Urea derivatives useful in the treatment of cancer

Abstract

This application relates to urea derivatives that can be used to treat cancer. 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 lesions and / or symptoms and / or progression of conditions, diseases, or illnesses (e.g., cancer) caused by increased (e.g., excessive) PI3Kα activation in a subject (e.g., a human). This disclosure also provides compositions containing said chemical entities, and methods of using and preparing them.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Application No. 63 / 210,370, filed June 14, 2021; U.S. Application No. 63 / 228,351, filed August 2, 2021; U.S. Application No. 63 / 288,909, filed December 13, 2021; U.S. Application No. 63 / 316,017, filed March 3, 2022; U.S. Application No. 63 / 319,236, filed March 11, 2022; and U.S. Application No. 63 / 348,261, filed June 2, 2022, the contents of which are hereby incorporated by reference. Technical Field

[0002] This disclosure provides compounds of formula (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα), and pharmaceutically acceptable salts thereof. These chemical entities can be used, for example, to treat lesions and / or symptoms and / or progression of conditions, diseases, or illnesses (e.g., cancer) caused by increased (e.g., excessive) PI3Kα activation in a subject (e.g., a human). This disclosure also provides compositions containing said chemical entities, and methods of using and preparing them. Background Technology

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

[0004] The PI3K pathway can be achieved through, for example... PIK3CA Point mutations in genes or via phosphatases and tensin homologs ( PTEN Activation occurs through gene inactivation. This pathway is activated in approximately 30%–50% of human cancers and contributes to resistance to various anticancer therapies. (See Martini, M. et al.) PI3K / AKT signaling pathway and cancer: An updated review Ann. Med. 2014, 46, 372-383 and Bauer, TM et al. Targeting PI3 Kinase in cancer. Pharmacol. Ther. 2015, 146, 53-60). PI3K consists of three subunits: the p85 regulatory subunit, the p55 regulatory subunit, and the p110 catalytic subunit. Based on their different structures and specific substrates, PI3K is divided into three classes: 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 most definitively involved type in human cancers. Class IA PI3K includes those from different genes (respectively...) PIK3CA , PIK3CB and PIK3CD The p110α, p110β, and p110δ catalytic subunits produced by ) and by PIK3CG The generated p110γ represents the only catalytic subunit in PI3K of the IB class. PIK3CA It is the gene encoding the p110α subunit, which is frequently mutated or amplified in many human cancers such as breast cancer, colon cancer, stomach cancer, cervical cancer, prostate cancer, and lung cancer. (See Samuels Y et al., Highfrequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554).

[0005] However, the development of PI3K inhibitors has been problematic for several reasons, including (i) the adaptive molecular mechanisms following therapeutic inhibition of PI3K; (ii) the inability to specifically inhibit signaling via PIK3CA mutations while circumventing endogenous p110α; (iii) the limited use of these therapies in rational combinations, including those with robust mechanistic support; and (iv) dose-limiting toxicities that prevent sustained inhibition of the PI3K pathway. (See Hanker et al.) Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors, Cancer Discovery, April 2019;9: 482-491). For example, apelisib is an α-selective PI3K inhibitor that is equivalent to both wild-type and mutant forms of PI3Kα. However, the therapeutic benefit of apelisib is limited by inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities, including hyperglycemia.

[0006] In addition, other factors and compensatory pathways affecting PI3K signaling exist, derived from clinical and in vitro laboratory studies, such as HRAS and KRAS mutations, which reduce sensitivity to PI3K inhibitors (and their knockdown has been shown to improve sensitivity to PI3K inhibitors). (See Misrha, R.; PI3K) Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci. 2021, 22, 3464).

