical compositions as provided herein.

[0019] The present disclosure also provides a method of treating a PI3Kα-related cancer in an individual, the method comprising: determining that the individual's cancer is a PI3Kα-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (I) or a medicine thereof a pharmaceutically acceptable salt or a pharmaceutical composition as provided herein.

[0020] Provided herein is a method of treating an individual, the method comprising administering a therapeutically effective amount of a compound of formula (I) to an individual who has clinical records indicating an imbalance in the expression or activity or content of the individual's PIK3CA gene, PI3Kα protein, or any of them. or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

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

[0022] Some embodiments of the methods and compositions described herein include a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1 is an independently selected halogen; m is 0, 1, 2 or 3; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1- C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; Ring A is 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4- 10-membered heterocyclyl; each R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl substituted by 1 or 2 hydroxyl groups or -NRARB as appropriate , hydroxyl, cyano, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl) , -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and 3-6 members substituted by 1 or 2 independently selected RG as appropriate. Heterocyclyl; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkane Base, -C(=O)(C1-C6 alkyl), C(=O)O(C1-C6 alkyl), -SO2(C1-C6 alkyl), optionally 3-6 members substituted by hydroxyl group Cycloalkyl or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered ring Alkyl, -SO2(C1-C6 alkyl) and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached form optionally substituted with 1-2 substituents independently selected from the following 4-10 membered heterocyclic group: hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, optionally substituted C1-C6 alkyl with hydroxyl, C1-C6 alkoxy group and C1-C6 haloalkoxy; each RA2, RB2 and RC2 is independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, as appropriate Hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 Cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H.

[0023] This article also provides a pharmaceutical composition, which includes a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0024] Provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof or as provided herein. Pharmaceutical compositions.

[0025] Also provided herein is a method for treating cancer in an individual in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof. ; and (b) administering to the individual a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0026] Provided herein is a method for treating a PI3Kα-related disease or disorder in an individual, the method comprising administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutical thereof to an individual identified or diagnosed as suffering from a PI3Kα-related disease or disorder. acceptable salts or pharmaceutical compositions as provided herein.

[0027] The present disclosure also provides a method of treating a PI3Kα-related disease or disorder in an individual, the method comprising: determining that the individual's cancer is a PI3Kα-related disease or disorder; and administering to the individual a therapeutically effective amount of Formula (II) compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0028] This article further provides a method of treating PI3Kα-related cancer in an individual, the method comprising administering to an individual identified or diagnosed as suffering from PI3Kα-related cancer a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable version thereof. Salts or pharmaceutical compositions as provided herein.

[0029] The present disclosure also provides a method of treating a PI3Kα-related cancer in an individual, the method comprising: determining that the individual's cancer is a PI3Kα-related cancer; and administering to the individual a therapeutically effective amount of a compound of formula (II) or a medicine thereof a pharmaceutically acceptable salt or a pharmaceutical composition as provided herein.

[0030] Provided herein is a method of treating an individual, the method comprising administering a therapeutically effective amount of a compound of formula (II) to an individual who has clinical records indicating an imbalance in the expression or activity or content of the individual's PIK3CA gene, PI3Kα protein, or any of them. or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0031] The present disclosure also provides a method for inhibiting PI3Kα in mammalian cells, which method includes contacting the mammalian cells with an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0032] Other embodiments include those described in the embodiments and / or claims. additional definitions

[0033] To facilitate understanding of the disclosures set forth herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those that are 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 of ordinary skill in the art to which this disclosure belongs. Patents, applications, published applications, and other publications mentioned throughout this specification and in the appendices are each incorporated by reference in their entirety.

[0034] The use of the term "about" in reference to a number or range of numbers means that the number or range of numbers mentioned is an approximation, for example, within experimental variability and / or statistical experimental error, and therefore the number or range of numbers may be consistent with the stated number or range of numbers. The stated figures or ranges of figures may differ by up to ±10%.

[0035] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means not having sustained deleterious effects on the overall health of the individual treated.

[0036] The term "inhibit" or "inhibition of" means reducing by a measurable amount or preventing it entirely (eg, 100% inhibition).

[0037] "API" means active pharmaceutical ingredient.

[0038] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a chemical entity administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including a compound as disclosed herein required to achieve a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any appropriate technique, such as dose escalation studies.

[0039] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, components are "pharmaceutically acceptable" insofar as they are compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with human and animal tissues or organs without undue toxicity, Irritation, allergic reactions, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients ", 6th edition; edited by Rowe et al.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; "Handbook of Pharmaceutical Additives", 3rd edition; edited by Ash and Ash; Gower Publishing Company: 2007; " Pharmaceutical Preformulation and Formulation, 2nd edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0040] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not produce significant irritation to an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are prepared by combining the compounds described herein with compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and Its analogues are obtained by acid reaction. 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 or by other predetermined methods, such as ammonium salts; alkali metal salts Salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; salts of organic bases, such as dicyclohexylamine; N-methyl-D-reduced glucosamine; ginseng (hydroxymethyl)methane Amines and salts with amino acids such as arginine, lysine and their analogs. The pharmacologically acceptable salt is not particularly limited as long as it can be used in pharmaceutical preparations. Examples of salts of the compounds described herein with bases include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; Salts with basic amino acids, such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specific examples of which are acid addition salts formed 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, etc. Acids, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids, such as asparagine Acid and glutamic acid.

[0041] The term "pharmaceutical composition" refers to a compound described herein together with other chemical components (collectively referred to herein as "pharmaceutically acceptable excipients"), such as carriers, stabilizers, diluents, Mixture of dispersing agents, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate administration of compounds to an organism. A variety of techniques exist in the art for administering compounds, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0042] 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, cattle, sheep, horses, primates and humans. In some embodiments, the subject is a human. In some embodiments, the individual has experienced and / or exhibited at least one symptom of the disease or condition to be treated and / or prevented.

[0043] As used herein, the terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, complete or partial relief of symptoms associated with a disease or disorder or condition, reduction in the severity of the disease, stabilization of the disease (i.e., no worsening), delay or slowing of disease progression, disease condition (e.g. improvement or alleviation of one or more symptoms of a disease, and remission (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to expected survival without treatment.

[0044] The term "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0045] The term "pendant oxy" refers to a divalent double bonded oxygen atom (i.e., "=O"). As used herein, a pendant oxy group is attached to a carbon atom to form a carbonyl group.

[0046] The term "hydroxy" refers to the -OH group.

[0047] The term "cyano" refers to the -CN group.

[0048] The term "alkyl" refers to a saturated aliphatic straight or branched chain hydrocarbon group containing the specified number of carbon atoms. For example, a C1-10 indicating group may have 1 to 10 (inclusive) carbon atoms therein. Alkyl groups may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tertiary butyl, n-hexyl. The term "saturated" as used herein means that there are only single bonds between the constituent carbon atoms and other available valencies occupied by hydrogen and / or other substituents as defined herein.

[0049] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by an independently selected halo group.

[0050] The term "alkoxy" refers to -O-alkyl (eg -OCH3).

[0051] The term "aryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group of 6 to 20 carbons in which at least one ring in the system is an aromatic ring (e.g., a monocyclic, bicyclic, 6-carbon, or polycyclic group of 6 to 20 carbons). A 10-carbon bicyclic or a 14-carbon tricyclic aromatic ring system); and 0, 1, 2, 3 or 4 atoms of each ring may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl and the like.

[0052] As used herein, the term "cycloalkyl" means having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3- A cyclic saturated hydrocarbon group with 10 ring carbons or 3-6 ring carbons, in which the cycloalkyl group may be substituted as appropriate. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups 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 and similar groups. Cycloalkyl also includes spiro rings (eg, spiro bicyclos, in which two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4] Nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane and similar groups. As used herein, the term "saturated" means that there are only single bonds between the constituent carbon atoms.

[0053] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic radical having 5 to 20 ring atoms, or 5, 6, 9, 10 or 14 ring atoms. Group; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O and S and at least one ring in the system is an aromatic ring (but not necessarily a heteroatom-containing Ring, such as tetrahydroisoquinolyl, such as tetrahydroquinolinyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, azolyl, diazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, Piranyl, pyridyl, pyrimidinyl, pyridyl, triyl, thiazolylbenzothienyl, benzodiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indo Azolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido[2,3-d]pyrimidinyl, pyrro[2,3-b]pyridinyl base, quinazolinyl, quinolinyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyridyl Azolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxa Cyclohexadiene, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][ 1,4]oxathiane, isoindoline and others. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, piperanyl, pyryl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylic analogs thereof, in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (for example), pyrimidinone (for example), pyridone (for example), pyridone (for example) and imidazolone (for example), wherein with the carbonyl Each adjacent ring nitrogen is tertiary (i.e., the pendant oxygen group (i.e., "=O") herein is a constituent of the heteroaromatic ring).

[0054] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms (e.g., 5 to 8 membered monocyclic, 8 to 12 membered bicyclic or 11-14 membered tricyclic ring system), if it is monocyclic, it has 1-3 heteroatoms; if it is bicyclic, it has 1-6 heteroatoms, or if it is tricyclic or polycyclic, it has 1-6 heteroatoms It has 1-9 heteroatoms selected from O, N or S (e.g. carbon atoms, and 1-3, 1-6 or 1- in the case of monocyclic, bicyclic or tricyclic rings respectively. 9 heteroatoms of N, O or S), where one or more ring atoms may be substituted by 1 to 3 pendant oxygen groups (forming, for example, lactams) and one or more N or S atoms, if the valency allows Can be substituted by 1-2 oxygen ion groups (forming, for example, N-oxide, S-oxide or S,S-dioxide); and 0, 1, 2 or 3 atoms of each ring can be Substituted with substituents. Examples of heterocyclic groups include piperyl, pyrrolidinyl, dialkyl, linyl, tetrahydrofuryl, tetrahydropyridyl, dihydropyryl, dihydropyridyl, dihydropyrrolyl, dihydrofuryl, dihydrogen Thienyl and similar groups. Heterocyclyl groups can contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane Alkane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrcyclopenta[c]pyrrole , 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0] Octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1. 0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[ 3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxa Bicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane and similar groups. Heterocyclyl also includes spirocycles (eg, spirobicycles in which two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclyl 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 alkane, 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-oxasspiro[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 similar groups.

[0055] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyridine, pyridine, pyridone, pyrrole, pyrazole, azole, thiazole, isoxazole, isothiazole, and the like.

[0056] As used herein, when a ring is described as "partially unsaturated," it is meant that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; e.g., the atoms that make up the ring one or more double or triple bonds), provided that the ring is non-aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0057] For the avoidance of doubt, and unless otherwise stated, for rings and ring systems (e.g., aryl groups described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., a tricyclic, polycyclic system) , heteroaryl, heterocyclyl, cycloalkyl and similar groups), it should be understood that such rings and cyclic groups include rings and cyclic groups with fused rings, including those in which the fusion point is located at: Rings and cyclic groups on: (i) adjacent ring atoms (such as [x.x.0] ring system, where 0 represents a zero-atom bridge (for example)); (ii) single ring atoms (spiro-fused ring system) ( for example), or (iii) a continuous array of ring atoms (a bridged ring system in which all bridge lengths are greater than 0) (for example).

[0058] Additionally, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms with the same atomic number but different mass numbers. By way of general example, and not limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include 13C and 14C.

[0059] Furthermore, compounds generally or specifically disclosed herein are intended to encompass all tautomeric forms. Thus, for example, a compound containing the moiety: encompasses tautomeric forms containing the moiety:. Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxyl encompasses the pyridinone or pyrimidinone tautomeric forms.

[0060] The compounds provided herein may encompass a variety of stereochemical forms. Compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures and non-enantiomers. Mixtures of enantiomers, as well as individual enantiomers and diastereomers resulting from structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying stereochemistry (e.g., a "planar" structure) and having one or more chiral centers, it is understood that all possible stereoisomers of the compound are represented. . Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies stereochemistry (e.g., a structure with "wedge" and / or "dashed" bonding) and has one or more chiral centers, it should be Understand the indicated stereoisomers that represent compounds.

[0061] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claimed scope.

Implementation

[0063] The present disclosure provides compounds of formula (I) and formula (II) that inhibit phosphatidyl inositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα) and their pharmaceutical uses Take the salt of acceptance. Such chemical entities may be used, for example, to treat a condition, disease or disorder in which increased (eg excessive) activation of PI3Kα contributes to lesions and / or symptoms and / or progression of the condition, disease or disorder (eg, cancer) in an individual (eg, a human). The present disclosure also provides compositions containing these chemical entities and methods of their use and preparation. Compounds of formula (I)

[0064] Some embodiments provide a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; Each R1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R2 is halogen, hydroxyl, optional C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl group, C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups optionally; R3 is C1-C6 alkyl, C1-C6 haloalkyl Or optionally, a C3-C6 cycloalkyl group substituted by 1 or 2 substituents independently selected from fluoro group and C1-C6 alkyl group; Ring A is a 6-10 membered aryl group, C3-C8 cycloalkyl group, 5 - 10-membered heteroaryl or 4-10-membered heterocyclyl; each R4 is independently selected from the group consisting of: (i) halogen, (ii) C1- substituted by 1 or 2 hydroxyl groups or -NRARB as appropriate C6 alkyl, (iii) optionally C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) )hydroxyl, (vi) cyano, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NREF), (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 by C1-C6 alkyl, (xvii) 3- optionally substituted by 1 or 2 independently selected RG 9-membered heterocyclyl, and (xviii) 3-6-membered cycloalkyl substituted by 1 or 2 independently selected RG as appropriate; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C(= O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2(C1-C6 alkyl), (viii) optionally substituted with hydroxyl 3-6 membered cycloalkyl, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NRB2RC2, 5-6 membered hetero Aryl, 3-6 membered cycloalkyl, SO2 (C1-C6 alkyl), -CO2H and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached are formed by 1-2 as appropriate 4-10 membered heterocyclic groups independently selected from the following substituents: hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1 optionally substituted with hydroxyl - C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; each RA2, RB2 and RC2 is independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, optionally substituted C1-C6 alkyl group by hydroxyl group, C1-C6 alkoxy group, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl group), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H; and wherein the compound is not a compound selected from the group consisting of : .

[0065] In some embodiments, when Z is NRx and R3 is methyl, Ring A is not phenyl.

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

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

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

[0069] Some embodiments provide compounds of formula (I) having formula (X): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl, or C3-C6 Cycloalkyl; each R1 is an independently selected halogen; m is 0, 1, 2 or 3; R2 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted by 1 or 2 fluoro groups C3-C6 cycloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or optionally a C3-C6 ring substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl Alkyl; Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl or 4-10-membered heterocyclyl; each R4 is independently selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O) substituted by 1 or 2 hydroxyl groups or -NRARB as appropriate NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl and 3-6 membered heterocyclyl optionally substituted by 1 or 2 independently selected RG or 3-6 membered cycloalkyl; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen, 4-6 membered heterocyclyl, C1 -C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), optionally 3-6 membered cycloalkyl substituted by hydroxyl group or optionally substituted by 1-2 A C1-C6 alkyl group independently selected from the following substituents: hydroxyl, -C(=O)NRB2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1-C6 alkyl ), -SO2(NH2; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl group; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1 -C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H; and wherein the compound is not a compound selected from the group consisting of:.

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

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

[0072] In some embodiments, the compounds described herein are compounds that are not selected from the groups described above (i.e., "excluded compounds"). In some embodiments, the excluded compounds are planar structures, as indicated above. In some embodiments, the excluded compounds are specific stereoisomers, such as specific enantiomers or diastereomers. In some embodiments, the excluded compounds are the R isomers. In some embodiments, the excluded compound is the S isomer. In some embodiments, one or more of the excluded compounds are the R isomer, and the remaining excluded compounds are the S isomer. In some embodiments, the excluded compounds are the R isomers. In some embodiments, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

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

[0074] In some embodiments, is. In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is . In some embodiments, is or.

[0075] In some embodiments, each R1 is an independently selected halogen. In some embodiments, each R1 is independently selected from fluorine and chlorine. In some embodiments, each R1 is independently selected from fluoro and bromo. In some embodiments, each R1 is fluoro. In some embodiments, at least one R1 is independently selected halogen. In some embodiments, at least one R1 is independently selected from fluoro and chloro. In some embodiments, at least one R1 is fluoro.

[0076] In some embodiments, at least one R1 is cyano. In some embodiments, at least one R1 is hydroxyl. In some embodiments, at least one R1 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, at least one R1 is C1-C6 alkyl substituted with hydroxyl. In some embodiments, at least one R1 is C1-C3 alkyl substituted with hydroxyl. In some embodiments, at least one R1 is hydroxymethyl. In some embodiments, at least one R1 is unsubstituted C1-C6 alkyl. In some embodiments, at least one R1 is methyl. In some embodiments, at least one R1 is C3-C6 cycloalkyl. In some embodiments, at least one R1 is cyclopropyl.

[0077] In some embodiments, m is 2; one R1 is halogen; and the other R1 is C1-C6 alkyl. In some embodiments, m is 2; one R1 is fluoro; and the other R1 is methyl. In some embodiments, m is 2; one R1 is halogen; and the other R1 is C3-C6 cycloalkyl. In some embodiments, m is 2; one R1 is halogen; and the other R1 is cyclopropyl. In some embodiments, m is 2; one R1 is fluoro; and the other R1 is cyano. In some embodiments, m is 2; one R1 is halogen; and the other R1 is halogen. In some embodiments, m is 2; one R1 is fluoro; and the other R1 is fluoro.

[0078] In some embodiments, R2 is hydroxyl. In some embodiments, R2 is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R2 is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R2 is C1-C3 alkyl substituted with hydroxyl. In some embodiments, R2 is hydroxymethyl. In some embodiments, R2 is unsubstituted C1-C6 alkyl. In some embodiments, R2 is unsubstituted C1-C3 alkyl. In some embodiments, R2 is methyl.

[0079] In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is C1-C3 haloalkyl. In some embodiments, R2 is difluoromethyl. In some embodiments, R2 is trifluoromethyl.

[0080] In some embodiments, R2 is halogen. In some embodiments, R2 is fluoro. In some embodiments, R2 is chloro.

[0081] In some embodiments, R2 is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro groups. In some embodiments, R2 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro groups. In some embodiments, R2 is C3-C6 cycloalkyl substituted with 1 fluoro group. In some embodiments, R2 is C3-C6 cycloalkyl substituted with 2 fluoro groups. In some embodiments, R2 is C3-C4 cycloalkyl substituted with 1 fluoro group. In some embodiments, R2 is C3-C4 cycloalkyl substituted with 2 fluoro groups. In some embodiments, R2 is unsubstituted C3-C6 cycloalkyl.

[0082] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C3 alkyl. In some embodiments, R3 is methyl, ethyl, tertiary butyl, or isopropyl. In some embodiments, R3 is methyl, ethyl or isopropyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl.

[0083] In some embodiments, R3 is C1-C6 haloalkyl. In some embodiments, R3 is C1-C3 haloalkyl. In some embodiments, R3 is difluoromethyl. In some embodiments, R3 is trifluoromethyl.

[0084] In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 fluoro group. In some embodiments, R3 is a C3-C6 cycloalkyl group substituted with 1 fluoro group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, R3 is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 methyl groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 or 2 methyl groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 methyl group. In some embodiments, R3 is a C3-C6 cycloalkyl group substituted with 1 methyl group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, R3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, the C3-C6 cycloalkyl group of R3 is cyclopropyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is cyclobutyl. In some embodiments, R3 is cyclopentyl. In some embodiments, R3 is cyclohexyl.