[0007] PIK3CA Deletion of the PI3Kα domain can significantly activate PI3K signaling and also enhance sensitivity to PI3K inhibitors (see Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426-1435). Therefore, targeting PI3Kα represents a potential approach for treating proliferative conditions such as cancer. Summary of the Invention

[0008] Some implementations provide a compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Independently selected from halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups optionally substituted with hydroxyl groups, and C3-C6 cycloalkyl groups; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Choose independently from the following groups: (i) Halogens, (ii) Optionally surrounded by one or two hydroxyl groups or -NR A R B Substituted C1-C6 alkyl groups, (iii) A C1-C6 alkoxy group optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups, (iv) C1-C6 haloalkyl groups, (v) Hydroxyl group, (vi) Cyano group, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii)-SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv)-CO2(C1-C6 alkyl), (xvi) 5-6-membered heteroaryl groups optionally substituted with C1-C6 alkyl groups, (xvii) R can be optionally selected by one or two independent choices. G Substituted 3-9 membered heterocyclic groups, and (xviii) R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently (i) Hydrogen, (ii) Hydroxyl group, (iii) 4-6 membered heterocyclic groups, (iv) C1-C6 haloalkyl groups, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2 (C1-C6 alkyl), (viii) Optionally hydroxyl-substituted 3- to 6-membered cycloalkyl groups, or (ix) C1-C6 alkyl groups optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), -CO2H and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl), and -CO2H; and The compounds are not selected from the following groups: .

[0009] Some implementations provide a compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Each R 1 Independently selected from halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups optionally substituted with hydroxyl groups, and C3-C6 cycloalkyl groups; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Choose independently from the following groups: (i) Halogens, (ii) Optionally surrounded by one or two hydroxyl groups or -NR A R B Substituted C1-C6 alkyl groups, (iii) A C1-C6 alkoxy group optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups, (iv) C1-C6 haloalkyl groups, (v) Hydroxyl group, (vi) Cyano group, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii)-SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv)-CO2(C1-C6 alkyl), (xvi) 5-6-membered heteroaryl groups optionally substituted with C1-C6 alkyl groups, (xvii) R can be optionally selected by one or two independent choices. G Substituted 3-9 membered heterocyclic groups, and (xviii) R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently (i) Hydrogen, (ii) Hydroxyl group, (iii) 4-6 membered heterocyclic groups, (iv) C1-C6 haloalkyl groups, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2 (C1-C6 alkyl), (viii) Optionally hydroxyl-substituted 3- to 6-membered cycloalkyl groups, or (ix) C1-C6 alkyl groups optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), -CO2H and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R GIndependently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl), and -CO2H; and The compounds are not selected from the following groups: .

[0010] Some implementations provide a compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Each R 1 Independently selected from halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups optionally substituted with hydroxyl groups, and C3-C6 cycloalkyl groups; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Choose independently from the following groups: (i) Halogens, (ii) Optionally surrounded by one or two hydroxyl groups or -NR A R B Substituted C1-C6 alkyl groups, (iii) A C1-C6 alkoxy group optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups, (iv) C1-C6 haloalkyl groups, (v) Hydroxyl group, (vi) Cyano group, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii)-SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv)-CO2(C1-C6 alkyl), (xvi) 5-6-membered heteroaryl groups optionally substituted with C1-C6 alkyl groups, (xvii) R can be optionally selected by one or two independent choices. G Substituted 3-9 membered heterocyclic groups, and (xviii) R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently (i) Hydrogen, (ii) Hydroxyl group, (iii) 4-6 membered heterocyclic groups, (iv) C1-C6 haloalkyl groups, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2 (C1-C6 alkyl), (viii) Optionally hydroxyl-substituted 3- to 6-membered cycloalkyl groups, or (ix) C1-C6 alkyl groups optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), -CO2H and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H.

[0011] Some implementations provide compounds of formula (I) having formula (X): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Halogens selected independently; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Independently selected from the group consisting of: halogens, optionally surrounded by one or two hydroxyl groups or -NR. A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and each optionally selected by one or two independent R groups. G Substituted 3-6 membered heterocyclic groups or 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen, 4-6 membered heterocyclic group, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2 (C1-C6 alkyl), -SO2 (NH2; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 RD1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and The compounds are not selected from the following groups: .