[0085] 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.

[0086] 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.

[0087] In some embodiments, Ring A is 5-10 membered heteroaryl. In some embodiments, Ring A is 9-10 membered heteroaryl. In some embodiments, Ring A is 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.

[0088] In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, imidazo[1,2- a]pyridyl or imidazo[1,2-a]pyrimidinyl. In some embodiments, Ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinonyl, 5,6,7,8-tetrahydro Imidazo[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]pyridyl. In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridyl. In some embodiments, Ring A is selected from the group consisting of and, where "*" indicates the point of attachment to the urea nitrogen atom in Formula (I).

[0089] In some embodiments, Ring A is a 5-6 membered heteroaryl. In some embodiments, Ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, azolyl, isoxazolyl, isothiazolyl, thiazolyl, furanyl A group consisting of azine group, diazolyl group, thiadiazolyl group, triazolyl group and thiiatriazolyl group. In some embodiments, Ring A is selected from the group consisting of pyridyl, pyrimidinyl, pyridyl, pyridyl, and triyl. In some embodiments, Ring A is pyrimidinyl, pyridyl, thiazolyl, thienyl, or pyrazolyl. In some embodiments, Ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, Ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, Ring A is selected from the group consisting of, where "*" 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, wherein "*" indicates the point of attachment to the urea nitrogen atom in Formula (I). In some embodiments, Ring A is 4-10 membered heterocyclyl. In some embodiments, Ring A is 6-9 membered heterocyclyl. In some embodiments, Ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopiranyl-1,1-dioxide.

[0090] In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridyl. In some embodiments, Ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridyl.

[0091] In some embodiments, Ring A is selected from the group consisting of 3-piperidinyl.

[0092] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0093] In some embodiments, one R4 is C1-C6 alkyl. In some embodiments, one R4 is unsubstituted C1-C6 alkyl. In some embodiments, one R4 is C1-C4 alkyl. In some embodiments, one R4 is tertiary butyl. In some embodiments, one R4 is methyl.

[0094] In some embodiments, one R4 is C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R4 is C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and cyclopropyl. In some embodiments, one R4 is C1-C6 alkoxy substituted with hydroxyl. In some embodiments, one R4 is C1-C6 alkoxy substituted with C3-C6 cycloalkyl. In some embodiments, one R4 is substituted C1-C6 alkoxycyclopropyl. In some embodiments, R4 is C1-C6 alkoxy. In some embodiments, R4 is C1-C3 alkoxy. In some embodiments, one R4 is methoxy.

[0095] In some embodiments, one R4 is C1-C6 haloalkyl. In some embodiments, one R4 is C1-C3 haloalkyl. In some embodiments, one R4 is difluoromethyl. In some embodiments, one R4 is trifluoromethyl.

[0096] In some embodiments, one R4 is hydroxyl. In some embodiments, one R4 is cyano. In some embodiments, one R4 is -CO2H. In some embodiments, one R4 is halogen. In some embodiments, one R4 is fluoro. In some embodiments, one R4 is chloro.

[0097] In some embodiments, one R4 is C1-C6 alkyl optionally substituted with 1-2 hydroxyl groups. In some embodiments, one R4 is C1-C6 alkyl substituted with 1-2 hydroxyl groups. In some embodiments, one R4 is C1-C6 alkyl substituted with 1 hydroxyl group. In some embodiments, one R4 is C1-C6 alkyl substituted with 2 hydroxyl groups. In some embodiments, one R4 is C1-C3 alkyl substituted with 2 hydroxyl groups. In some embodiments, one R4 is C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, one R4 is C1-C6 alkyl substituted with -NRARB. In some embodiments, one R4 is methyl or ethyl substituted with -NRARB. In some embodiments, one R4 is unsubstituted C1-C6 alkyl. In some embodiments, one R4 is methyl.

[0098] In some embodiments, one R4 is -NRARB.

[0099] In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NRB2RC2. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl or -C(=O)NH2. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is -C(=O)O(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is -C(=O)OCH3. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 4-6 membered heterocyclyl (e.g., oxetane). In some embodiments, RA and One of RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl base or 1-hydroxy-2-propyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl-substituted butyl (eg, 2-hydroxy-2-methyl-1-propyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, each of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, each of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is C1-C6 alkyl. In some embodiments, each of RA and RB is C1-C3 alkyl. In some embodiments, each RA and RB is methyl.

[0100] In some embodiments, both RB2 and RC2 are hydrogen. In some embodiments, one of RB2 and RC2 is hydrogen and the other of RB2 and RC2 is C1-C6 alkyl. In some embodiments, one of RB2 and RC2 is hydrogen and the other of RB2 and RC2 is methyl. In some embodiments, both RB2 and RC2 are methyl.

[0101] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 haloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 haloalkyl. In some embodiments, each of RA and RB is C1-C6 haloalkyl. In some embodiments, each of RA and RB is C1-C3 haloalkyl.

[0102] In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl.

[0103] In some embodiments, one R4 is -C(=O)NRRCRD.

[0104] In some embodiments, each of RC and RD is hydrogen. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C3 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is methyl. In some embodiments, RC and RD are each C1-C6 alkyl. In some embodiments, each of RC and RD is C1-C3 alkyl. In some embodiments, each of RC and RD is methyl. In some embodiments, one of RC and RD is C1-C6 alkyl and the other of RC and RD is C1-C3 alkyl.

[0105] In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 haloalkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C3 haloalkyl. In some embodiments, each of RC and RD is C1-C6 haloalkyl. In some embodiments, one of RC and RD is C1-C6 alkyl and the other of RC and RD is C1-C6 haloalkyl.

[0106] In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from: hydroxyl, halogen , -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy substituted by hydroxyl group as appropriate. In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from: hydroxyl, halogen, -C(= O) NRB1RC1, -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy and C1-C6 haloalkoxy.

[0107] In some embodiments, each of RB1 and RC1 is hydrogen. In some embodiments, one of RB1 and RC1 is hydrogen and the other of RB1 and RC1 is C1-C6 alkyl. In some embodiments, one of RB1 and RC1 is hydrogen and the other of RB1 and RC1 is methyl. In some embodiments, RB1 and RC1 are each independently selected C1-C6 alkyl. In some embodiments, each RB1 and RC1 is methyl.

[0108] In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl. In some embodiments, RC and RD together with the nitrogen atom to which they are attached form an azetidine or pipera.

[0109] In some embodiments, one R4 is -SO2(NREF). In some embodiments, RE and RF are each hydrogen. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 alkyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C3 alkyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is methyl. In some embodiments, RE and RF are each C1-C6 alkyl. In some embodiments, RE and RF are each C1-C3 alkyl. In some embodiments, RE and RF are each methyl.

[0110] In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 haloalkyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C3 haloalkyl. In some embodiments, RE and RF are each C1-C6 haloalkyl. In some embodiments, one of RE and RF is C1-C6 alkyl and the other of RE and RF is C1-C6 haloalkyl.

[0111] In some embodiments, one R4 is -SO2(C1-C6 alkyl). In some embodiments, one R4 is -SO2(C1-C3 alkyl). In some embodiments, one R4 is -SO2Et. In some embodiments, one R4 is -SO2Me.

[0112] In some embodiments, one R4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, one R4 is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, one R4 is -S(=O)(=NH)Me.

[0113] In some embodiments, one R4 is -C(=O)(C1-C6 alkyl). In some embodiments, one R4 is -C(=O)(C1-C3 alkyl). In some embodiments, one R4 is -C(=O)Me.

[0114] In some embodiments, one R4 is -CO2 (C1-C6 alkyl). In some embodiments, one R4 is -CO2 (C1-C3 alkyl). In some embodiments, one R4 is -CO2Me.

[0115] In some embodiments, one R4 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R4 is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, one R4 is 5-6 membered heteroaryl. In some embodiments, one R4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, azolyl, isoxazolyl, isothiazolyl, thiazolyl, furan group consisting of thiadiazolyl, thiadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridyl, pyridinyl and triazyl. In some embodiments, one R4 is methyl-substituted tetrazolyl. In some embodiments, one R4 is pyrazolyl. In some embodiments, one R4 is unsubstituted pyrazolyl. In some embodiments, one R4 is 1-pyrazolyl.

[0116] In some embodiments, one R4 is a 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 3-membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 4-membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 5-membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 7-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, R4 heterocyclyl is spirocycle. In some embodiments, one R4 is a 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, one R4 is a 3-6 membered heterocyclyl substituted with 2 independently selected RGs. In some embodiments, one R4 is unsubstituted 3-6 membered heterocyclyl.

[0117] In some embodiments, one R4 is a 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is a 3-6 membered cycloalkyl substituted with 1 or 2 independently selected RGs. In some embodiments, one R4 is 3-6 membered cycloalkyl substituted with 1 RG. In some embodiments, one R4 is a 3-6 membered cycloalkyl substituted with 2 independently selected RGs. In some embodiments, one R4 is unsubstituted 3-6 membered cycloalkyl.

[0118] In some embodiments, 1 or 2 independently selected RGs are 1 RG. In some embodiments, 1 or 2 independently selected RGs are 2 independently selected RGs. In some embodiments, when 2 RGs are present, they may be bonded to the same atom, subject to valence permitting. In some embodiments, when 2 RGs are present, they can bond to adjacent atoms if their valence allows. In some embodiments, when there are 2 RGs, the 2 RGs are different. In some embodiments, when there are 2 RGs, the 2 RGs are the same. In some embodiments, one RG is fluoro. In some embodiments, one RG is cyano. In some embodiments, one RG is hydroxyl. In some embodiments, one RG is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one RG is 2-hydroxy-2-propyl. In some embodiments, one RG is C1-C6 alkyl. In some embodiments, one RG is C1-C3 alkyl. In some embodiments, one RG is methyl. In some embodiments, one RG is ethyl.

[0119] In some embodiments, one RG is C1-C6 alkoxy. In some embodiments, one RG is C1-C3 alkoxy. In some embodiments, one RG is methoxy.

[0120] In some embodiments, an RG is -NRA1RB1. In some embodiments, each RA1 and RB1 is hydrogen. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C3 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is methyl. In some embodiments, each of RA1 and RB1 is C1-C6 alkyl. In some embodiments, each RA1 and RB1 is methyl.

[0121] In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C3 haloalkyl. In some embodiments, each of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, one of RA1 and RB1 is C1-C6 alkyl and the other of RA1 and RB1 is C1-C6 haloalkyl.

[0122] In some embodiments, an RG is =NRA2. In some embodiments, an RG is =NH. In some embodiments, RA2 is hydrogen. In some embodiments, RA2 is C1-C6 alkyl. In some embodiments, RA2 is methyl.

[0123] In some embodiments, an RG is -C(=O)NRClRD1. In some embodiments, one RG is -CO2NH2. In some embodiments, one RG is -CO2NHCH3. In some embodiments, each of RC1 and RD1 is hydrogen. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C3 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is methyl. In some embodiments, each of RC1 and RD1 is C1-C6 alkyl. In some embodiments, each of RC1 and RD1 is C1-C3 alkyl. In some embodiments, each of RC1 and RD1 is methyl.

[0124] In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 haloalkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C3 haloalkyl. In some embodiments, RC1 and RD1 are each C1-C6 haloalkyl. In some embodiments, one of RC1 and RD1 is C1-C6 alkyl and the other of RC1 and RD1 is C1-C6 haloalkyl.

[0125] In some embodiments, one RG is -CO2 (C1-C6 alkyl). In some embodiments, one RG is -CO2CH3. In some embodiments, one RG is C1-C6 haloalkyl. In some embodiments, one RG is trifluoromethyl. In some embodiments, one RG is difluoromethyl. In some embodiments, one RG is C3-C6 cycloalkyl. In some embodiments, one RG is cyclopropyl. In some embodiments, one RG is -CO2H.

[0126] In some embodiments, one RG is C1-C6 haloalkoxy. In some embodiments, one RG is C1-C3 haloalkoxy. In some embodiments, one RG is difluoromethoxy. In some embodiments, one RG is trifluoromethoxy.

[0127] In some embodiments, one RG is -SO2(C1-C6 alkyl). In some embodiments, one RG is -SO2CH3.

[0128] In some embodiments, the 3-9 membered heterocyclyl of R4 is a 3-6 membered heterocyclyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is a 5-6 membered heterocyclyl group. In some embodiments, the 3-6 membered heterocyclyl group of R4 is azetidinyl, azetidin-2-onyl, linyl, piperanyl or tetrahydropyranyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is 1-azetidinyl, 1-azetidin-2-one, 1-piperyl, 1-linyl or 4-tetrakis Hydropyranyl. In some embodiments, the 3-9 membered heterocyclyl of R4 is selected from the group consisting of:. In some embodiments, the 3-9 membered heterocyclyl of R4 (e.g., the 3-6 membered heterocyclyl of R4) is, wherein Q is one or more carbons optionally via -C(=O)-, NH , O or S substituted C1-C3 alkylene group. In some embodiments, Q is a C1-C3 alkylene group in which one or more carbons are optionally replaced with -C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene group in which one or more carbons are optionally replaced with -C(=O)- or NH. In some embodiments, the 3-9 membered heterocyclyl of R4 is selected from the group consisting of:.

[0129] In some embodiments, one R4 is unsubstituted 3-6 membered heterocyclyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is a 5-6 membered heterocyclyl group. In some embodiments, R4 is azetidinyl, linyl, or tetrahydropyranyl. In some embodiments, R4 is selected from the group consisting of:.

[0130] In some embodiments, is, wherein: C3 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, -SO2(NRERF), -SO2(C1-C6 alkyl) and 1 or 2 independently selected ones as appropriate RG-substituted 3-6-membered heterocyclyl and optionally 3-6-membered cycloalkyl substituted by 1 or 2 independently selected RGs. In some embodiments, X is N. In some embodiments, X is CR4A2. In some embodiments, R4A1 and, when present, R4A2 are independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amine, - C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2Me and optionally an azetidinyl group substituted by 1-2 independently selected fluoro groups, hydroxyl groups or methyl groups. In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl. In some embodiments, X is N and R4A1 is a 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, RC and RD together with the nitrogen atom to which they are attached form an azetidine or pipera.

[0131] In some embodiments,

[0132] In some embodiments, is, wherein: R4B is selected from -NRARB and a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1 is Selected from fluorine group, hydroxyl group, C1-C6 haloalkyl group and C1-C6 alkyl group. In some embodiments, RG1 is selected from fluorine, hydroxyl, and C1-C6 alkyl.

[0133] In some embodiments, is, wherein: R4B is selected from -NRARB and a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1 is Selected from fluorine group, hydroxyl group, methoxy group, methyl group, ethyl group, amino group, hydroxymethyl group, 2-hydroxy-2-propyl group, -C(O)Me, -C(O)NH2, =NH, Difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl and C1-C6 alkyl. In some embodiments, RG1 is selected from fluoro, hydroxy, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O) NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl and C1-C6 alkyl. In some embodiments, RG1 is selected from fluorine, hydroxyl, and C1-C6 alkyl.

[0134] In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl. In some embodiments, RA One of and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments , one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, RA and RB are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and RB are each C1-C6 alkyl substituted with hydroxyl. In some In embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is Hydroxy-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is a C1-C6 alkyl. In some embodiments, each of RA and RB is a C1-C3 alkyl group. In some embodiments, each of RA and RB is methyl.

[0135] In some embodiments, R4B is an amine group or a 4-6 membered heterocyclyl group having one nitrogen atom and optionally substituted with 1-2 independently selected RGs; wherein RG is selected from the group consisting of fluorine, hydroxyl and C1-C6 alkyl.

[0136] In some embodiments, R4B is; wherein ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperinyl, linyl, thiolinyl, each containing 1-2 = O, and each is optionally substituted with 1-2 RG independently selected from the following: fluoro, hydroxyl, trifluoromethyl, amine, cyclopropyl, -CO2CH3 and C1-C6 alkyl. In some embodiments, R4B is; wherein ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperyl or linyl, each optionally substituted with 1-2 RG independently selected from the following : Fluorine group, hydroxyl group, trifluoromethyl group, amino group, cyclopropyl group, -CO2CH3 and C1-C6 alkyl group. In some embodiments, R4B is; wherein ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperyl or linyl, each optionally substituted with 1-2 RG independently selected from the following : Fluorine group, hydroxyl group, trifluoromethyl group and C1-C6 alkyl group. In some embodiments, R4B is; wherein ring B is azetidinyl, pyrrolidinyl or piperidinyl, each optionally substituted with 1-2 RG independently selected from the following: fluoro, hydroxyl and C1-C6 alkyl. In some embodiments, Ring B is azetidinyl.

[0137] In some embodiments, Ring B is unsubstituted.

[0138] In some embodiments, Ring B is substituted with 1 RG. In some embodiments, RG is fluoro. In some embodiments, RG is cyano. In some embodiments, RG is an amine group, and in some embodiments, RG is a hydroxyl group. In some embodiments, RG is C1-C3 alkyl. In some embodiments, RG is methyl. In some embodiments, RG is ethyl. In some embodiments, RG is -CO2CH3. In some embodiments, RG is methoxy. In some embodiments, RG is methoxy.

[0139] In some embodiments, Ring B is substituted with 2 RG. In some embodiments, each RG is fluoro. In some embodiments, each RG is C1-C3 alkyl. In some embodiments, each RG is methyl. In some embodiments, one RG is hydroxyl and the other RG is methyl. In some embodiments, one RG is hydroxyl and the other RG is ethyl. In some embodiments, one RG is amine and the other RG is methyl. In some embodiments, one RG is hydroxyl and the other RG is cyclopropyl. In some embodiments, one RG is fluoro and the other RG1 is methyl. In some embodiments, one RG is hydroxyl and the other RG is fluoro. In some embodiments, one RG is hydroxyl and the other RG is trifluoromethyl. In some embodiments, each RG is bonded to Ring B in a position opposite to the nitrogen to which Ring A is bonded.

[0140] In some embodiments, is, wherein 1 or 2 independently selected RGs are attached at the 3-position of the azetidine. In some embodiments, the group consisting of is selected. In some embodiments, the group consisting of is selected. In some embodiments, the group consisting of is selected.

[0141] In some embodiments, Z is zero.

[0142] In some embodiments, Z is NRx.

[0143] In some embodiments, Rx is hydrogen.

[0144] In some embodiments, Rx is C1-C6 alkyl. In some embodiments, Rx is C1-C3 alkyl. In some embodiments, Rx is methyl. In some embodiments, Rx is ethyl. In some embodiments, Rx is n-propyl. In some embodiments, Rx is isopropyl.

[0145] In some embodiments, Rx is C3-C6 cycloalkyl. In some embodiments, Rx is C3-C4 cycloalkyl. In some embodiments, Rx is cyclopropyl. In some embodiments, Rx is cyclobutyl.

[0146] In some embodiments, each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 alkyl. In some embodiments, each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is selected from methyl, ethyl, isopropyl or tertiary butyl.

[0147] In some embodiments, each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 haloalkyl. In some embodiments, each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is trifluoromethyl.

[0148] In some embodiments, m is 2, one R4 is halogen, and the other R4 is -SO2(C1-C6 alkyl). In some embodiments, m is 2, one R4 is chloro, and the other R4 is -SO2CH3.

[0149] In some embodiments, m is 2, one R4 is C1-C6 alkoxy, and the other R4 is -C(=O)NRRCRD.

[0150] In some embodiments, m is 2, one R4 is methoxy, and the other R4 is -C(O)NHCH3. In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl group, hydroxyl group, cyano group, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0151] In some embodiments, each R1 is a fluoro group; m is 1 or 2; R2 is a C1-C6 alkyl group; R3 is a C1-C6 alkyl group; Ring A is a phenyl or 5-6 membered heteroaryl group ; Each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, - C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3- 6-membered heterocyclyl; and n is 1 or 2.

[0152] In some embodiments, each R1 is a fluoro group; m is 1 or 2; R2 is a C1-C6 alkyl group; R3 is a C1-C6 alkyl group; Ring A is a phenyl or 5-6 membered heteroaryl group ; Each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, - C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and optionally 1 or 2 An independently selected RG-substituted 3-6-membered heterocyclyl group; and n is 1 or 2.

[0153] In some embodiments, each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano , -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5 -6-membered heteroaryl and unsubstituted 3-6-membered heterocyclyl; and n is 1 or 2.

[0154] In some embodiments, each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of -NHRB and optionally 4-6 membered heterocyclyl substituted by 1-2 RG; and n is 1 or 2.

[0155] In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 alkyl. In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is selected from methyl, ethyl, isopropyl, or tertiary butyl.

[0156] In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 haloalkyl. In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is trifluoromethyl.

[0157] In some embodiments, Z is O; m is 2, one R4 is halogen, and the other R4 is -SO2 (C1-C6 alkyl). In some embodiments, m is 2, one R4 is chloro, and the other R4 is -SO2CH3.

[0158] In some embodiments, Z is O; m is 2, one R4 is C1-C6 alkoxy, and the other R4 is -C(=O)NRRCRD.

[0159] In some embodiments, Z is O; m is 2, one R4 is methoxy, and the other R4 is -C(O)NHCH3. In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl group, hydroxyl group, cyano group, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0160] In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; R3 is C1-C6 alkyl; Ring A is phenyl or 5-6 Member heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O )NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and non- Substituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0161] In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; R3 is C1-C6 alkyl; Ring A is phenyl or 5-6 Member heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O )NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and as appropriate 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; and n is 1 or 2.

[0162] In some embodiments, Z is O; each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 Haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; Each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, Hydroxy, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O )Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0163] In some embodiments, Z is O; each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 Haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of -NHRB and optionally 4-6 membered heterocyclyl substituted by 1-2 RG; and n is 1 or 2.

[0164] In some embodiments, Z is NRx; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 alkyl. In some embodiments, Z is NRx; each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is selected from methyl, ethyl, isopropyl, or tertiary butyl.

[0165] In some embodiments, Z is NRx; each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; and R3 is C1-C6 haloalkyl. In some embodiments, Z is O; each R1 is fluoro; m is 1 or 2; R2 is methyl; and R3 is trifluoromethyl.

[0166] In some embodiments, Z is NRx; m is 2, one R4 is halogen, and the other R4 is -SO2(C1-C6 alkyl). In some embodiments, m is 2, one R4 is chloro, and the other R4 is -SO2CH3.

[0167] In some embodiments, Z is NRx; m is 2, one R4 is C1-C6 alkoxy, and the other R4 is -C(=O)NRRCRD.

[0168] In some embodiments, Z is NRx; m is 2, one R4 is methoxy, and the other R4 is -C(O)NHCH3. In some embodiments, Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl group, hydroxyl group, cyano group, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0169] In some embodiments, Z is NRx; Each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; R3 is C1-C6 alkyl; Ring A is phenyl or 5-6 Member heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O )NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and non- Substituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0170] In some embodiments, Z is NRx; Each R1 is fluoro; m is 1 or 2; R2 is C1-C6 alkyl; R3 is C1-C6 alkyl; Ring A is phenyl or 5-6 Member heteroaryl; each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O )NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and as appropriate 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; and n is 1 or 2.

[0171] In some embodiments, Z is NRx; Each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 Haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; Each R4 is independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, Hydroxy, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O )Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclyl; and n is 1 or 2.

[0172] In some embodiments, Z is NRx; Each R1 is fluoro, cyano or methyl; m is 1 or 2; R2 is C1-C3 alkyl; R3 is C1-C3 alkyl or C1-C3 Haloalkyl; Ring A is phenyl or 5-6 membered heteroaryl; each R4 is independently selected from the group consisting of -NHRB and optionally 4-6 membered heterocyclyl substituted by 1-2 RG; and n is 1 or 2.

[0173] In some embodiments, the compound of formula (I) has formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or optionally 1 or 2 independently selected from fluorine group and C1-C6 alkyl C3-C6 cycloalkyl substituted by a substituent; Ring A1 is a 6-membered heteroaryl; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy substituted by -NRARB as appropriate Base, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O) (=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), optionally 5-6 members substituted by C1-C6 alkyl Heteroaryl, 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs and 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RGs; wherein R4 is bonded At the position paraposition to the N atom in the urea moiety of ring A1; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen, 4-6 membered heterocyclyl, C1- C6 haloalkyl, 3-6-membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, 3-6-membered cycloalkyl radical, -SO2(C1-C6 alkyl) and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RG is independently selected from the group consisting of Group: Fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl , C3-C6 cycloalkyl and -CO2H.

[0174] 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.

[0175] 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.

[0176] In some embodiments of formula (I-A), it is, wherein: R4B is selected from -NRARB and a 4-6 membered heterocycle including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1 group; wherein RG1 is selected from fluorine group, hydroxyl group and C1-C6 alkyl group.

[0177] In some embodiments of Formula (I-A), each of RA and RB is hydrogen.

[0178] In some embodiments of formula (I-A), each of RA and RB is a 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 4-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 5-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 1,1-dioxonyltetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 6-membered heterocyclyl.

[0179] In some embodiments of formula (I-A), each of RA and RB is a C1-C6 haloalkyl group. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 haloalkyl. In some embodiments of Formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl.

[0180] In some embodiments of Formula (I-A), each of RA and RB is a 3-6 membered cycloalkyl group optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is unsubstituted 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 3-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 4-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is cis- or trans-3-hydroxycyclobutyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 5-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 6-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is a C1-C6 alkyl group and the other of RA and RB is a 3-6 membered cycloalkyl group substituted with a hydroxyl group.

[0181] In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is optionally selected from hydroxyl, 3-6 members via 1-2 members independently. Cycloalkyl, -SO2(C1-C6 alkyl) and -SO2(NH2) substituents substituted C1-C6 alkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In Formula In some embodiments of (I-A), one of RA and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2 -propyl). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments of formula (I-A) , one of RA and RB is hydrogen and the other of RA and RB is methyl.

[0182] In some embodiments of Formula (I-A), each of RA and RB is a C1-C6 alkyl group optionally substituted with hydroxyl. In some embodiments of formula (I-A), each of RA and RB is a C1-C6 alkyl group substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is methyl and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl). In some embodiments of formula (I-A), each of RA and RB is a C1-C6 alkyl group. In some embodiments of formula (I-A), each of RA and RB is C1-C3 alkyl. In some embodiments of formula (I-A), each of RA and RB is methyl.

[0183] In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with cyclopropyl and hydroxyl, such as 1-cyclopropyl-2- Hydroxyethyl. In some embodiments of Formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted by 3-6 membered cycloalkyl.

[0184] In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl) . In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2CH3, such as 1-(methylsulfonyl) ) prop-2-yl. In some embodiments of formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with -SO2 (C1-C6 alkyl) base. In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted by -SO2(C1-C6 alkyl).

[0185] In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a C1-C3 alkyl substituted with -SO2(NH2), such as 1-amine sulfonamide Propan-2-yl. In some embodiments of formula (I-A), one of RA and RB is C1-C6 alkyl, hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), R4B is a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted by 1-2 independently selected RG; wherein RG is selected from fluorine group, hydroxyl group and C1-C6 alkyl.

[0186] In some embodiments of formula (I-A), R4B is; wherein ring B is azetidinyl, pyrrolidinyl or piperidinyl, each of which is independently selected from fluorine through 1-2 as appropriate , RG substitution of hydroxyl and C1-C6 alkyl groups. In some embodiments of Formula (I-A), Ring B is azetidinyl.

[0187] In some embodiments of Formula (I-A), Ring B is unsubstituted.

[0188] In some embodiments of Formula (I-A), Ring B is substituted with 1 RG. In some embodiments of formula (I-A), RG is fluoro. In some embodiments of formula (I-A), RG is cyano. In some embodiments of formula (I-A), RG is hydroxyl. In some embodiments of formula (I-A), RG is C1-C3 alkyl. In some embodiments of formula (I-A), RG is methyl. In some embodiments of formula (I-A), RG is -CO2CH3.

[0189] In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected RGs. In some embodiments of formula (I-A), each RG is fluoro. In some embodiments of Formula (I-A), each RG is C1-C3 alkyl. In some embodiments of Formula (I-A), each RG is methyl. In some embodiments of formula (I-A), one RG is hydroxyl and the other RG is C1-C3 alkyl. In some embodiments of Formula (I-A), one RG is hydroxyl and the other RG is methyl. In some embodiments of formula (I-A), one RG is fluoro and the other RG is C1-C3 alkyl. In some embodiments of Formula (I-A), one RG is fluoro and the other RG is methyl. In some embodiments of formula (I-A), one RG is hydroxyl and the other RG is fluoro. In some embodiments of Formula (I-A), one RG is hydroxyl and the other RG is trifluoromethyl.

[0190] In some embodiments of Formula (I-A), wherein 1 or 2 independently selected RGs are at the 3-position of the azetidine. In some embodiments of formula (I-A), is selected from the group consisting of:. In some embodiments of formula (I-A), is selected from the group consisting of:.

[0191] In some embodiments, the compound of formula (I) is formula (I-B): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or optionally 1 or 2 independently selected from fluorine group and C1-C6 alkyl C3-C6 cycloalkyl substituted by a substituent; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl substituted by -NRARB as appropriate, Hydroxy, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl base), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, optionally substituted by 1 or 3-6 membered heterocyclyl substituted by 2 independently selected RGs and 3-6 membered cycloalkyl substituted by 1 or 2 independently selected RGs as appropriate; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl optionally substituted by hydroxyl or optionally 1-2 independently C1-C6 alkyl substituted with substituents selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl) and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached Together they form a 4-6 membered heterocyclyl group; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(= O) NRC1RD1, -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0192] In some embodiments, R1A and R1B are each fluoro;

[0193] In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is C1-C3 alkyl. In some embodiments, R2 is methyl.

[0194] In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is C1-C3 haloalkyl. In some embodiments, R2 is trifluoromethyl.

[0195] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C3 alkyl. In some embodiments, R3 is methyl, ethyl or isopropyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl.

[0196] In some embodiments, R3 is C1-C6 haloalkyl. In some embodiments, R3 is C1-C3 haloalkyl. In some embodiments, R3 is trifluoromethyl.

[0197] In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro groups. In some embodiments, R3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, the C3-C6 cycloalkyl group of R3 is cyclopropyl. In some embodiments, R3 is cyclopropyl.

[0198] In some embodiments, R4 is C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, R4 is C1-C3 alkyl optionally substituted with -NRARB. In some embodiments, R4 is methyl optionally substituted with -NRARB. In some embodiments, R4 is C1-C4 alkyl. In some embodiments, R4 is methyl.

[0199] In some embodiments, R4 is C1-C6 alkoxy. In some embodiments, R4 is C1-C3 alkoxy. In some embodiments, R4 is methoxy.

[0200] In some embodiments, R4 is C1-C6 haloalkyl. In some embodiments, R4 is C1-C3 haloalkyl. In some embodiments, R4 is trifluoromethyl.

[0201] In some embodiments, R4 is hydroxyl. In some embodiments, R4 is cyano. In some embodiments, R4 is -CO2H. In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl. In some embodiments, RA One of and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments , one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, RA and RB are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and RB are each C1-C6 alkyl substituted with hydroxyl. In some In embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is Hydroxy-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is a C1-C6 alkyl. In some embodiments, each of RA and RB is a C1-C3 alkyl group. In some embodiments, each of RA and RB is methyl.

[0202] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 haloalkyl. In some embodiments, each of RA and RB is C1-C6 haloalkyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 haloalkyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl.

[0203] In some embodiments, each of RA and RB is a 4-6 membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 4-6 membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 4-membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 5-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 1,1-dioxonyltetrahydrothiophen-3-yl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 6-membered heterocyclyl.

[0204] In some embodiments, RA and RB are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is unsubstituted 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 3-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 4-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is cis- or trans-3-hydroxycyclobutyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 5-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 6-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is 3-6 membered cycloalkyl substituted with hydroxyl.

[0205] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is optionally selected from hydroxyl, 3-6 membered cycloalkyl, - C1-C6 alkyl substituted by the substituents of SO2 (C1-C6 alkyl) and -SO2 (NH2).

[0206] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with cyclopropyl and hydroxyl, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, both RA and RB are C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0207] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2CH3, such as 1-(methylsulfonyl)propan-2- base. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, both RA and RB are C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(NH2), such as 1-amidosulfonylpropane-2- base. In some embodiments, one of RA and RB is C1-C6 alkyl, hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, both RA and RB are C1-C6 alkyl substituted with -SO2(NH2).

[0208] In some embodiments, one R4 is -C(=O)NRRCRD. In some embodiments, each of RC and RD is hydrogen. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C3 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is methyl. In some embodiments, RC and RD are each C1-C6 alkyl. In some embodiments, each of RC and RD is C1-C3 alkyl. In some embodiments, each of RC and RD is methyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 haloalkyl. In some embodiments, RC and RD are each C1-C6 haloalkyl. In some embodiments, one of RC and RD is C1-C6 alkyl and the other of RC and RD is C1-C6 haloalkyl. In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl. In some embodiments, RC and RD together with the nitrogen atom to which they are attached form an azetidine or pipera.

[0209] In some embodiments, one R4 is -SO2(NREF). In some embodiments, RE and RF are each hydrogen. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 alkyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is methyl. In some embodiments, RE and RF are each C1-C6 alkyl. In some embodiments, RE and RF are each C1-C3 alkyl. In some embodiments, RE and RF are each methyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 haloalkyl. In some embodiments, RE and RF are each C1-C6 haloalkyl. In some embodiments, one of RE and RF is C1-C6 alkyl and the other of RE and RF is C1-C6 haloalkyl.

[0210] In some embodiments, R4 is -SO2(C1-C6 alkyl). In some embodiments, R4 is -SO2(C1-C3 alkyl). In some embodiments, R4 is -SO2Me. In some embodiments, R4 is -SO2Et.

[0211] In some embodiments, R4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R4 is -S(=O)(=NH)Me.

[0212] In some embodiments, R4 is -C(=O)(C1-C6 alkyl). In some embodiments, R4 is -C(=O)(C1-C3 alkyl). In some embodiments, R4 is -C(=O)Me.

[0213] In some embodiments, R4 is -CO2(C1-C6 alkyl). In some embodiments, R4 is -CO2(C1-C3 alkyl). In some embodiments, R4 is -CO2Me.

[0214] In some embodiments, one R4 is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R4 is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R4 is 5-6 membered heteroaryl. In some embodiments, R4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, azolyl, isoxazolyl, isothiazolyl, thiazolyl, furyl , diazolyl, thiadiazolyl, triazolyl and the group consisting of thitriazolyl, pyridyl, pyrimidinyl, pyridyl, pyridyl and triyl. In some embodiments, R4 is pyrazolyl. In some embodiments, one R4 is methyl-substituted tetrazolyl. In some embodiments, one R4 is pyrazolyl. In some embodiments, one R4 is unsubstituted pyrazolyl. In some embodiments, one R4 is 1-pyrazolyl.

[0215] In some embodiments, R4 is a 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, R4 is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RGs. In some embodiments, R4 is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4 is a 3-6 membered heterocyclyl substituted with 2 independently selected RGs.

[0216] In some embodiments, RG is fluoro. In some embodiments, RG is cyano. In some embodiments, RG is hydroxyl. In some embodiments, RG is C1-C6 alkyl. In some embodiments, RG is C1-C3 alkyl. In some embodiments, RG is methyl.

[0217] In some embodiments, RG is C1-C6 alkoxy. In some embodiments, RG is C1-C3 alkoxy. In some embodiments, RG is methoxy.

[0218] In some embodiments, an RG is -NRA1RB1. In some embodiments, each RA1 and RB1 is hydrogen. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C3 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is methyl. In some embodiments, each of RA1 and RB1 is C1-C6 alkyl. In some embodiments, each of RA1 and RB1 is C1-C3 alkyl. In some embodiments, each RA1 and RB1 is methyl.

[0219] In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, each of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, one of RA1 and RB1 is C1-C6 alkyl and the other of RA1 and RB1 is C1-C6 haloalkyl.

[0220] In some embodiments, an RG is -C(=O)NRClRD1. In some embodiments, each of RC1 and RD1 is hydrogen. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C3 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is methyl. In some embodiments, each of RC1 and RD1 is C1-C6 alkyl. In some embodiments, each of RC1 and RD1 is methyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 haloalkyl. In some embodiments, RC1 and RD1 are each C1-C6 haloalkyl. In some embodiments, one of RC1 and RD1 is C1-C6 alkyl and the other of RC1 and RD1 is C1-C6 haloalkyl.

[0221] In some embodiments, one RG is -CO2 (C1-C6 alkyl). In some embodiments, one RG is -CO2CH3.

[0222] In some embodiments, one RG is C1-C6 haloalkyl. In some embodiments, one RG is trifluoromethyl.

[0223] In some embodiments, one RG is C3-C6 cycloalkyl. In some embodiments, one RG is cyclopropyl.

[0224] In some embodiments, RG is -CO2H.

[0225] In some embodiments, the 3-6 membered heterocyclyl of R4 is a 5-6 membered heterocyclyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is azetidinyl, azetidin-2-onyl, linyl, piperanyl or tetrahydropyranyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is 1-azetidinyl, 1-azetidin-2-one, 1-piperyl, 1-linyl or 4-tetrakis Hydropyranyl.

[0226] In some embodiments, R4 is unsubstituted 3-6 membered heterocyclyl. In some embodiments, R4 is 5-6 membered heterocyclyl. In some embodiments, R4 is azetidinyl, linyl, or tetrahydropyranyl.

[0227] In some embodiments, R4 is selected from the group consisting of:.

[0228] In some embodiments, R4 is selected from -NRARB and a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1 is selected from fluoro , hydroxyl and C1-C6 alkyl.

[0229] In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl. In some embodiments, RA One of and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments , one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, RA and RB are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and RB are each C1-C6 alkyl substituted with hydroxyl. In some In embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is Hydroxy-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is a C1-C6 alkyl. In some embodiments, each of RA and RB is a C1-C3 alkyl group. In some embodiments, each of RA and RB is methyl.

[0230] In some embodiments, R4 is a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RGs; wherein RG is selected from fluoro, hydroxyl and C1- C6 alkyl.

[0231] In some embodiments, the compound of formula (I) is formula (I-C): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; R4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, - SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2( C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD , RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring group; each RG is independently selected from the group consisting of: fluoro group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, -C(=O)NRC1RD1 and -CO2H.

[0232] In some embodiments, the compound of formula (I) is formula (I-D): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; R4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, - SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2( C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD , RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group; each RG is independently Selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0233] In some embodiments, the compound of formula (I) is formula (I-E): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; R4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, - SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2( C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD , RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring group; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1 -C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0234] In some embodiments, the compound of formula (I) is formula (I-F): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; R4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, - SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2( C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD , RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring group; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1 -C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H; and wherein the compound is not.

[0235] Some embodiments provide a compound of formula (I-F), wherein the compound is not a compound selected from the group consisting of:.