[0012] This article also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0013] This article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0014] This article also provides a method for treating cancer in subjects in need, the method comprising (a) determining the relationship between the cancer and... PIK3CA (a) dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them; and (b) administration to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0015] This article provides a method for treating a subject with a PI3Kα-related disease or condition, the method comprising administering to a subject identified or diagnosed with a PI3Kα-related disease or condition 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 disclosure also provides a method for treating a subject with a PI3Kα-related disease or condition, the method comprising: determining that the subject's cancer is a PI3Kα-related disease or condition; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0017] This article further provides a method for treating a subject with PI3Kα-related cancer, the method comprising administering to a subject identified or diagnosed with PI3Kα-related cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0018] This disclosure also provides a method for treating a subject with PI3Kα-related cancer, the method comprising: determining that the subject's cancer is PI3Kα-related cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0019] This article provides a method for treating a subject, the method comprising indicating the subject's [condition / condition] to a clinical record. PIK3CA Subjects with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of these genes are given a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

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

[0021] Some embodiments of the methods and compositions described herein include compounds of formula (II): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Halogens selected independently; m can be 0, 1, 2, or 3; R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Independently selected from the group consisting of: optionally surrounded by 1 or 2 hydroxyl groups or -NR A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -NR AR B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, -C(=O)(C1-C6 alkyl), C(=O)O(C1-C6 alkyl), -SO2(C1-C6 alkyl), a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl) and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1-CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H.

[0022] This article also provides a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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

[0024] This article also provides a method for treating cancer in subjects in need, the method comprising (a) determining the relationship between the cancer and... PIK3CA (a) dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them; and (b) administration to a subject of a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0025] This article provides a method for treating a subject with a PI3Kα-related disease or condition, the method comprising administering to a subject identified or diagnosed with a PI3Kα-related disease or condition a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0026] This disclosure also provides a method for treating a subject with a PI3Kα-related disease or condition, the method comprising: determining that the subject's cancer is a PI3Kα-related disease or condition; and administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0027] This article further provides a method for treating a subject with PI3Kα-related cancer, the method comprising administering to a subject identified or diagnosed with PI3Kα-related cancer a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0028] This disclosure also provides a method for treating a subject with PI3Kα-related cancer, the method comprising: determining that the subject's cancer is PI3Kα-related cancer; and administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

[0029] This article provides a method for treating a subject, the method comprising indicating the subject's [condition / condition] to a clinical record. PIK3CASubjects with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of these genes are given a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as provided herein.

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

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

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

[0033] The term “about” when referring 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 differ from the stated number or range of numbers by up to ±10%.

[0034] As used herein, the term “acceptable” in relation to formulations, compositions, or ingredients means that they do not have a lasting harmful effect on the overall health of the subject being treated.

[0035] The terms “inhibit” or “inhibition of” mean a reduction in a measurable amount or complete prevention (e.g., 100% inhibition).

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

[0037] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient amount of an applied chemical entity that will alleviate, to a certain extent, one or more symptoms of the disease or symptom being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising compounds as disclosed herein required to achieve a clinically significant reduction in the symptoms of a disease. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as dose escalation studies.

[0038] The term "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, a component is "pharmaceuticalally acceptable" if it is compatible with other components of the pharmaceutical formulation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example... Remington: The Science and Practice of Pharmacy, 21st edition; 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.

[0039] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the 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 obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In other cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acidic group with a base to form a salt or by other predetermined methods, such as ammonium salts; alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts of organic bases, such as dicyclohexylamine. N1,3-methyl-D-reduced glucosamine; tris(hydroxymethyl)methylamine; and salts with amino acids such as arginine and lysine. Pharmacologically acceptable salts are not specifically limited, provided they are suitable for pharmaceutical applications. Examples of salts formed by the compounds described herein with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. Salts can be acid addition salts, specific examples of which are 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, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0040] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components (collectively referred to herein as "pharmaceuticalally acceptable excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of the compound to a living organism. Various techniques for administering compounds exist in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

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

[0042] As used herein, the term “treat” or “treatment” refers to a therapeutic or palliative measure. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms related to the disease or condition, reduction of disease severity, morbid stabilization (i.e., no worsening) of the disease, delay or slowing of disease progression, improvement or mitigation of the disease morbidity (e.g., one or more symptoms of the disease), and remission (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extended survival compared to expected survival without treatment.

[0043] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

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

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

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

[0047] The term "alkyl" refers to a saturated aliphatic hydrocarbon group containing a specified number of carbon atoms, which can be straight-chain or branched. For example, C 1-10 The indicator group may have 1 to 10 carbon atoms (including the endpoints). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used herein, the term "saturated" means that only a single bond exists between the constituent carbon atom and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0048] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogen groups.

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

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

[0051] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may optionally be substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group may comprise a plurality of fused and / or bridging 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, etc. Cycloalkyl groups also include spirocyclic (e.g., spirobicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl 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, etc. As used herein, the term "saturated" means that only single bonds exist between the constituent carbon atoms.

[0052] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is an aromatic ring (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroleyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl-benzothiophene, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophene-pyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridyl, quinazolinyl, quinolinyl, thiophene[2,3- c ]pyridyl, pyrazolo[3,4- b ]pyridyl, pyrazolo[3,4- c ]pyridyl, pyrazolo[4,3- c Pyridine, pyrazolo[4,3- b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[ b [1,4] Dioxins, benzo[ d [1,3]m-dioxacyclopentene, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b [1,4]Oxythiohexacyclohexadiene, isoindoline, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindoline, pyranyl, pyrazinyl, and pyrimidinyl. For illustrative purposes, the heteroaryl group also includes aromatic lactams, aromatic cyclic ureas, or their alkylene analogues, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary ring nitrogen (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., ), pyrimidinone (e.g., ), pyridazinone (e.g., ), pyrazinone (e.g., or ) and imidazolids (e.g., One or more of the following, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary ring nitrogen (i.e., the oxo group (i.e., "=O") in this text is a constituent part of the heteroaryl ring).

[0053] The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system (e.g., a 5-8 member monocyclic, 8-12 member bicyclic, or 11-14 member tricyclic ring system) having 3-16 ring atoms, wherein if it is a monocyclic ring, it has 1-3 heteroatoms; if it is a bicyclic ring, it has 1-6 heteroatoms; or if it is a tricyclic or polycyclic ring, it has 1-9 heteroatoms selected from O, N, or S (e.g., carbon atoms, and in the case of monocyclic, bicyclic, or tricyclic rings, having 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively), wherein, where valence permits, one or more ring atoms may be substituted by 1-3 oxo groups (forming, for example, lactams) and one or more N or S atoms may be substituted by 1-2 oxo ion groups (forming, for example, N-oxides, S-oxides, or S,S-dioxides); and wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazine, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophene, etc. Heterocyclic groups may include multiple fused and bridging rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopentano[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3- Azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclic groups also include spirocyclic groups (e.g., spirobicyclo, where the two rings are connected by only one atom).Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[3.5]decane, and others. Spiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, etc.

[0054] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridinone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, etc.

[0055] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the ring atoms), provided that the ring is not an aromatic ring. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0056] For the avoidance of doubt, and unless otherwise stated, for ring and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, cycloalkyl, etc. as described herein) containing a number of ring atoms sufficient to form a bicyclic or higher-order ring system (e.g., tricyclic, polycyclic systems), it should be understood that such ring and cyclic groups encompass ring and cyclic groups having fused rings, including ring and cyclic groups in which the fusion point is located at: (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., (ii) Monocyclic atoms (spiro-fused ring systems) (e.g., ), or (iii) a continuous array of ring atoms (a bridging ring system in which all bridge lengths are greater than 0) (e.g., ).