[0236] In some embodiments, the compound of formula (I) is formula (I-G): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen or absent (the benzene ring is monosubstituted by R1A) ; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups as appropriate; R4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, - SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2( C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RA1, RB, RB1, RC, RC1, RD , RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring group; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1 -C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0237] In some embodiments, the compound of formula (I) is formula (I-H): or a pharmaceutically acceptable salt thereof, wherein: R1A is halogen; R1B is halogen, cyano, cyclopropyl or absent ( The benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl or C1-C6 haloalkyl; R4 is independently selected from the group consisting of: C1 -C6 alkyl, optionally C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, C1-C6 haloalkyl, -NRARB and optionally 1 Or 2 independently selected RG-substituted 3-9-membered heterocyclyl; each RA, RB, RC1 and RD1 are independently hydrogen, 4-6-membered heterocyclyl, optionally via hydroxyl group or -C(=O)NRB2RC2 Substituted C1-C6 alkyl, -C(=O)O(C1-C6 alkyl) or C1-C6 haloalkyl; each RA2, RB2 and RC2 is independently hydrogen or C1-C6 alkyl; each RG is independently is selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy base, -SO2 (C1-C6 alkyl) and -CO2H.

[0238] In some embodiments, the compound of formula (I) is formula (I-J): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl; R4 is independently selected from the group consisting of: depending on Case: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NREF) substituted by -NRARB , -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl base), a 5-6 membered heteroaryl group optionally substituted by a C1-C6 alkyl group, a 3-6 membered heterocyclyl group optionally substituted by 1 or 2 independently selected RGs, and a 3-6 membered heterocyclyl group optionally substituted by 1 or 2 independently selected RGs. Selected RG-substituted 3-6-membered cycloalkyl; wherein R4 is bonded to ring A1 at a position opposite to the N atom of the urea moiety; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF is independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, optionally 3-6 membered cycloalkyl substituted by hydroxyl, or optionally 1-2 independently selected from hydroxyl, 3 C1-C6 alkyl substituted by the substituents of -6-membered cycloalkyl, -SO2(C1-C6 alkyl) and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached form 4-6 Member heterocyclyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, - CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0239] 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.

[0240] 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.

[0241] In some embodiments of formula (I-A), it is, wherein: R4B is selected from -NRARB and a 4-6 membered heterocycle including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1 group; wherein RG1 is selected from fluorine group, hydroxyl group and C1-C6 alkyl group.

[0242] In some embodiments of Formula (I-A), each of RA and RB is hydrogen.

[0243] In some embodiments of Formula (I-A), each of RA and RB is a 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 4-6 membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 4-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 5-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 1,1-dioxonyltetrahydrothiophen-3-yl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a 6-membered heterocyclyl.

[0244] In some embodiments of formula (I-A), RA and RB are each C1-C6 haloalkyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 haloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 haloalkyl. In some embodiments of Formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl.

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

[0246] In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is optionally selected from hydroxyl, 3-6 members via 1-2 members independently. Cycloalkyl, -SO2(C1-C6 alkyl) and -SO2(NH2) substituents substituted C1-C6 alkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (e.g., 2-hydroxy-1-propyl. In Formula In some embodiments of (I-A), one of RA and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2 -propyl). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments of formula (I-A) , one of RA and RB is hydrogen and the other of RA and RB is methyl.

[0247] In some embodiments of Formula (I-A), each of RA and RB is a C1-C6 alkyl group optionally substituted with hydroxyl. In some embodiments of formula (I-A), each of RA and RB is a C1-C6 alkyl group substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of formula (I-A), one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments of Formula (I-A), one of RA and RB is methyl and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl). In some embodiments of formula (I-A), each of RA and RB is a C1-C6 alkyl group. In some embodiments of formula (I-A), each of RA and RB is C1-C3 alkyl. In some embodiments of formula (I-A), each of RA and RB is methyl.

[0248] In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with cyclopropyl and hydroxyl, such as 1-cyclopropyl-2- Hydroxyethyl. In some embodiments of Formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted by 3-6 membered cycloalkyl.

[0249] In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl) . In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2CH3, such as 1-(methylsulfonyl) ) prop-2-yl. In some embodiments of formula (I-A), one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with -SO2 (C1-C6 alkyl) base. In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted by -SO2(C1-C6 alkyl).

[0250] In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is a C1-C3 alkyl substituted with -SO2(NH2), such as 1-amine sulfonamide Propan-2-yl. In some embodiments of formula (I-A), one of RA and RB is C1-C6 alkyl, hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), RA and RB are both C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of formula (I-A), R4B is a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted by 1-2 independently selected RG; wherein RG is selected from fluorine group, hydroxyl group and C1-C6 alkyl.

[0251] In some embodiments of formula (I-A), R4B is; wherein ring B is azetidinyl, pyrrolidinyl or piperidinyl, each of which is independently selected from fluorine through 1-2 as appropriate , RG substitution of hydroxyl and C1-C6 alkyl groups. In some embodiments of Formula (I-A), Ring B is azetidinyl.

[0252] In some embodiments of Formula (I-A), Ring B is unsubstituted.

[0253] In some embodiments of Formula (I-A), Ring B is substituted with 1 RG. In some embodiments of formula (I-A), RG is fluoro. In some embodiments of formula (I-A), RG is cyano. In some embodiments of formula (I-A), RG is hydroxyl. In some embodiments of formula (I-A), RG is C1-C3 alkyl. In some embodiments of formula (I-A), RG is methyl. In some embodiments of formula (I-A), RG is -CO2CH3.

[0254] In some embodiments of Formula (I-A), Ring B is substituted with 2 independently selected RGs. In some embodiments of formula (I-A), each RG is fluoro. In some embodiments of Formula (I-A), each RG is C1-C3 alkyl. In some embodiments of Formula (I-A), each RG is methyl. In some embodiments of formula (I-A), one RG is hydroxyl and the other RG is C1-C3 alkyl. In some embodiments of Formula (I-A), one RG is hydroxyl and the other RG is methyl. In some embodiments of formula (I-A), one RG is fluoro and the other RG is C1-C3 alkyl. In some embodiments of Formula (I-A), one RG is fluoro and the other RG is methyl. In some embodiments of formula (I-A), one RG is hydroxyl and the other RG is fluoro. In some embodiments of Formula (I-A), one RG is hydroxyl and the other RG is trifluoromethyl.

[0255] In some embodiments of Formula (I-A), wherein 1 or 2 independently selected RGs are at the 3-position of the azetidine. In some embodiments of formula (I-A), is selected from the group consisting of:. In some embodiments of formula (I-A), is selected from the group consisting of:.

[0256] In some embodiments, the compound of formula (I) is formula (I-K): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; R4 is independently selected from the group consisting of: C1-C6 optionally substituted with -NRARB Alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRRCD, -SO2(NRERF), -SO2(C1-C6 alkyl ), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), optionally via C1-C6 5-6-membered heteroaryl substituted by alkyl, 3-6-membered heterocyclyl optionally substituted by 1 or 2 independently selected RG and 3-6-membered heterocyclyl optionally substituted by 1 or 2 independently selected RG Cycloalkyl; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen, 4-6 membered heterocyclyl, C1-C6 haloalkyl, optionally substituted by hydroxyl 3-6 membered cycloalkyl or optionally C1 substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl) and -SO2(NH2) -C6 alkyl; or RC and RD together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 Alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0257] In some embodiments, R1A and R1B are each fluoro;

[0258] In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is C1-C3 alkyl. In some embodiments, R2 is methyl.

[0259] In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is C1-C3 haloalkyl. In some embodiments, R2 is trifluoromethyl.

[0260] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C3 alkyl. In some embodiments, R3 is methyl, ethyl or isopropyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl.

[0261] In some embodiments, R3 is C1-C6 haloalkyl. In some embodiments, R3 is C1-C3 haloalkyl. In some embodiments, R3 is trifluoromethyl.

[0262] In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R3 is C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro groups. In some embodiments, R3 is C3-C6 cycloalkyl substituted with 1 or 2 fluoro groups. In some embodiments, R3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, the C3-C6 cycloalkyl group of R3 is cyclopropyl. In some embodiments, R3 is cyclopropyl.

[0263] In some embodiments, R4 is C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, R4 is C1-C3 alkyl optionally substituted with -NRARB. In some embodiments, R4 is methyl optionally substituted with -NRARB. In some embodiments, R4 is C1-C4 alkyl. In some embodiments, R4 is methyl.

[0264] In some embodiments, R4 is C1-C6 alkoxy. In some embodiments, R4 is C1-C3 alkoxy. In some embodiments, R4 is methoxy.

[0265] In some embodiments, R4 is C1-C6 haloalkyl. In some embodiments, R4 is C1-C3 haloalkyl. In some embodiments, R4 is trifluoromethyl.

[0266] In some embodiments, R4 is hydroxyl. In some embodiments, R4 is cyano. In some embodiments, R4 is -CO2H. In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl. In some embodiments, RA One of and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments , one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, RA and RB are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and RB are each C1-C6 alkyl substituted with hydroxyl. In some In embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is Hydroxy-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is a C1-C6 alkyl. In some embodiments, each of RA and RB is a C1-C3 alkyl group. In some embodiments, each of RA and RB is methyl.

[0267] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 haloalkyl. In some embodiments, each of RA and RB is C1-C6 haloalkyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 haloalkyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 haloalkyl.

[0268] In some embodiments, each of RA and RB is a 4-6 membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 4-6 membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 4-membered heterocyclyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 5-membered heterocyclyl. In some embodiments of Formula (I-A), one of RA and RB is hydrogen and the other of RA and RB is 1,1-dioxonyltetrahydrothiophen-3-yl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 6-membered heterocyclyl.

[0269] In some embodiments, RA and RB are each 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 3-6 membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 3-6 membered cycloalkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is unsubstituted 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 3-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 4-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is cis- or trans-3-hydroxycyclobutyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 5-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is a 6-membered cycloalkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is 3-6 membered cycloalkyl substituted with hydroxyl.

[0270] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is optionally selected from 1-2 independently selected from hydroxyl, 3-6 membered cycloalkyl, - C1-C6 alkyl substituted by the substituents of SO2 (C1-C6 alkyl) and -SO2 (NH2).

[0271] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with 3-4 membered cycloalkyl and hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with cyclopropyl and hydroxyl, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with 3-6 membered cycloalkyl. In some embodiments, both RA and RB are C1-C6 alkyl substituted with 3-6 membered cycloalkyl.

[0272] In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2CH3, such as 1-(methylsulfonyl)propan-2- base. In some embodiments, one of RA and RB is C1-C6 alkyl and the other of RA and RB is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, both RA and RB are C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with -SO2(NH2), such as 1-amidosulfonylpropane-2- base. In some embodiments, one of RA and RB is C1-C6 alkyl, hydrogen and the other of RA and RB is C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, both RA and RB are C1-C6 alkyl substituted with -SO2(NH2).

[0273] In some embodiments, one R4 is -C(=O)NRRCRD. In some embodiments, each of RC and RD is hydrogen. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C3 alkyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is methyl. In some embodiments, RC and RD are each C1-C6 alkyl. In some embodiments, each of RC and RD is C1-C3 alkyl. In some embodiments, each of RC and RD is methyl. In some embodiments, one of RC and RD is hydrogen and the other of RC and RD is C1-C6 haloalkyl. In some embodiments, RC and RD are each C1-C6 haloalkyl. In some embodiments, one of RC and RD is C1-C6 alkyl and the other of RC and RD is C1-C6 haloalkyl. In some embodiments, RC and RD, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl. In some embodiments, RC and RD together with the nitrogen atom to which they are attached form an azetidine or pipera.

[0274] In some embodiments, one R4 is -SO2(NRERF). In some embodiments, RE and RF are each hydrogen. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 alkyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is methyl. In some embodiments, RE and RF are each C1-C6 alkyl. In some embodiments, RE and RF are each C1-C3 alkyl. In some embodiments, RE and RF are each methyl. In some embodiments, one of RE and RF is hydrogen and the other of RE and RF is C1-C6 haloalkyl. In some embodiments, RE and RF are each C1-C6 haloalkyl. In some embodiments, one of RE and RF is C1-C6 alkyl and the other of RE and RF is C1-C6 haloalkyl.

[0275] In some embodiments, R4 is -SO2(C1-C6 alkyl). In some embodiments, R4 is -SO2(C1-C3 alkyl). In some embodiments, R4 is -SO2Me. In some embodiments, R4 is -SO2Et.

[0276] In some embodiments, R4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R4 is -S(=O)(=NH)Me.

[0277] In some embodiments, R4 is -C(=O)(C1-C6 alkyl). In some embodiments, R4 is -C(=O)(C1-C3 alkyl). In some embodiments, R4 is -C(=O)Me.

[0278] In some embodiments, R4 is -CO2(C1-C6 alkyl). In some embodiments, R4 is -CO2(C1-C3 alkyl). In some embodiments, R4 is -CO2Me.

[0279] In some embodiments, one R4 is 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, one R4 is 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R4 is 5-6 membered heteroaryl. In some embodiments, R4 is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, azolyl, isoxazolyl, isothiazolyl, thiazolyl, furyl , diazolyl, thiadiazolyl, triazolyl and the group consisting of thitriazolyl, pyridyl, pyrimidinyl, pyridyl, pyridyl and triyl. In some embodiments, R4 is pyrazolyl. In some embodiments, one R4 is methyl-substituted tetrazolyl. In some embodiments, one R4 is pyrazolyl. In some embodiments, one R4 is unsubstituted pyrazolyl. In some embodiments, one R4 is 1-pyrazolyl.

[0280] In some embodiments, R4 is a 3-6 membered heterocyclyl optionally substituted with 1 or 2 independently selected RGs. In some embodiments, R4 is 3-6 membered heterocyclyl substituted with 1 or 2 independently selected RGs. In some embodiments, R4 is 3-6 membered heterocyclyl substituted with 1 RG. In some embodiments, R4 is a 3-6 membered heterocyclyl substituted with 2 independently selected RGs.

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

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

[0283] In some embodiments, an RG is -NRA1RB1. In some embodiments, each RA1 and RB1 is hydrogen. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C3 alkyl. In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is methyl. In some embodiments, each of RA1 and RB1 is C1-C6 alkyl. In some embodiments, each of RA1 and RB1 is C1-C3 alkyl. In some embodiments, each RA1 and RB1 is methyl.

[0284] In some embodiments, one of RA1 and RB1 is hydrogen and the other of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, each of RA1 and RB1 is C1-C6 haloalkyl. In some embodiments, one of RA1 and RB1 is C1-C6 alkyl and the other of RA1 and RB1 is C1-C6 haloalkyl.

[0285] In some embodiments, an RG is -C(=O)NRClRD1. In some embodiments, each of RC1 and RD1 is hydrogen. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C3 alkyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is methyl. In some embodiments, each of RC1 and RD1 is C1-C6 alkyl. In some embodiments, each of RC1 and RD1 is methyl. In some embodiments, one of RC1 and RD1 is hydrogen and the other of RC1 and RD1 is C1-C6 haloalkyl. In some embodiments, RC1 and RD1 are each C1-C6 haloalkyl. In some embodiments, one of RC1 and RD1 is C1-C6 alkyl and the other of RC1 and RD1 is C1-C6 haloalkyl.

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

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

[0288] In some embodiments, one RG is C3-C6 cycloalkyl. In some embodiments, one RG is cyclopropyl.

[0289] In some embodiments, RG is -CO2H.

[0290] In some embodiments, the 3-6 membered heterocyclyl of R4 is a 5-6 membered heterocyclyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is azetidinyl, azetidin-2-onyl, linyl, piperanyl or tetrahydropyranyl. In some embodiments, the 3-6 membered heterocyclyl group of R4 is 1-azetidinyl, 1-azetidin-2-one, 1-piperyl, 1-linyl or 4-tetrakis Hydropyranyl.

[0291] In some embodiments, R4 is unsubstituted 3-6 membered heterocyclyl. In some embodiments, R4 is 5-6 membered heterocyclyl. In some embodiments, R4 is azetidinyl, linyl, or tetrahydropyranyl.

[0292] In some embodiments, R4 is selected from the group consisting of:.

[0293] In some embodiments, R4 is selected from -NRARB and a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RG1; wherein RG1 is selected from fluoro , hydroxyl and C1-C6 alkyl.

[0294] In some embodiments, each of RA and RB is hydrogen. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl optionally substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is ethyl substituted with hydroxyl (eg, 2-hydroxy-1-propyl. In some embodiments, RA One of and RB is hydrogen and the other of RA and RB is propyl substituted with hydroxyl (e.g., 2-hydroxyl-propyl or 1-hydroxy-2-propyl). In some embodiments , one of RA and RB is hydrogen and the other of RA and RB is C1-C3 alkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is methyl. In some embodiments, RA and RB are each C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, RA and RB are each C1-C6 alkyl substituted with hydroxyl. In some In embodiments, one of RA and RB is C1-C3 alkyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is C1-C3 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is methyl and the other of RA and RB is Hydroxy-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, each of RA and RB is a C1-C6 alkyl. In some embodiments, each of RA and RB is a C1-C3 alkyl group. In some embodiments, each of RA and RB is methyl.

[0295] In some embodiments, R4 is a 4-6 membered heterocyclyl group including one nitrogen ring member and optionally substituted with 1-2 independently selected RGs; wherein RG is selected from fluoro, hydroxyl and C1- C6 alkyl.

[0296] In some embodiments, the compound of formula (I) is formula (I-L): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano Base, -CO2H, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heteroaryl substituted by 1 or 2 independently selected RGs Ring group; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD, together with the nitrogen atom to which it is attached, forms a 4-6 membered heterocyclyl group; Each RG is independently selected from the group consisting of: fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, - NRA1RB1, -C(=O)NRC1RD1 and -CO2H.

[0297] In some embodiments, the compound of formula (I) is formula (I-M): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano Base, -CO2H, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heteroaryl substituted by 1 or 2 independently selected RGs Ring group; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or RC and RD together with to which they are attached The nitrogen atoms together form a 4-6 membered heterocyclic group; each RG is independently selected from the group consisting of: fluorine group, cyano group, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, -NRA1RB1, - C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0298] In some embodiments, the compound of formula (I) is formula (I-N): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano Base, -CO2H, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heteroaryl substituted by 1 or 2 independently selected RGs Ring group; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD, together with the nitrogen atom to which it is attached, forms a 4-6 membered heterocyclyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy base, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0299] In some embodiments, the compound of formula (I) is formula (I-O): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano Base, -CO2H, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heteroaryl substituted by 1 or 2 independently selected RGs Ring group; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD, together with the nitrogen atom to which it is attached, forms a 4-6 membered heterocyclyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy base, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0300] In some embodiments, the compound of formula (I) is formula (I-P): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen or does not exist (the benzene ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or as appropriate C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R4 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano Base, -CO2H, -NRARB, -C(=O)NRRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6 membered heteroaryl and optionally 3-6 membered heteroaryl substituted by 1 or 2 independently selected RGs Ring group; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl substituted by hydroxyl as appropriate; or RC and RD, together with the nitrogen atom to which it is attached, forms a 4-6 membered heterocyclyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy base, -NRA1RB1, -C(=O)NRC1RD1, -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0301] In some embodiments, the compound of formula (I) is formula (I-Q): or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; R1A is halogen; R1B is halogen, cyano, cyclopropyl or absent (the phenyl ring is monosubstituted by R1A); R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl or C1- C6 haloalkyl; R4 is independently selected from the group consisting of: C1-C6 alkyl, optionally C1-C6 alkyl substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl Oxygen, C1-C6 haloalkyl, -NRARB and optionally 3-9 membered heterocyclyl substituted by 1 or 2 independently selected RG; each RA, RB, RC1 and RD1 are independently hydrogen, 4-6 Member heterocyclyl, C1-C6 alkyl optionally substituted by hydroxyl or -C(=O)NRB2RC2, -C(=O)O(C1-C6 alkyl) or C1-C6 haloalkyl; each RA2, RB2 and RC2 are independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluoro group, hydroxyl group, C1-C6 alkyl group optionally substituted with hydroxyl group, C1-C6 alkoxy group, =NRA2, -C(=O)NRC1RD1, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl) and -CO2H.

[0302] In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not selected from the group consisting of Group of compounds:.

[0303] In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not selected from the group consisting of Group of compounds:.

[0304] In some embodiments, the compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein; and wherein the compound is not selected from the group consisting of Group of compounds:.

[0305] In some embodiments, a compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein.

[0306] In some embodiments, a compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein.

[0307] In some embodiments, a compound of Formula (I) is or a pharmaceutically acceptable salt thereof, wherein R3, R4, and Ring A are as described herein. Non-limiting exemplary compounds

[0308] In some embodiments, the compound is selected from the group consisting of a compound in Examples 1-195 (eg, compound 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 A

[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 B

[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 C

[0312] In some embodiments, the compound is selected from the group consisting of compounds depicted in Table D or a pharmaceutically acceptable salt thereof. Pharmaceutical Compositions and Administration General Principles

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

[0314] In some embodiments, a chemical entity may be administered in combination with one or more commonly known pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopherol polyethylene glycol 1000 amber Acid esters; 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, glyamine Acids, sorbic acid, potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal dioxide Silicon; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymer; and lanolin . Cyclodextrins such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrin, including 2-hydroxypropyl-β-cyclodextrin and 3- Hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives may also be used to enhance delivery of the compounds described herein. Dosage forms or compositions may be prepared containing in the range of 0.005% to 100% a chemical entity as described herein and the remainder consisting of pharmaceutically acceptable excipients. Covered compositions may contain from 0.001% to 100% of a chemical entity provided herein, in one embodiment, from 0.1% to 95%, in another embodiment, from 75% to 85%, in another embodiment. , 20% to 80%. Practical methods of preparing such dosage forms are known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd ed. (Pharmaceutical Press) , London, UK. 2012). Routes of administration and composition components

[0315] In some embodiments, a chemical entity described herein, or a pharmaceutical composition thereof, may be administered to an individual in need thereof via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasacral Intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal , intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intracanalicular, intratumoral, intrauterine, intravascular, intravenous, Nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, superficial, transdermal, transmucosal, transtracheal , ureter, urethra and vagina. In certain embodiments, the preferred route of administration is parenterally (eg, intratumoral).

[0316] The compositions may be formulated for parenteral administration, for example, formulated for injection via the intravenous, intramuscular, subcutaneous, or even intraperitoneal route. Generally, such compositions may be prepared in injectable forms, such as liquid solutions or suspensions; they may also be prepared in solid forms suitable for preparation of solutions or suspensions after the addition of liquid prior to injection; and the formulations may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure.

[0317] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol solutions; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be readily injected. They should also be stable under the conditions of manufacture and storage and must be preserved to prevent contaminating effects of microorganisms such as bacteria and fungi.

[0318] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols such as glycerol, propylene glycol and liquid polyethylene glycols and the like, suitable mixtures thereof, and vegetable oils. Proper flow properties can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases it is preferred to include an isotonic agent such as sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the composition of agents that delay absorption, such as aluminum monostearate and gelatin.

[0319] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent, along with various other ingredients enumerated above, as appropriate, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those listed above. In the case where sterile powders are used to prepare sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any other required ingredients from a previously sterile filtered solution.

[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" -Based Drug Delivery Systems" "Neoplasia." 2006,10, 788-795.

[0321] Pharmaceutically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, Synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerol gelatin, hydrogenated vegetable oils, poloxamer, polyethylene glycol of various molecular weights and fatty acid esters of polyethylene glycol Mixed petroleum jelly, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol , Sodium methylparabenzoate, Sodium propylparabenzoate, Diethylamine, Carbomer, Carbopol, Methoxybenzoate, Polyethylene glycol Stearyl octadecyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, gum, carboxyl metabisulfite, sodium ethylenediaminetetraacetate, 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, the chemical entities described herein can be prepared by combining the chemical entities described herein with a suitable non-irritating pharmaceutically acceptable excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax. To prepare suppositories, these excipients or carriers are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

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

[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 each of the following: a) fillers or extenders, such as Starch, lactose, sucrose, glucose, mannitol and silicic acid; b) Binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) Humectants such as Glycerin; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution delaying agents, such as paraffin; f) absorption enhancers, such as tetrahydrofuran grade ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, Solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using pharmaceutically acceptable excipients such as lactose or nogalactose and high molecular weight polyethylene glycols and the like.

[0325] In one embodiment, the composition will be in the form of a unit dosage form such as a pill or lozenge, and thus, the composition may contain a diluent, such as lactose, sucrose, in addition to the chemical entities provided herein. , dicalcium phosphate or the like; lubricant, such as magnesium stearate or the like; and binder, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives or the like things. In another solid dosage form, a powder, pill, solution or suspension (for example in propyl carbonate, vegetable oil, PEG, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose based capsule). Also encompassed are unit dosage forms in which one or more chemical entities or additional active agents are physically separated as provided herein; for example, capsules (or tablets within capsules) with granules of each drug; two-layer tablets; two-compartment gelatin capsules, etc. Enteric-coated or delayed-release oral dosage forms are also covered.

[0326] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants or preservatives particularly suitable 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, pharmaceutically acceptable excipients are sterile and generally free of undesirable materials. These compositions can be sterilized by conventional and well-known sterilization techniques. For various oral dosage forms, pharmaceutically acceptable excipients, such as tablets and capsules, do not need to be sterile. USP / NF standards are usually sufficient.

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

[0329] Examples include technologies targeting the upper gastrointestinal tract, such as the Accordion Pill (Intec Pharma), floating capsules, and substances that adhere to mucosal walls.

[0330] Other examples include lower gastrointestinal tract targeting technologies. To target various areas in the intestinal tract, several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available. These materials are typically polymers designed to dissolve or corrode at a specific pH range, selected based on the region of the gastrointestinal tract where drug release is desired. These substances are also used to protect acid-labile drugs from gastric juice destruction or to limit exposure in situations where the active ingredient may irritate the upper gastrointestinal tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polymer) Vinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer) and Marcoat). Other technologies include dosage forms that respond to local flora in the gastrointestinal tract, pressure-controlled colonic delivery capsules, and pulseincaps.

[0331] The eye composition may include, but is not limited to, any one or more of the following: viscosity elements (such as carboxymethyl cellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (such as Pluronic ( Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories), Purite (Stable Oxychlorine Complex; Allergan)).

[0332] Topical compositions may include ointments and creams. Ointments are semi-solid preparations usually based on paraffin grease or other petroleum derivatives. Creams containing the selected active agent are usually viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are usually water washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, typically includes paraffin esters and fatty alcohols such as cetyl or stearyl alcohol; although optional, the aqueous phase usually exceeds the volume of the oil phase and typically contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. Like other carriers or vehicles, the ointment base should be inert, stable, nonirritating, and nonsensitizing.

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

[0334] Dosage may vary depending on patient needs, the severity of the condition being treated, and the particular compound employed. The appropriate dosage for a particular situation can be determined by one skilled in the art of medicine. The total daily dose may be divided into portions and administered in multiple portions throughout the day or by providing continuous delivery.

[0335] In some embodiments, a compound described herein is administered at a dose of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; 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 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg ; about 0.1 mg / Kg to about 200 mg / Kg; about 0.1 mg / Kg to about 150 mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg). plan

[0336] The aforementioned dosage may be daily (e.g., in a single dose or in two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, or twice a week). , biweekly, monthly) investment.

[0337] In some embodiments, the compound described herein is administered over a time period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days 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 another embodiment, the period of discontinuation of administration 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 more. In one embodiment, a therapeutic compound is administered to an individual for a period of time followed by a period of time apart. In another embodiment, the therapeutic compound is administered during a first period of time and is followed by a second period of time, wherein administration of the therapeutic compound is discontinued during the second period of time, followed by the initiation of a third period of time of the therapeutic compound. dosing, and then discontinuing dosing during a fourth time period after the third time period. In one aspect of this embodiment, the period of administration of the therapeutic compound, followed by the period of cessation of administration, is repeated for a determined or undetermined period of time. In another embodiment, the dosing period lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days 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 another embodiment, the stop administration period 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 more. Treatment Indications

[0338] Provided herein are methods for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα) encoded by the PIK3CA gene. For example, provided herein are PI3Kα inhibitors suitable for the treatment or prevention of diseases or conditions associated with dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them (i.e., PI3Kα-related diseases or conditions) , 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 ( MCAP) and hemimegalencephaly), congenital lipomas (eg, vascular malformation overgrowth), epidermal nevi and skeletal / spinal abnormalities (eg, CLOVES syndrome), and fibrofatty hyperplasia (FH) or cancer (eg, PI3Kα-related cancers).

[0339] As used herein, a "PI3Kα inhibitor" includes any compound that exhibits inactivating activity (e.g., inhibits or decreases) PI3Kα. In some embodiments, a PI3Kα inhibitor can be selective for PI3Kα with one or more mutations.

[0340] The ability of a test compound to act as a PI3Kα inhibitor can be demonstrated by analytical methods known in the art. The compounds and compositions provided herein can be assayed for activity as PI3Kα inhibitors in vitro, in vivo, or in cell lines. In vitro assays include assays that measure kinase inhibition. Alternative in vitro assays quantify the ability of inhibitors to bind to protein kinases, and can be performed by radiolabeling the compound prior to binding, isolating the compound / kinase complex and determining the amount of radiolabeled binding, or by performing a procedure in which novel compounds are combined with Measured in competition experiments incubated with kinases bound to known radioligands.

[0341] The potency of PI3Kα inhibitors as provided herein can be determined by EC50 values. Compounds with lower EC50 values ​​are more potent inhibitors relative to compounds with higher EC50 values, as determined under substantially similar conditions. In some embodiments, substantially similar conditions include in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3Kα, mutant PI3Kα, or fragments of either, A594 cells, U2OS cells, A431 cells, Ba / F3 cells or 3T3 cells) to determine the degree of PI3Kα-dependent phosphorylation.

[0342] The potency of PI3Kα inhibitors as provided herein can also be determined by IC50 values. Compounds with lower IC50 values ​​are more potent inhibitors relative to compounds with higher IC50 values, measured under substantially similar conditions. In some embodiments, substantially similar conditions include in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3Kα, mutant PI3Kα, or fragments of either, 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) to determine the degree of PI3Kα-dependent phosphorylation.

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

[0344] In some embodiments, compounds provided herein can exhibit potent and selective inhibition of PI3Kα. For example, compounds provided herein can bind to the helical phospholipidyl inositol kinase homology domain catalytic domain of PI3Kα. In some embodiments, compounds provided herein can exhibit nemolar potency against PI3Kα kinase comprising one or more mutations, such as those in Tables 1 and 2.

[0345] In some embodiments, compounds provided herein exhibit potent and selective inhibition of mutant PI3Kα. For example, compounds provided herein can bind to ectopic positions within the kinase domain. In some embodiments, compounds provided herein can exhibit nemolar potency against PI3Kα proteins containing activating mutations, with minimal activity against related kinases (eg, wild-type PI3Kα). Inhibition of wild-type PI3Kα may cause adverse side effects (such as diarrhea and skin rashes), which may affect quality of life and compliance. In some cases, inhibition of wild-type PI3Kα may cause dose-limiting toxicity. See, for example, 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 wild-type PI3Kα inhibitors).

[0346] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selectively targets PI3Kα. For example, a compound of formula (I) or a pharmaceutically acceptable salt thereof can selectively target PI3Kα over another kinase or non-kinase target.

[0347] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit inhibition relative to wild-type PI3Kα for PI3Kα containing one or more mutations as described herein (e.g., as shown in Table 1 or one or more mutations described in Table 2) greater inhibition of PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit an inhibition of PI3Kα containing one or more mutations as described herein that is at least 2-fold, 3-fold greater relative to wild-type PI3Kα. 5x, 5x, 10x, 25x, 50x or 100x inhibition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold inhibition of PI3Kα containing one or more mutations as described herein relative to wild-type PI3Kα. . In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold inhibition of PI3Kα having a combination of mutations described herein relative to wild-type PI3Kα.

[0348] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit approximately 2-fold inhibition relative to wild-type PI3Kα containing one or more mutations as described herein. to approximately 10-fold inhibition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit an inhibition of PI3Kα containing one or more mutations as described herein, from about 10-fold to about 100-fold relative to wild-type PI3Kα. times of inhibition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit an inhibition of PI3Kα containing one or more mutations as described herein, from about 100-fold to about 1000-fold relative to wild-type PI3Kα. times of inhibition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may exhibit an inhibition of PI3Kα containing one or more mutations as described herein, from about 1,000-fold to about 10,000-fold relative to wild-type PI3Kα. times of inhibition.

[0349] Compounds of formula (I) or pharmaceutically acceptable salts thereof are suitable for the treatment of diseases and conditions that can be treated with PI3Kα inhibitors, such as PI3Kα-related diseases and conditions, such as PIK3CA-related overgrowth syndrome (PROS) and hyperplasia Sexual conditions, such as cancer, including blood cancers and solid tumors (such as advanced or metastatic solid tumors).

[0350] In some embodiments, the subject has been identified or diagnosed as having a cancer with dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof (PI3Kα-related cancer) (e.g., using regulatory agency approval (e.g., FDA-approved assay or test kit). In some embodiments, the individual has a tumor that is positive for dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof (e.g., using a regulatory agency-approved assay or panel). For example, an individual has a tumor that is positive for a mutation as described in Table 1 or Table 2. The individual may be an individual with a tumor that is positive for an imbalance in the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either (e.g., identified using a regulatory agency-approved (e.g., FDA-approved) assay or panel). The individual may be an individual whose tumor has a disorder of the PIK3CA gene, the PI3Kα protein, or the expression or activity or content thereof (eg, where the tumor is identified using a regulatory agency-approved (eg, FDA-approved) panel or assay). In some embodiments, the individual is suspected of having a PI3Kα-related cancer. In some embodiments, the individual's clinical record indicates that the individual has a tumor with a dysregulated expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or any one thereof (and, as appropriate, the clinical record indicates that the individual uses the methods provided herein) treatment with any combination).

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

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

[0353] In certain embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is suitable for preventing diseases and disorders as defined herein (e.g., PIK3CA-associated overgrowth syndrome (PROS) and cancer) . As used herein, the term "prevention" means delaying the onset, recurrence or spread of all or part of a disease or condition, or symptoms thereof, as described herein.

[0354] As used herein, the term "PI3Kα-related disease or disorder" refers to a disorder associated with the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one (e.g., one or more) thereof (e.g., as described herein). A disease or condition associated with or characterized by any type of disorder in the expression or activity or content of the PIK3CA gene or PI3Kα protein or either. Non-limiting examples of PI3Kα-related diseases or disorders include, for example, PIK3CA-related overgrowth syndrome (PROS), brain disorders (e.g., megalencephaly-capillary malformation (MCAP) and hemimegalencephaly), congenital adiposity neoplasms (e.g., vascular malformation overgrowth), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibrofatty hyperplasia (FH) or cancers (e.g., PI3Kα-related cancers).

[0355] As used herein, the term "PI3Kα-related cancer" refers to a cancer that is associated with or has a dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either. Non-limiting examples of PI3Kα-related cancers are described herein.

[0356] The phrase "dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either" refers to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., abnormality in control). Gene mutations caused by cancer cells (e.g., PIK3CA gene mutations that cause PI3Kα expression that contains at least one amino acid deletion compared with wild-type PI3Kα; PIK3CA gene mutations that cause one or more point mutations compared with wild-type PI3Kα PIK3CA gene mutation that expresses PI3Kα; PIK3CA gene mutation that causes PI3Kα expression that has at least one inserted amino acid compared with wild-type PI3Kα; gene duplication that causes an increase in PI3Kα content in cells; or regulation that causes an increase in PI3Kα content in cells Sequence (e.g., promoter and / or enhancer) mutations; alternative splice forms of PI3Kα mRNA that produce a PI3Kα in which at least one amino acid in PI3Kα is deleted compared to wild-type PI3Kα); or wild-type in mammalian cells Increased expression (e.g., increased content) of PI3Kα. As another example, dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either may be caused by a mutation in the PIK3CA gene encoding PI3Kα that is constitutively active, or by a PIK3CA that does not contain the mutation. Activity increases compared to the protein encoded by the gene. Non-limiting examples of PI3Kα point mutations / substitutions / insertions / deletions are described in Tables 1 and 2.

[0357] The term "activating mutation" with respect to PI3Kα describes a mutation in the PIK3CA gene that causes PI3Kα to exhibit, for example, increased kinase activity compared to wild-type PI3Kα (e.g., when analyzed under the same conditions). For example, the activating mutation may be one of the mutations in the PIK3CA gene that causes, for example, an increase in kinase activity compared to wild-type PI3Kα (e.g., when analyzed under the same conditions) with one or more (e.g., two, Performance of PI3Kα with three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (eg, any combination of any of the amino acid substitutions described herein). In another example, the activating mutation can be one of the mutations in PIK3CA that causes, for example, one or more (e.g., two, three, four, five, six, seven) compared to wild-type PI3Kα. PI3Kα expression of amino acid deletions (e.g., when analyzed under the same conditions). In another example, the activating mutation can be one of the mutations in the PIK3CA gene that causes, for example, at least one (eg, 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 PI3Kα performance of amino acid insertion (e.g. when analyzed under the same conditions). Additional examples of activating mutations are known in the art.

[0358] The term "wild type" or "wild-type" describes a nucleic acid typically found in individuals who do not suffer from a disease or disorder associated with the nucleic acid or protein in question (e.g., the PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) sequence.

[0359] The term "wild type PI3Kα" or "wild-type PI3Kα" describes a person who does not suffer from a PI3Kα-related disease, such as a PI3Kα-related cancer (and, as appropriate, does not have an increased risk of developing a PI3Kα-related disease). found in individuals who are at risk and / or not suspected of having a PI3Kα-related disease), or in individuals who are not at increased risk of developing a PI3Kα-related disease, such as PI3Kα-related cancer (and, as appropriate, are not at increased risk of developing a PI3Kα-related disease and / or are not suspected Normal PI3Kα nucleic acid (such as PIK3CA or PI3Kα mRNA) or protein found in cells or tissues of individuals with PI3Kα-related diseases).

[0360] Provided herein is a method of treating cancer (e.g., PI3Kα-related cancer) in an individual in need of such treatment, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof. For example, provided herein are methods for treating PI3Kα-related cancer in an individual in need of such treatment, the method comprising a) detecting the expression or activity of the PIK3CA gene, the PI3Kα protein, or any one thereof in a sample from the individual; content imbalance; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof, comprises one or more PI3Kα protein substitutions / point mutations / insertions. Non-limiting examples of PI3Kα protein substitutions / insertions / deletions are described in Tables 1 and 2.

[0361] In some embodiments, the PI3Kα protein substitution / insertion / deletion is selected from the group consisting of: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T , M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R and their combinations. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid.

[0362] In some embodiments of any of the methods or uses described herein, the cancer (eg, PI3Kα-related cancer) is selected from the group consisting of hematological cancers and solid tumors.

[0363] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from the group consisting of breast cancer (including HER2+ and HER2- breast cancer, ER+ breast cancer, and triple-negative breast cancer), endometrium Cancer, lung cancer (including lung adenocarcinoma and lung squamous cell carcinoma), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell carcinoma, such as oral Pharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), renal cancer, pancreatic neuroendocrine tumors (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 selected from the group consisting of breast cancer (including HER2+ and HER2- breast cancer, ER+ breast cancer, and triple-negative breast cancer), colorectal cancer, Rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), renal cancer, pancreatic nerve Endocrine tumors (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including lung adenocarcinoma and lung squamous cell carcinoma) and endometrial cancer.

[0365] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-related cancer) is selected from the group consisting of breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer carcinoma, esophageal 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 PI3Kα associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα associated cancer is lung cancer.

[0367] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is selected from the group consisting of the cancers described in Table 1 and Table 2. Table 1 Amino acid substitution / insertion / deletion A of PI3Kα protein Amino acid position Non-limiting exemplary mutations Non-limiting exemplary PI3Kα-related cancers 1 M1 (translation start site) Astrocytoma glioblastoma multiforme 4 R4* (nonsense mutation) glioblastoma multiforme 9 E9G gastric adenocarcinoma 10 L10_M16del glioblastoma multiforme 11 W11L, W11S, W11_P18del (missing in the same frame) lung adenocarcinoma, Oligodendritic glioma, endometrioid cancer 12 G12D endometrioid cancer 13 I13T colon adenocarcinoma 19 R19I endometrioid cancer 27 P27T hepatocellular carcinoma 36 C36Y endometrioid cancer 38 R38C、 R38H、 R38L、 R38S endometrioid cancer papillary renal cell carcinoma Mastoid gastric adenocarcinoma Mucinous adenocarcinoma of the colon and rectum glioblastoma multiforme cervical squamous cell carcinoma hepatocellular carcinoma endometrioid cancer diffuse gastric adenocarcinoma lung squamous cell carcinoma endometrioid cancer 39 E39G、 E39K endometrioid cancer glioblastoma multiforme 57 P57L skin melanoma 65 E65K lung squamous cell carcinoma 66 S66C bladder urothelial carcinoma 69 i69N colon adenocarcinoma 71 V71I Head and neck squamous cell carcinoma 75 Q75E bladder urothelial carcinoma cervical squamous cell carcinoma Head and neck squamous cell carcinoma 78 E78* (nonsense mutation) lung squamous cell carcinoma 80 E80K mixed endometrial cancer of uterus 81 E81* (nonsense mutation), E81del (in-frame deletion), E81K colon adenocarcinoma glioblastoma multiforme colon adenocarcinoma Uterine serous carcinoma / uterine papillary serous carcinoma glioblastoma multiforme endometrioid cancer lung squamous cell carcinoma Mucinous adenocarcinoma of the colon and rectum Invasive breast duct cancer cervical squamous cell carcinoma Head and neck squamous cell carcinoma 83 F83L, F83S Invasive breast lobular carcinoma 84 D84H lung adenocarcinoma 86 T86S hepatocellular carcinoma 87 R87T lung adenocarcinoma 88 R88Q Invasive breast duct cancer rectal adenocarcinoma colon adenocarcinoma prostate adenocarcinoma cervical squamous cell carcinoma Uterine carcinosarcoma / uterine malignant Mullerian mixed tumor (Uterine Malignant Mixed Mullerian Tumor) tubular gastric adenocarcinoma Oligodendritic glioma mucinous gastric adenocarcinoma glioblastoma multiforme gastric adenocarcinoma endometrioid cancer mixed endometrial cancer of uterus Head and neck squamous cell carcinoma Mucinous adenocarcinoma of the colon and rectum Invasive breast lobular carcinoma Intestinal gastric adenocarcinoma bladder urothelial carcinoma 90 C90G, C90R, C90Y glioblastoma multiforme cervical squamous cell carcinoma 93 R93P, R93Q, R93W Mucinous adenocarcinoma of the colon and rectum gastric adenocarcinoma glioblastoma multiforme endometrioid cancer tubular gastric adenocarcinoma mucinous gastric adenocarcinoma bladder urothelial carcinoma cervical squamous cell carcinoma colon adenocarcinoma 102 I102del endometrioid cancer 103 E103G, E103_G106delinsD (deletion in the same frame), E103_P104del (deletion in the same frame) glioblastoma multiforme Invasive breast duct cancer 104 P104L, P104R, P104T Invasive breast duct cancer Head and neck squamous cell carcinoma lung adenocarcinoma colon adenocarcinoma Uterine serous carcinoma / uterine papillary serous carcinoma 105 V105del, V105_R108del endometrioid cancer Invasive breast duct cancer 106 G106D, G106R, G106S, G106V, G106_R108del (missing in the same frame), G106_N107del (missing in the same frame) mixed endometrial cancer of uterus Invasive breast duct cancer Mucinous adenocarcinoma of the colon and rectum mucinous carcinoma Oligodendritic glioma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer rectal adenocarcinoma lung squamous cell carcinoma cervical squamous cell carcinoma tubular gastric adenocarcinoma endometrioid cancer 107 N107S endometrioid cancer lung adenocarcinoma 108 R108C, R108H, R108L prostate adenocarcinoma endometrioid cancer glioblastoma multiforme Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Mucinous adenocarcinoma of the colon and rectum tubular gastric adenocarcinoma colon adenocarcinoma Uterine serous carcinoma / uterine papillary serous carcinoma mixed endometrial cancer of uterus Invasive breast duct cancer lung squamous cell carcinoma 109 E109_I112delinsD (missing in the same frame) Invasive breast duct cancer 110 E110del endometrioid cancer Oligodendritic glioma Invasive breast lobular carcinoma Invasive breast duct cancer mixed endometrial cancer of uterus colon adenocarcinoma Head and neck squamous cell carcinoma lung adenocarcinoma papillary thyroid cancer 111 K111del, K111E, K111N, K111R, K111_L113del (missing in the same frame) endometrioid cancer Invasive breast duct cancer Oligodendritic glioma Head and neck squamous cell carcinoma colon adenocarcinoma Intestinal gastric adenocarcinoma gastric adenocarcinoma endometrioid cancer lung adenocarcinoma Esophageal adenocarcinoma lung squamous cell carcinoma glioblastoma multiforme 113 L113del endometrioid cancer 115 R115L, R115P serous ovarian cancer bladder urothelial carcinoma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus endometrioid cancer Uterine serous carcinoma / uterine papillary serous carcinoma rectal adenocarcinoma cervical squamous cell carcinoma 116 E116K rectal adenocarcinoma 118 G118D glioblastoma multiforme Invasive breast duct cancer endometrioid cancer bladder urothelial carcinoma Oligodendritic glioma Esophageal adenocarcinoma Astrocytoma lung squamous cell carcinoma Invasive breast lobular carcinoma Uterine serous carcinoma / uterine papillary serous carcinoma mucinous carcinoma mixed endometrial cancer of uterus gastric adenocarcinoma pancreatic adenocarcinoma papillary thyroid cancer rectal adenocarcinoma 123 M123I lung adenocarcinoma 124 P124A lung adenocarcinoma 151 V151M bladder urothelial carcinoma Astrocytoma 165 Y165H mixed endometrial cancer of uterus 170 N170S endometrioid cancer 182 Y182H gastric adenocarcinoma 213 H213N skin melanoma 224 A224S colon adenocarcinoma 239 L239R colon adenocarcinoma 258 D258N rectal adenocarcinoma 262 L262I skin melanoma 266 P266T endometrioid cancer 267 L267M skin melanoma 272 Y272* (nonsense mutation) renal leukocyte carcinoma 274 R274K bladder urothelial carcinoma 279 L279I endometrioid cancer 282 M282V endometrioid cancer 292 S292I glioblastoma multiforme 296 Q296E lung adenocarcinoma 300 D300V lung squamous cell carcinoma 310 R310C endometrioid cancer 322 T322A endometrioid cancer 335 R335G Head and neck squamous cell carcinoma 337 K337N rectal adenocarcinoma 339 L339I cervical squamous cell carcinoma endometrioid cancer 342 T342S lung adenocarcinoma 344 V344A, V344G, V344M endometrioid cancer Mucinous adenocarcinoma of the colon and rectum colon adenocarcinoma cervical squamous cell carcinoma rectal adenocarcinoma Head and neck squamous cell carcinoma Invasive Breast Cancer (NOS) mixed endometrial cancer of uterus glioblastoma multiforme 345 N345H, N345I, N345K, N345T, N345Y Invasive breast lobular carcinoma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer Invasive Breast Cancer (NOS) lung adenocarcinoma Mucinous adenocarcinoma of the colon and rectum bladder urothelial carcinoma colon adenocarcinoma Leiomyosarcoma glioblastoma multiforme endometrioid cancer seminoma tubular gastric adenocarcinoma Invasive breast duct cancer Head and neck squamous cell carcinoma gastric adenocarcinoma diffuse gastric adenocarcinoma prostate adenocarcinoma Invasive breast duct cancer Oligodendritic glioma 350 D350G, D350N lung squamous cell carcinoma Invasive breast duct cancer endometrioid cancer colon adenocarcinoma endometrioid cancer mucinous gastric adenocarcinoma lung adenocarcinoma Invasive breast lobular carcinoma 351 I351T endometrioid cancer 357 R357Q endometrioid cancer Mucinous adenocarcinoma of the colon and rectum colon adenocarcinoma 359 G359R endometrioid cancer 363 G363A Head and neck squamous cell carcinoma 364 G364R mixed endometrial cancer of uterus Intestinal gastric adenocarcinoma colon adenocarcinoma 365 E365K, E365V endometrioid cancer bladder urothelial carcinoma Mucinous adenocarcinoma of the colon and rectum diffuse gastric adenocarcinoma Invasive breast duct cancer Head and neck squamous cell carcinoma 366 P366R Invasive breast duct cancer 378 C378F, C378R, C378Y Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer Oligodendritic glioma 379 S379T skin melanoma 380 N380S diffuse gastric adenocarcinoma 390 D390N lung adenocarcinoma 392 Y392H endometrioid cancer 398 R398H Invasive breast duct cancer 399 A399T cervical squamous cell carcinoma 401 R401Q endometrioid cancer 405 S405F Intestinal gastric adenocarcinoma 406 I406V mixed endometrial cancer of uterus 412 R412Q gastric adenocarcinoma 417 E417K bladder urothelial carcinoma 418 E418K endometrioid cancer rectal adenocarcinoma mucinous carcinoma Head and neck squamous cell carcinoma bladder urothelial carcinoma 420 C420R endometrioid cancer tubular gastric adenocarcinoma lung squamous cell carcinoma Invasive breast duct cancer Uterine serous carcinoma / uterine papillary serous carcinoma colon adenocarcinoma Intestinal gastric adenocarcinoma gastric adenocarcinoma Head and neck squamous cell carcinoma Invasive Breast Cancer (NOS) Astrocytoma cervical squamous cell carcinoma 432 Y432C cervical squamous cell carcinoma 447 P447_L455del (missing in the same frame) Invasive breast duct cancer 449 P449L, P449S endometrioid cancer 450 H450_P458del (missing in the same frame) Invasive breast duct cancer 451 G451R, G451V, G451_D454del (missing in the same frame) Head and neck squamous cell carcinoma bladder urothelial carcinoma colon adenocarcinoma 452 L452_G460del (missing in the same frame) Invasive breast duct cancer 453 E453del, E453K, E453Q, E453_G460delinsDDF (missing in the same frame), E453_L455del Oligodendritic glioma mixed endometrial cancer of uterus Intestinal gastric adenocarcinoma Invasive breast duct cancer Invasive breast lobular carcinoma Head and neck squamous cell carcinoma Astrocytoma gastric adenocarcinoma bladder urothelial carcinoma lung squamous cell carcinoma cervical squamous cell carcinoma lung adenocarcinoma mucinous carcinoma endometrioid cancer Uterine serous carcinoma / uterine papillary serous carcinoma glioblastoma multiforme colon adenocarcinoma 454 D454Y endometrioid cancer 455 L455_G463del (missing in the same frame) glioblastoma multiforme 463 G463_N465delinsD (missing in the same frame) endometrioid cancer 469 E469A, E469delinsDK (inserted in the same frame) rectal adenocarcinoma Invasive breast duct cancer 471 P471A, P471L bladder urothelial carcinoma rectal adenocarcinoma endometrioid cancer Oligoastrocytoma hepatocellular carcinoma 474 E474A prostate adenocarcinoma 475 L475F skin melanoma 479 W479* endometrioid cancer 495 H495L, H495Y lung squamous cell carcinoma endometrioid cancer 499 S499F bladder urothelial carcinoma 519 R519G Head and neck squamous cell carcinoma 520 D520V Invasive breast lobular carcinoma 522 E522A endometrioid cancer 531 L531V Invasive breast duct cancer 539 P539R, P539S Invasive breast duct cancer pancreatic adenocarcinoma endometrioid cancer lung squamous cell carcinoma 542 E542A, E542G, E542K, E542Q, E542V Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer colon adenocarcinoma prostate adenocarcinoma Invasive breast duct cancer Invasive breast lobular carcinoma Endocervical adenocarcinoma Intestinal gastric adenocarcinoma prostate adenocarcinoma papillary renal cell carcinoma Oligoastrocytoma hepatocellular carcinoma bladder urothelial carcinoma Mucinous adenocarcinoma of the colon and rectum diffuse gastric adenocarcinoma lung squamous cell carcinoma gastric ring cell carcinoma Head and neck squamous cell carcinoma Invasive Breast Cancer (NOS) mucinous carcinoma Invasive breast duct cancer cervical squamous cell carcinoma glioblastoma multiforme lung adenocarcinoma 545 E545A, E545D, E545G, E545K, E545Q Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer colon adenocarcinoma prostate adenocarcinoma Invasive breast duct cancer Invasive breast lobular carcinoma Endocervical adenocarcinoma Intestinal gastric adenocarcinoma papillary renal cell carcinoma Oligoastrocytoma hepatocellular carcinoma bladder urothelial carcinoma Mucinous adenocarcinoma of the colon and rectum diffuse gastric adenocarcinoma lung squamous cell carcinoma gastric ring cell carcinoma Head and neck squamous cell carcinoma Invasive Breast Cancer (NOS) mucinous carcinoma cervical squamous cell carcinoma glioblastoma multiforme Oligodendritic glioma lung adenocarcinoma serous ovarian cancer Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Astrocytoma rectal adenocarcinoma gastric adenocarcinoma skin melanoma Esophageal squamous cell carcinoma Invasive mixed mucinous breast cancer intrahepatic cholangiocarcinoma renal leukocyte carcinoma seminoma Esophageal adenocarcinoma tubular gastric adenocarcinoma mixed endometrial cancer of uterus 546 Q546E, Q546H, Q546K, Q546P, Q546R endometrioid cancer rectal adenocarcinoma Oligodendritic glioma gastric adenocarcinoma Esophageal adenocarcinoma bladder urothelial carcinoma Invasive Breast Cancer (NOS) Invasive breast duct cancer colon adenocarcinoma glioblastoma multiforme Uterine serous carcinoma / uterine papillary serous carcinoma Undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma / high-grade spindle cell sarcoma Astrocytoma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Oligoastrocytoma Invasive breast lobular carcinoma tubular gastric adenocarcinoma Head and neck squamous cell carcinoma cervical squamous cell carcinoma Intestinal gastric adenocarcinoma 547 E547D, E547K lung squamous cell carcinoma gastric adenocarcinoma 552 W552C bladder urothelial carcinoma 569 L569I Uterine serous carcinoma / uterine papillary serous carcinoma prostate adenocarcinoma 576 S576Y endometrioid cancer 581 A581S skin melanoma 589 D589N cervical squamous cell carcinoma 600 E600K, E600V endometrioid cancer bladder urothelial carcinoma lung adenocarcinoma Invasive breast lobular carcinoma Mastoid gastric adenocarcinoma 603 D603H Invasive breast duct cancer 604 C604R endometrioid cancer Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Uterine serous carcinoma / uterine papillary serous carcinoma Head and neck squamous cell carcinoma 606 Y606C Head and neck squamous cell carcinoma 607 P607Q skin melanoma 609 P609H colon adenocarcinoma 614 F614I Invasive breast duct cancer 617 R617Q, R617W endometrioid cancer 617 R617W endometrioid cancer 629 S629C Invasive breast duct cancer 636 V636L bladder urothelial carcinoma 642 E642K Uterine serous carcinoma / uterine papillary serous carcinoma 643 Q643H endometrioid cancer 658 L658F colon adenocarcinoma 667 F667L endometrioid cancer lung squamous cell carcinoma Uterine serous carcinoma / uterine papillary serous carcinoma 673 S673T Invasive breast duct cancer 674 E674* (nonsense mutation), E674D, E674Q papillary thyroid cancer skin melanoma bladder urothelial carcinoma 682 Q682K, Q682Rfs*18 (frame shift missing) skin melanoma glioblastoma multiforme 683 R683M skin melanoma 684 F684L endometrioid cancer 693 R693H cervical squamous cell carcinoma 710 E710Q bladder urothelial carcinoma 711 K711N Astrocytoma 722 E722K colon adenocarcinoma 725 D725G, D725N colon adenocarcinoma endometrioid cancer 726 E726K cervical squamous cell carcinoma endometrioid cancer Invasive breast duct cancer hepatocellular carcinoma lung adenocarcinoma Esophageal squamous cell carcinoma Esophageal adenocarcinoma rectal adenocarcinoma Head and neck squamous cell carcinoma lung squamous cell carcinoma Invasive breast lobular carcinoma bladder urothelial carcinoma colon adenocarcinoma 729 K729N skin melanoma 732 M732I colon adenocarcinoma 737 E737K skin melanoma 741 R741Q serous ovarian cancer 744 F744I gastric adenocarcinoma 746 D746Y skin melanoma 749 Q749H skin melanoma 752 L752V bladder urothelial carcinoma 766 L766F Invasive breast duct cancer 770 R770Q endometrioid cancer 773 S773F skin melanoma 777 R777M, R777K skin melanoma colon adenocarcinoma 791 E791Q bladder urothelial carcinoma 811 M811I endometrioid cancer 816 I816S endometrioid cancer 818 R818C, R818H skin melanoma endometrioid cancer 849 E849K serous ovarian cancer 852 R852Q Leiomyosarcoma Uterine serous carcinoma / uterine papillary serous carcinoma 865 G865D skin melanoma 866 L866F, L866W cervical squamous cell carcinoma endometrioid cancer 879 Q879R gastric adenocarcinoma 886 K886E Undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma / high-grade spindle cell sarcoma 901 C901F endometrioid cancer Astrocytoma Invasive breast duct cancer Head and neck squamous cell carcinoma 903 G903E Uterine serous carcinoma / uterine papillary serous carcinoma 905 C905S Head and neck squamous cell carcinoma 909 F909C Esophageal adenocarcinoma 914 G914R Uterine serous carcinoma / uterine papillary serous carcinoma Astrocytoma 929 L929M endometrioid cancer 930 F930V endometrioid cancer 939 D939G Invasive Breast Cancer (NOS) endometrioid cancer Invasive breast duct cancer 948 K948E Intestinal gastric adenocarcinoma 951 R951C rectal adenocarcinoma 953 P953S endometrioid cancer 956 L956F bladder urothelial carcinoma 958 Q958R mixed endometrial cancer of uterus 970 E970K Esophageal squamous cell carcinoma Head and neck squamous cell carcinoma Mucinous adenocarcinoma of the colon and rectum colon adenocarcinoma 971 C971R Head and neck squamous cell carcinoma 978 E978K bladder urothelial carcinoma 979 R979G pancreatic adenocarcinoma 985 Y985* biphasic pleural mesothelioma 989 L989V Invasive breast duct cancer 992 R992L, R992P bladder urothelial carcinoma Uterine serous carcinoma / uterine papillary serous carcinoma mucinous carcinoma 997 L997I endometrioid cancer 1002 F1002L endometrioid cancer 1004 M1004I, M1004R, M1004V endometrioid cancer Invasive breast duct cancer bladder urothelial carcinoma lung squamous cell carcinoma 1005 M1005V Oligodendritic glioma 1006 L1006R endometrioid cancer 1007 G1007R endometrioid cancer Invasive breast duct cancer Head and neck squamous cell carcinoma colon adenocarcinoma Endocervical adenocarcinoma 1012 E1012Q bladder urothelial carcinoma 1015 S1015Y Mucinous adenocarcinoma of the colon and rectum 1016 F1016C endometrioid cancer 1017 D1017N pancreatic adenocarcinoma 1020 A1020T endometrioid cancer 1021 Y1021C, Y1021H Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus colon adenocarcinoma Invasive breast duct cancer Uterine serous carcinoma / uterine papillary serous carcinoma endometrioid cancer gastric adenocarcinoma Mucinous adenocarcinoma of the colon and rectum tubular gastric adenocarcinoma 1025 T1025A, T1025S endometrioid cancer Invasive breast duct cancer Mucinous adenocarcinoma of the colon and rectum mixed endometrial cancer of uterus 1023 R1023Q † colorectal cancer 1026 L1026I skin melanoma 1029 D1029H Uterine serous carcinoma / uterine papillary serous carcinoma 1037 E1037K Invasive breast duct cancer 1040 M1040I, M1040V Head and neck squamous cell carcinoma Invasive breast duct cancer 1043 M1043I, M1043L, M1043T, M1043V Invasive breast lobular carcinoma tubular gastric adenocarcinoma endometrioid cancer Mucinous adenocarcinoma of the colon and rectum papillary thyroid cancer Esophageal squamous cell carcinoma colon adenocarcinoma Invasive breast duct cancer bladder urothelial carcinoma pancreatic adenocarcinoma Oligodendritic glioma Uterine serous carcinoma / uterine papillary serous carcinoma glioblastoma multiforme Head and neck squamous cell carcinoma 1044 N1044I, N1044K, N1044Y endometrioid cancer Invasive breast duct cancer 1045 D1045A, D1045V endometrioid cancer lung squamous cell carcinoma 1047 H1047L, H1047Q, H1047R, H1047Y Esophageal squamous cell carcinoma endometrioid cancer hepatocellular carcinoma skin melanoma Mucinous adenocarcinoma of the colon and rectum bladder urothelial carcinoma cervical squamous cell carcinoma intrahepatic cholangiocarcinoma mixed endometrial cancer of uterus Invasive breast duct cancer renal leukocyte carcinoma Uterine serous carcinoma / uterine papillary serous carcinoma Head and neck squamous cell carcinoma lung squamous cell carcinoma Invasive breast lobular carcinoma Invasive Breast Cancer (NOS) Astrocytoma colon adenocarcinoma Leiomyosarcoma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Oligodendritic glioma serous ovarian cancer mucinous gastric adenocarcinoma rectal adenocarcinoma Intestinal gastric adenocarcinoma diffuse gastric adenocarcinoma prostate adenocarcinoma lung adenocarcinoma gastric adenocarcinoma tubular gastric adenocarcinoma adrenocortical carcinoma Undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma / high-grade spindle cell sarcoma glioblastoma multiforme Oligoastrocytoma 1048 H1048R colon adenocarcinoma renal leukocyte carcinoma 1049 G1049R Intestinal gastric adenocarcinoma bladder urothelial carcinoma renal leukocyte carcinoma Invasive breast duct cancer Invasive breast lobular carcinoma endometrioid cancer colon adenocarcinoma 1052 T1052K hepatocellular carcinoma colon adenocarcinoma 1055 M1055I mixed endometrial cancer of uterus 1058 I1058M Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus 1065 H1065L Invasive breast lobular carcinoma 1066 A1066V mixed endometrial cancer of uterus 1068 N1068Y, N1068fs*5 (frame shift insertion) Epithelioid pleural mesothelioma dedifferentiated liposarcoma Head and neck squamous cell carcinoma 1069 *1069Wext*4 (non-stop mutation) glioblastoma multiforme AUnless otherwise mentioned, mutations in Table 1 can be found in the cBioPortal database derived from: Cerami et al. The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Open Platform for Exploring Multidimensional Cancer Genomics Data". "Cancer Discovery". May 2, 2012; 401; and Gao et al. "Integrative analysis of complex cancer genomics and clinical profiles using cBioPortal of complex cancer genomics and clinical profiles using the cBioPortal). Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colorectal cancers. PIK3CA mutations in gastric and colon cancer). "Eur J Cancer". 2005 July;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075. Table 2. Additional PI3Kα protein amino acid substitutions / insertions / deletions A Amino acid position Non-limiting exemplary mutations Non-limiting exemplary PI3Kα-related cancers 1043 M1043I, M1043L, M1043T, M1043V Invasive breast lobular carcinoma tubular gastric adenocarcinoma endometrioid cancer Mucinous adenocarcinoma of the colon and rectum papillary thyroid cancer Esophageal squamous cell carcinoma colon adenocarcinoma Invasive breast duct cancer bladder urothelial carcinoma pancreatic adenocarcinoma Oligodendritic glioma Uterine serous carcinoma / uterine papillary serous carcinoma glioblastoma multiforme Head and neck squamous cell carcinoma 1044 N1044I, N1044K, N1044Y endometrioid cancer Invasive breast duct cancer 1045 D1045A, D1045V endometrioid cancer lung squamous cell carcinoma 1047 H1047L, H1047Q, H1047R, H1047Y Esophageal squamous cell carcinoma endometrioid cancer hepatocellular carcinoma skin melanoma Mucinous adenocarcinoma of the colon and rectum bladder urothelial carcinoma cervical squamous cell carcinoma intrahepatic cholangiocarcinoma mixed endometrial cancer of uterus Invasive breast duct cancer renal leukocyte carcinoma Uterine serous carcinoma / uterine papillary serous carcinoma Head and neck squamous cell carcinoma lung squamous cell carcinoma Invasive breast lobular carcinoma Invasive Breast Cancer (NOS) Astrocytoma colon adenocarcinoma Leiomyosarcoma Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus Oligodendritic glioma serous ovarian cancer mucinous gastric adenocarcinoma rectal adenocarcinoma Intestinal gastric adenocarcinoma diffuse gastric adenocarcinoma prostate adenocarcinoma lung adenocarcinoma gastric adenocarcinoma tubular gastric adenocarcinoma adrenocortical carcinoma Undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma / high-grade spindle cell sarcoma glioblastoma multiforme Oligoastrocytoma 1048 H1048R colon adenocarcinoma renal leukocyte carcinoma 1049 G1049R Intestinal gastric adenocarcinoma bladder urothelial carcinoma renal leukocyte carcinoma Invasive breast duct cancer Invasive breast lobular carcinoma endometrioid cancer colon adenocarcinoma 1052 T1052K hepatocellular carcinoma colon adenocarcinoma 1055 M1055I mixed endometrial cancer of uterus 1058 I1058M Uterine carcinosarcoma / malignant Mullerian mixed tumor of uterus 1065 H1065L Invasive breast lobular carcinoma 1066 A1066V mixed endometrial cancer of uterus 1068 N1068Y, N1068fs*5 (frame shift insertion) Epithelioid pleural mesothelioma dedifferentiated liposarcoma Head and neck squamous cell carcinoma A Unless otherwise mentioned, mutations in Table 2 can be found in the cBioPortal database derived from: Cerami et al. The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Open Platform for Exploring Multidimensional Cancer Genomics Data". "Cancer Discovery". May 2, 2012; 401; and Gao et al. "Integrative analysis of complex cancer genomics and clinical profiles using cBioPortal of complex cancer genomics and clinical profiles using the cBioPortal). Sci. Signal. 6, pl1 (2013). † Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colorectal cancers. PIK3CA mutations in gastric and colon cancer). "Eur J Cancer". 2005 July;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0368] In some embodiments, the dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them comprises a splice variant of the PI3Kα mRNA such that the expressed protein is deletion of at least one residue (similar to wild-type PI3Kα Alternative splice variants of PI3Kα (protein comparison), resulting in constitutive activity of the PI3Kα protein domain.

[0369] In some embodiments, the dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them comprises at least one point mutation in the PIK3CA gene, resulting in the production of a protein having one or more amine groups in the PIK3CA gene. Acid substitution or insertion or deletion of the PI3Kα protein results in a PI3Kα protein in which one or more amino acids are inserted or removed compared to the wild-type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity compared to a wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation. In some embodiments, compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to a wild-type PI3Kα protein or a PI3Kα protein that does not comprise the same mutation.

[0370] Exemplary sequence of human phosphoinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILN REIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPY MNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NE LRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQ IIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMKAYLA IRQHANLFIN LFSMML GSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0371] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable compounds thereof, are suitable for use in the treatment of cancers identified as having one or more PI3Kα mutations. Accordingly, provided herein are methods for treating an individual diagnosed with (or identified as having) cancer, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0372] Also provided herein are methods for treating an individual identified or diagnosed as having a PI3Kα-related cancer, comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions. In some embodiments, the expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or either in an individual or in a biologic sample from an individual is identified by using a regulatory agency-approved (e.g., FDA-approved) test or assay. disorder, or an individual is identified or diagnosed as having a PI3Kα-related cancer by performing any of the non-limiting examples of assays described herein. In some embodiments, tests or assays are provided in kit form. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0373] The term "regulatory agency" means the national agency that approves the medical use of a medicinal product in the country. For example, a non-limiting example of a regulatory agency is the United States Food and Drug Administration (FDA).

[0374] Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a PI3Kα-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or its Pharmaceutically acceptable salts, or pharmaceutical compositions thereof. Some embodiments of these methods further comprise administering to the individual another anti-cancer agent (eg, immunotherapy). In some embodiments, the individual was previously treated with another anti-cancer treatment, such as at least partial resection of the tumor or radiation therapy. In some embodiments, the expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or either in an individual or in a biologic sample from an individual is identified by using a regulatory agency-approved (e.g., FDA-approved) test or assay. disorder, or an individual is determined to have a PI3Kα-related cancer by performing any of the non-limiting examples of assays described herein. In some embodiments, tests or assays are provided in kit form. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0375] Methods of treating an individual are also provided, comprising analyzing a sample obtained from the individual to determine whether the individual has a disorder of the PIK3CA gene, the PI3Kα protein, or the expression or activity or content of either, and treating the individual determined to have PIK3CA. An individual with a disorder in the expression or activity or content of the gene, the PI3Kα protein, or any of them is administered (e.g., specifically or selectively administered) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof. Some embodiments of these methods further comprise administering to the individual another anti-cancer agent (eg, immunotherapy). In some embodiments of these methods, the subject was previously treated with another anti-cancer treatment, such as at least partial removal of the tumor or radiation therapy. In some embodiments, the individual is an individual suspected of having a PI3Kα-related cancer, an individual exhibiting one or more symptoms of a PI3Kα-related cancer, or an individual who is at increased risk of developing a PI3Kα-related cancer. In some embodiments, the analysis uses next-generation sequencing, pyrosequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting analytical methods that can be used in these methods are described herein. Additional analytical methods are also known in the art.

[0376] Also provided are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for treating PI3Kα-related cancer in an individual who is identified or diagnosed as having PI3Kα-related cancer by: Samples obtained from the individual are analyzed (e.g., in vitro analysis) to determine whether the individual has an imbalance in the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one of them, where the expression of the PIK3CA gene, the PI3Kα protein, or any one of them is or the presence of an imbalance in activity or content identifies the individual as having a PI3Kα-related 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 the treatment of PI3Kα-related cancer in an individual who is identified or diagnosed as having a PI3Kα-related cancer by: The obtained sample is analyzed to determine whether the individual has an imbalance in the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them, wherein the presence of an imbalance in the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them The individual is identified as having a PI3Kα-related cancer. Some embodiments of any of the methods or uses described herein further include recording in the individual's clinical record (e.g., a computer-readable medium) that, by performing an analysis, it is determined that the individual has the PIK3CA gene, the PI3Kα protein, or any one thereof. If the performance or activity or content is disordered, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition should be administered. In some embodiments, the analysis uses next-generation sequencing, pyrosequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0377] Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are also provided for use in the treatment of cancer in an individual in need thereof, or in an individual identified or diagnosed as having a PI3Kα-related 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 the treatment of cancer in an individual identified or diagnosed as having PI3Kα-related cancer. In some embodiments, a disorder in the expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or either, is identified in an individual or in a biologic sample from an individual using a regulatory agency-approved (eg, FDA-approved) panel, Identifying or diagnosing an individual as having a PI3Kα-related cancer. As provided herein, PI3Kα-related cancers include cancers described herein and known in the art.

[0378] In some embodiments of any of the methods or uses described herein, the individual is identified or diagnosed as having a cancer that has a dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them as described herein. In some embodiments of any of the methods or uses, the subject has a tumor that is positive for a dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them. In some embodiments of any of the methods or uses described herein, the individual may be an individual with a tumor that is positive for a dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof. In some embodiments of any of the methods or uses described herein, the individual may be an individual whose tumor has a dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof. In some embodiments of any of the methods or uses described herein, the individual is suspected of having a PI3Kα-related cancer. In some embodiments, provided herein are methods for treating PI3Kα-related cancer in an individual in need of such treatment, the method comprising a) detecting expression of the PIK3CA gene, PI3Kα protein, or any one thereof in a sample from the individual; or Imbalance in activity or content; and b) administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any of them comprises one or more PI3Kα protein point mutations / insertions / deletions. Non-limiting examples of PI3Kα protein point mutations / insertions / deletions are described in Tables 1 and 2. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is selected from the group consisting of: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V , H1047L, H1047Q, H1047R, H1047Y and G1049R. In some embodiments, cancers with dysregulated expression or activity or levels of the PIK3CA gene, the PI3Kα protein, or either, are determined using regulatory agency-approved (eg, FDA-approved) assays or panels. In some embodiments, tumors with dysregulated expression or activity or levels of the PIK3CA gene, the PI3Kα protein, or either, are determined using a regulatory agency-approved (eg, FDA-approved) assay or panel.

[0379] In some embodiments of any of the methods or uses described herein, the individual's clinical record indicates that the individual has a tumor that has a dysregulated expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either. Also provided are methods of treating an individual, which comprise administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable amount thereof to an individual who has clinical records indicating an imbalance in the expression or activity or content of the individual's PIK3CA gene, PI3Kα protein, or any of them. Take the salt of acceptance.

[0380] In some embodiments, methods provided herein include analyzing a sample obtained from an individual to determine whether the individual has a dysregulation of the PIK3CA gene, the PI3Kα protein, or the expression or amount of either. In some such embodiments, the methods also comprise administering to an individual determined to have a disorder in the expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or any of them, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable amount thereof. Take it with a pinch of salt. In some embodiments, the method includes determining, via analysis of a sample obtained from the individual, that the individual has a disorder in the expression or activity or amount of the PIK3CA gene, the PI3Kα protein, or any one thereof. In such embodiments, the method also includes administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof is due to one or more point mutations in the PIK3CA gene (e.g., any one or more of the PI3Kα point mutations described herein). By). One or more point mutations in the PIK3CA gene can cause, for example, the translation of a PI3Kα protein with 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 cause, for example, the translation of a PI3Kα protein having one or more of the following amino acids: 542, 545, 1043, and 1047 and 1049. In some embodiments, the dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof is one or more PI3Kα amino acid substitutions (e.g., any of the PI3Kα amino acid substitutions described herein ). Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (eg, immunotherapy).

[0381] In some embodiments of any of the methods or uses described herein, a sample from an individual is used to determine whether the individual has a disorder of the PIK3CA gene or PI3Kα protein, or the expression or activity or content of either. Analytical methods may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, split FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting (Northern blotting) and PCR-based amplification (such as RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay may detect disorders of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either, using other detection methods known in the art (see, eg, references cited herein). In some embodiments, the sample is a biological sample or biopsy sample (eg, a paraffin-embedded biopsy sample) from an individual. In some embodiments, the individual is an individual who is suspected of having a PI3Kα-related cancer, an individual who has one or more symptoms of a PI3Kα-related cancer, and / or an individual who is at increased risk of developing a PI3Kα-related cancer).

[0382] In some embodiments, liquid bioassays (variably referred to as fluid bioassays or fluid phase bioassays) can be used to identify disorders of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either. 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 disorders of the expression or activity or content of the PIK3CA gene, PI3Kα protein, or any of them. Liquid bioassays may be performed on biological samples that are relatively easy to obtain from an individual (e.g., via a simple blood draw) and may be used to detect tumor burden and / or the expression or activity of the PIK3CA gene, PI3Kα protein, or any of these, or Content imbalance is generally less invasive than traditional methods. In some embodiments, liquid bioassays can be used to detect the presence of disorders of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or either at an earlier stage than traditional methods. In some embodiments, biological samples for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph fluid, intracystic fluid, feces, ascites, and its combination. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid bioassays can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using the liquid bioassay is circulating tumor DNA (ctDNA) derived from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques such as (without limitation) next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify the expression or activity of the PIK3CA gene, the PI3Kα protein, or either or content imbalance.

[0383] Also provided is a method for inhibiting PI3Kα activity in a cell, which comprises contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is ex vivo. In some embodiments, the contact is in vivo. In some embodiments, the contacting is in vivo, wherein the method includes administering to an individual with cells having aberrant PI3Kα activity an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cells are PI3Kα-associated cancer cells. As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes administering a compound provided herein to an individual, such as a human, having a PI3Kα protein, and, for example, introducing a compound provided herein into a cell or cell containing a PI3Kα protein. in samples of purified preparations.

[0384] This article also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or contact with its pharmaceutical compositions.

[0385] This article further provides a method of increasing cell death in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. Contact with pharmaceutical compositions. Also provided herein is a method for increasing tumor cell death in an individual. The method involves administering to the individual an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof effective to increase tumor cell death.

[0386] The phrase "therapeutically effective amount" means, when administered to an individual in need of such treatment, sufficient to (i) treat a disease or disorder associated with the PI3Kα protein, (ii) attenuate, ameliorate, or eliminate one of the specified diseases, conditions, or disorders or a plurality of symptoms, or (iii) an amount of a compound that delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of compound of formula (I) or a pharmaceutically acceptable salt thereof that will correspond to this amount will vary depending on factors such as the particular compound, the condition and severity of the disease, the identity (e.g., weight) of the individual in need of treatment, However, it can still be determined routinely by those skilled in the art.

[0387] When used as a pharmaceutical, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, may be administered in the form of pharmaceutical compositions as described herein. combination

[0388] In the field of medical oncology, it is common practice to use a combination of different treatment modalities to treat each individual with cancer. In medical oncology, other components of such combination treatments or therapies in addition to the compositions provided herein may be, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies. For example, the surgery may be open or minimally invasive. Therefore, compounds of formula (I) or pharmaceutically acceptable salts thereof may also be suitable as adjuvants for cancer treatment, that is, they may be used with one or more other therapies or therapeutic agents, e.g., by the same or different mechanisms of action. Use combinations of effective chemotherapeutic agents. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered prior to administration of additional therapeutic agents or additional therapies. For example, one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered to an individual in need thereof over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (eg, tumor burden) prior to at least partial resection of the tumor. In some embodiments, one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered to an individual in need thereof over a period of time and under one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces tumor size (eg, tumor burden) prior to one or more rounds of radiation therapy.

[0389] In some embodiments, the individual has cancer (e.g., locally advanced or metastatic tumors) that is refractory to standard therapies (e.g., administration of chemotherapeutic agents such as multiple kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine) )) treatment or intolerance to this standard therapy. In some embodiments, the individual has cancer (e.g., locally advanced or metastatic tumors) that is refractory to previous therapies (e.g., administration of chemotherapeutic agents such as multiple kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)) or intolerance to the previous therapy. In some embodiments, the individual has cancer for which there is no standard therapy (eg, locally advanced or metastatic tumors). In some embodiments, the individual has not received PI3Kα inhibitor treatment. For example, the individual has not received treatment with a selective PI3Kα inhibitor. In some embodiments, the individual is not treatment-naive with a PI3Kα inhibitor. In some embodiments, the individual is naïve to kinase inhibitor treatment. In some embodiments, the subject is not naïve to kinase inhibitor treatment. In some embodiments, the subject has undergone prior therapy. For example, treatment with a multikinase inhibitor (MKI) or another PI3K inhibitor, such as buparlisib (BKM120), ibecoxib (BYL719), WX-037, cobancoxib (copanlisib) (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), tenicoxib (GDC-0032, RG7604), sonolisib (PX -866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), GEDDA gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, atroxib aptolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS -9820, AMG319 or GSK2636771.

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

[0391] Non-limiting examples of additional therapeutic agents include: other therapeutic agents targeting PI3Kα (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, therapeutic agents targeting the RAS pathway (including as described herein mTOR inhibitors as mentioned above), PARP inhibitors, other kinase inhibitors (such as therapeutics targeting receptor tyrosine kinases (such as Trk inhibitors or multiple kinase inhibitors)), farnesyl transferase inhibitors, signaling Transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERM / SERD), checkpoint inhibitors, apoptotic pathway modulators (e.g., obataclax); Cell Toxic chemotherapeutic agents, angiogenesis-targeted therapies, immune-targeted agents (including immunotherapy), and radiation therapy.

[0392] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (gefitinib) (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®) , lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO -1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775 , icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF -299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414) , ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (such as deoxyshikonin, isobutylshikonin, acetyl violet herbivorin, β,β-dimethylacrylonitrile and acetylshikonin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib ( ibrutinib), WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086 , Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988 , varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258) , SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL- 140. RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-armed autologous T cells and EGFR CAR -T therapy. In some embodiments, the therapeutic agent targeting EGFR is selected from the group consisting of 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, such as KADCYLA®), lapatinib, KU004, neratinib (such as NERLYNX®), Daco afatinib (such as VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (such as TUKYSA™), erlotinib (such as TARCEVA®), bilotinib, poziotinib , CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, peritinib, S-22261 1 and AEE -788.

[0394] As used herein, "therapeutic agent targeting the RAS pathway" includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allotopic 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 of the proteins in the RAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF) , MEK, ERK, PI3K, AKT and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in the RAS pathway, for example, a RAS pathway modulator can be selective for RAS (also known as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, a therapeutic agent targeting the RAS pathway is a "KRAS pathway modulator." KRAS pathway modulators include any compound that exhibits inactivating activity (eg, kinase inhibition, allotopic 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 of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., as described herein Other PI3K inhibitors mentioned above), AKT and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in the RAS pathway, for example, a KRAS pathway modulator can 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 therapeutic agents targeting KRAS (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1 , VSA9, AA12 and MRTX-849.

[0396] Other non-limiting examples of therapeutics targeting RAS include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitors are vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 ( (

[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 combinations thereof.

[0398] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetyloxycalcium diol), 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-side-oxyzeratrol, 5-iodotuberculicide, GDC0994, ONC201 or their combination.

[0399] In some embodiments, the other PI3K inhibitor is another PI3Kα inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitors are selected from the group consisting of bupacoxib (BKM120), apicoxib (BYL719), WX-037, cobancoxib (ALIQOPATM, BAY80-6946), datoricoxib (NVP-BEZ235, BEZ-235), tenicoxib (GDC-0032, RG7604), sonocoxib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, Picoxib (GDC-0941), Piracoxib (XL147, SAR245408), Gdalecoxib (PF-05212384, PKI-587), Celacoxib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, atrocoxib (GDC-0980), omecoxib (GSK2126458, GSK458), voltacoxib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, Wortmannin, LY294002, PI-103, Ligosetin, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771 or their combination.

[0400] In some embodiments, the AKT inhibitor is selected from the group consisting of miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afresertib, DC120, 2-[4- (2-Aminoprop-2-yl)phenyl]-3-phenylquinoline, MK-2206, edelfosine, miltefosine, perifosine, mustardyl phosphate Choline, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (triciribine phosphate monohydrate ), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] Pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201 or combinations thereof.

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

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

[0403] In some embodiments, the chemotherapeutic agent includes anthracycline, cyclophosphamide, taxane, platinum-based agent, mitomycin, gemcitabine (gemcitabine), eribulin (HALAVENTM) or combinations thereof.

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

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

[0406] In some embodiments, the platinum-based agent is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, nedplatin, triplatinum tetranitrate, phenanthroplatin (phenanthriplatin), picoplatin (picoplatin), satraplatin (satraplatin) and combinations thereof.

[0407] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib (talazoparib), rucaparib (rucaparib), niraparib (Vitamin), Liparib (veliparib), BGB-290 (pamiparib), CEP 9722, E7016, iniparib (iniparib), IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, 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 (vorozole), formestane and fadrozole.

[0409] Non-limiting examples of selective estrogen receptor modulators or degraders (SERM / SERD) include tamoxifen, fulvestrant, brilanestrant, moxa elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502 and SHR9549.

[0410] Non-limiting examples of immunotherapy include immune checkpoint therapy, atezolizumab (TECENTRIQ®), and albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies 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 PD1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or its combination. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or other combination. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo et al., J Hematol Oncol. 11: 39 (2018).

[0411] In some embodiments, the additional therapy or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, trastuzumab-metansin conjugate, pertuzumab Anti, paclitaxel, albumin-bound paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib ( ribociclib), palbociclib, buparlisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG 479, LSZ102, LEE011, cetuximab , AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, ancesatran and their combinations.

[0412] In some embodiments, additional therapeutic agents may also be administered to treat possible side effects of a particular anti-cancer therapy and / or as palliative therapy, such as opioids and corticosteroids. In some embodiments, additional therapies or therapeutic agents described herein are selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transporter 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 ( exenatide) (BYETTA®, BYDUREON®, incretin analog-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 empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), repagliflozin ( remogliflozin), serfliflozin, licofliflozin, sotagliflozin (ZYNQUISTATM) and tofogliflozin.

[0415] Non-limiting examples of DPP-4 inhibitors include sitagliptin (JANUVIA®), vildagliptin (vildagliptin), saxagliptin (ONGLYZA®), linagliptin (linagliptin) (TRADJENDA®), gemigliptin (gemigliptin), alagliptin (anagliptin), teneligliptin (teneligliptin), alogliptin (alogliptin), trelagliptin (NESINA® ), omarigliptin, evogliptin and dutogliptin.

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

[0417] Therefore, this article also provides a method of treating cancer, which includes administering to an individual in need thereof a pharmaceutical combination for treating cancer, which includes (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof , (b) additional therapeutic agents and (c) as appropriate, at least one pharmaceutically acceptable carrier, used simultaneously, separately or sequentially to treat cancer, wherein the compound of formula (I) or its pharmaceutically acceptable carrier of salt and additional therapeutic agents are effective in treating cancer.

[0418] In some embodiments, the additional therapeutic agent includes any of the above therapies or therapeutic agents that are standard of care for cancers with dysregulation of the expression or activity or content of the PIK3CA gene, the PI3Kα protein, or any one thereof.

[0419] Such additional therapeutic agents may be combined with one or more doses of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or administered according to the same or different administration schedules and in accordance with standard pharmaceutical practices known to those skilled in the art.

[0420] This article also provides (i) a pharmaceutical combination for treating cancer in an individual in need thereof, which includes (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one an additional therapeutic agent (such as any of the exemplary additional therapeutic agents described herein or known in the art) and (c) at least one pharmaceutically acceptable carrier, as appropriate, administered simultaneously, separately, or sequentially For the treatment of cancer, an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an additional therapeutic agent is effective in treating cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) such The use of a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product containing such combination as a combined preparation for simultaneous, separate or sequential use; and a method for treating cancer in an individual in need thereof Methods. In some embodiments, the cancer is a PI3Kα-associated cancer.

[0421] As used herein, the term "pharmaceutical combination" refers to a medical therapy resulting from mixing or combining more than one active ingredient and containing 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 (eg, a chemotherapeutic agent) are administered simultaneously to an individual in a single composition or dosage form. The term "non-fixed combination" means that a compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated with at least one additional therapeutic agent (e.g., a chemotherapeutic agent) into separate compositions or dosage forms such that they can be used in different interventions. Simultaneous, concurrent, or sequential administration to an individual in need thereof under time constraints, wherein such administration provides effective amounts of two or more compounds in the individual's body. Such combinations are also suitable for mixed therapies, such as the administration of three or more active ingredients.

[0422] Therefore, this article also provides a method of treating cancer, which includes administering to an individual in need a pharmaceutical combination for treating cancer, the pharmaceutical combination including (a) a compound of formula (I) or a pharmaceutically acceptable compound thereof salts, and (b) an additional therapeutic agent, wherein the compound of formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered together in an amount Effective in treating cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously in separate dosage forms. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered sequentially in any order in a combined therapeutically effective amount, for example, in a daily or intermittent dosage form. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously in a combined dosage form. Example

[0423] Embodiment 1: A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rx is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; Each R1 is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; R2 is halogen, hydroxyl, optional C1-C6 alkylalkyl substituted by hydroxyl, C1-C6 haloalkyl, optionally C3-C6 cycloalkyl substituted by 1 or 2 fluoro groups; R3 is C1-C6 alkyl, C1-C6 halogen Alkyl or C3-C6 cycloalkyl optionally substituted by 1 or 2 substituents independently selected from fluoro group and C1-C6 alkyl; Ring A is a 6-10 membered aryl group, C3-C8 cycloalkyl , 5-10 membered heteroaryl or 4-10 membered heterocyclyl; each R4 is independently selected from the group consisting of: (i) halogen, (ii) optionally substituted by 1 or 2 hydroxyl groups or -NRARB C1-C6 alkyl, (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) Hydroxy, (vi) Cyano, (vii)-CO2H, (viii)-NRARB, (ix)=NRA2, (x)-C(=O)NRCRD, (xi)-SO2(NRERF), ( xii)-SO2(C1-C6 alkyl), (xiii)-S(=O)(=NH)(C1-C6 alkyl), (xiv)-C(=O)(C1-C6 alkyl), (xv) -CO2 (C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, (xvii) optionally substituted by 1 or 2 independently selected RG 3-9 membered heterocyclyl, and (xviii) 3-6 membered cycloalkyl substituted by 1 or 2 independently selected RG as appropriate; n is 0, 1 or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE and RF are independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C (=O)(C1-C6 alkyl), (vi)-C(=O)O(C1-C6 alkyl), (vii)-SO2(C1-C6 alkyl), (viii) optionally via hydroxyl Substituted 3-6 membered cycloalkyl, or (ix) optionally substituted C1-C6 alkyl with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NRB2RC2, 5-6 Member heteroaryl, 3-6 membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H and -SO2(NH2); or RC and RD together with the nitrogen atom to which they are attached are formed as appropriate by 1 - 2 4-10 membered heterocyclyl groups independently selected from the following substituents: hydroxyl, halogen, -C(=O)NRB1RC1, -SO2(C1-C6 alkyl), -CO2H, optionally via hydroxyl Substituted C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; each RA2, RB2 and RC2 is independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of Group: fluoro group, cyano group, hydroxyl group, optionally substituted C1-C6 alkyl group with hydroxyl group, C1-C6 alkoxy group, -NRA1RB1, =NRA2, -C(=O)NRC1RD1, -CO2(C1-C6 alkane base), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H; and the compound is not selected from the group consisting of Group of compounds:.

[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: The compound of embodiment 1 or 2, wherein is.

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

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

[0429] Embodiment 7: The compound of any one of embodiments 1-6, wherein each R1 is halogen.

[0430] Embodiment 8: The compound of any one of embodiments 1-7, wherein each R1 is selected from fluorine and chlorine.

[0431] Embodiment 9: The compound of any one of embodiments 1-8, wherein each R1 is a fluoro group.

[0432] Embodiment 10: The compound of any one of embodiments 1-6, wherein one R1 is cyano.

[0433] Embodiment 11: The compound of any one of embodiments 1-6, wherein one R1 is C1-C6 alkyl.

[0434] Embodiment 12: The compound of any one of embodiments 1-6, wherein one R1 is C3-C6 cycloalkyl.

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

[0436] Embodiment 14: The compound of any one of embodiments 1-13, wherein R2 is C1-C6 alkyl.

[0437] Embodiment 15: The compound of Embodiment 14, wherein R2 is methyl.

[0438] Embodiment 16: The compound of any one of embodiments 1-13, wherein R2 is C1-C6 haloalkyl.

[0439] Embodiment 17: The compound of Embodiment 16, wherein R2 is difluoromethyl.

[0440] Embodiment 18: The compound of Embodiment 16, wherein R2 is trifluoromethyl.

[0441] Embodiment 19: The compound of any one of embodiments 1-13, wherein R2 is halogen.

[0442] Embodiment 20: The compound of any one of embodiments 1-13, wherein R2 is C3-C6 cycloalkyl optionally substituted by 1 or 2 fluoro groups.

[0443] Embodiment 21: The compound of any one of embodiments 1-13 or 20, wherein R2 is a C3-C6 cycloalkyl group substituted by 1 or 2 fluoro groups.

[0444] Embodiment 22: The compound of any one of embodiments 1-13 or 21, wherein R2 is unsubstituted C3-C6 cycloalkyl.

[0445] Embodiment 23: The compound of any one of embodiments 1-22, wherein R3 is C1-C6 alkyl.

[0446] Embodiment 24: The compound of any one of embodiments 1-23, wherein R3 is methyl, ethyl or isopropyl.

[0447] Embodiment 25: The compound of any one of embodiments 1-23, wherein R3 is methyl.

[0448] Embodiment 26: The compound of any one of embodiments 1-23, wherein R3 is ethyl.

[0449] Embodiment 27: The compound of any one of embodiments 1-23, wherein R3 is isopropyl.

[0450] Embodiment 28: The compound of any one of embodiments 1-22, wherein R3 is C1-C6 haloalkyl.

[0451] Embodiment 29: The compound of any one of embodiments 1-22 and 28, wherein R3 is trifluoromethyl.

[0452] Embodiment 30: The compound of any one of embodiments 1-22, wherein R3 is optionally a C3-C6 cycloalkyl substituted by 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl. base.

[0453] Embodiment 31: The compound of any one of embodiments 1-22 and 30, wherein R3 is a C3-C6 cycloalkyl group substituted by 1 or 2 fluoro groups.

[0454] Embodiment 32: The compound of any one of embodiments 1-22 and 30, wherein R3 is unsubstituted C3-C6 cycloalkyl.

[0455] Embodiment 33: The compound of any one of embodiments 1-22, 30 and 31, wherein the C3-C6 cycloalkyl group of R3 is cyclopropyl.

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

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

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

[0459] Embodiment 37: The compound of any one of embodiments 1-33 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: The compound of any one of embodiments 1-33, wherein Ring A is a 5-10 membered heteroaryl group.

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

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

[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 1-33 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, isobenzofuranone, Isoindolinonyl or imidazo[1,2-a]pyridyl.

[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 quinazolone.

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

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

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

[0483] Embodiment 61: The compound of any one of embodiments 1-33, 39 and 51-52, wherein ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazole And [1,2-a]pyridyl.

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

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

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

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

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

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

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

[0491] Embodiment 69: The compound of any one of embodiments 1-33 and 68, wherein ring A is a 6-9 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-thiopiranyl-1,1-dioxide things.

[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: The compound of any one of embodiments 1-33 and 68-70, wherein ring A is 3-piperidinyl, 4-piperidinyl or.

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

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

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

[0501] Embodiment 78: The compound of any one of embodiments 1-77, wherein one R4 is an unsubstituted C1-C6 alkyl group.

[0502] Embodiment 79: The compound of any one of embodiments 1-78, wherein one R4 is methyl.

[0503] Embodiment 80: The compound of any one of embodiments 1-77, wherein one R4 is optionally a C1-C6 alkane substituted by 1-2 substituents independ...

Claims

1. A compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, (IA), wherein: Ring A1 is 5-pyrimidinyl; R1A is halogen; R1B is halogen or absent; R2 is C1-C6 alkyl or C1-C6 haloalkyl; R3 is C1-C6 alkyl, C1-C6 haloalkyl or, as appropriate, C3-C6 cycloalkyl substituted with one or two independent substituents selected from fluorine and C1-C6 alkyl; R4 is independently selected from the following groups of constituents: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NRARB, -C(=O)NRCRD, -SO2(NRERF), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, 3-6-membered heterocyclic, 3-6-membered cycloalkyl, and 3-6-membered cycloalkyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkyl, 1-2-membered RG, and R4 is bonded to the position of the N atom in the urea moiety of ring A1; Each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RF is independently hydrogen, a 4-6 member heterocyclic group, a C1-C6 haloalkyl group, a 3-6 member cycloalkyl group substituted with a hydroxyl group as appropriate, or a C1-C6 alkyl group substituted with one or two independent substituents selected from the following: hydroxyl, 3-6 member cycloalkyl, -SO2 (C1-C6 alkyl) and -SO2 (NH2); or RC and RD together with the nitrogen atom attached thereto form a 4-6 member heterocyclic group; and each RG is independently selected from the group consisting of: fluorinated, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1RB1, -C(=O)NRC1RD1, -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

2. The compound of claim 1 or its pharmaceutically acceptable salt or stereoisomer, wherein R1A and R1B are each fluorine groups.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt or stereoisomer, wherein R2 is a C1-C6 alkyl group.

4. The compound of claim 3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is methyl.

5. A compound of claim 1 or 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 haloalkyl group.

6. The compound of claim 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is trifluoromethyl.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is -NRARB.

8. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the group consisting of: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ...

9. A compound of 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the following structure:

10. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, which is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the following structure; 11. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, which is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the following structure; 12. The compound of claim 9 or its pharmaceutically acceptable salt or stereoisomer is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

13. The compound of claim 12 or its pharmaceutically acceptable salt or stereoisomer is (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

14. The compound of claim 12 or its pharmaceutically acceptable salt or stereoisomer is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

16. Use of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of a medicament for the treatment of cancer.

17. Use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a medicament for treating solid tumors, wherein the solid tumor has one or more PI3Kα mutations, and wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and has the following structure:

18. Use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a medicament for treating cancer, wherein the cancer has one or more PI3Kα mutations, wherein the cancer is selected from breast cancer, endometrial cancer, bladder cancer and head and neck cancer, and wherein the compound is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and has the following structure:

19. As claimed in claims 17 or 18, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and has the following structure:

20. The use of the compound as claimed in claim 17 or 18, wherein the compound or a pharmaceutically acceptable salt or stereoisomer of the compound or the compound thereof is 1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

21. The use as claimed in claim 20, wherein the compound or a pharmaceutically acceptable salt or stereoisomer thereof (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

22. As used in claim 21, wherein the cancer is breast cancer.

23. As used in claim 22, wherein the mutation of one or more PI3Kα is selected from the group consisting of: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y and G1049R and combinations thereof.