[0057] Furthermore, 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 having the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0058] Furthermore, the compounds disclosed herein, either generally or specifically, are intended to include all tautomer forms. Thus, for example, compounds containing the following moiety: It covers tautomer forms containing the following parts: Similarly, the pyridyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group covers the pyridinone or pyrimidinone tautomer forms.

[0059] The compounds provided herein encompass a wide range of stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, and mixtures of enantiomers (e.g., R and S isomers), including racemic mixtures, as well as individual enantiomers and diastereomers arising from structural asymmetries in certain compounds. Unless otherwise indicated, when a disclosed compound is named or described without specifying a stereochemistry (e.g., a “planar” structure) and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Similarly, unless otherwise indicated, when a disclosed compound is named or described with specifying a stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it should be understood to represent the indicator stereoisomer of the compound.

[0060] Details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of this disclosure will be apparent from the description, the drawings, and the claims. Detailed Implementation

[0061] This disclosure provides compounds of formula (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform α (PI3Kα), and pharmaceutically acceptable salts thereof. These chemical entities can be used, for example, to treat lesions and / or symptoms and / or progression of conditions, diseases, or illnesses (e.g., cancer) caused by increased (e.g., excessive) PI3Kα activation in a subject (e.g., a human). This disclosure also provides compositions containing said chemical entities, and methods of using and preparing them.

[0062] Compound of formula (I) Some implementations provide a compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Independently selected from halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups optionally substituted with hydroxyl groups, and C3-C6 cycloalkyl groups; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Choose independently from the following groups: (i) Halogens, (ii) Optionally surrounded by one or two hydroxyl groups or -NR A R B Substituted C1-C6 alkyl groups, (iii) A C1-C6 alkoxy group optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups, (iv) C1-C6 haloalkyl groups, (v) Hydroxyl group, (vi) Cyano group, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii)-SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv)-CO2(C1-C6 alkyl), (xvi) 5-6-membered heteroaryl groups optionally substituted with C1-C6 alkyl groups, (xvii) R can be optionally selected by one or two independent choices. G Substituted 3-9 membered heterocyclic groups, and (xviii) R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently (i) Hydrogen, (ii) Hydroxyl group, (iii) 4-6 membered heterocyclic groups, (iv) C1-C6 haloalkyl groups, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2 (C1-C6 alkyl), (viii) Optionally hydroxyl-substituted 3- to 6-membered cycloalkyl groups, or (ix) C1-C6 alkyl groups optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2 (C1-C6 alkyl), -CO2H and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and RC2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl), and -CO2H; and The compounds are not selected from the following groups: .

[0063] In some implementations, when Z is NR x And R 3 When it is methyl, ring A is not phenyl.

[0064] Some implementations provide compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compounds are not selected from the group consisting of: .

[0065] Some implementations provide compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compounds are not selected from the group consisting of: .

[0066] Some implementations provide compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compounds are not selected from the group consisting of: .

[0067] Some embodiments provide a compound of formula (I) having formula (X): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Halogens selected independently; m can be 0, 1, 2, or 3; R 2 It can be a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Independently selected from the group consisting of: halogens, optionally surrounded by one or two hydroxyl groups or -NR. A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups optionally substituted with C1-C6 alkyl, and each optionally with one or two independently selected R groups. G Substituted 3-6 membered heterocyclic groups or 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen, 4-6 membered heterocyclic group, C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), 3-6 membered cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2 (C1-C6 alkyl), -SO2 (NH2); or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NRA1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and The compounds are not selected from the following groups: .

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

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

[0070] In some embodiments, the compounds described herein are not selected from the group above (i.e., "excluded compounds"). In some embodiments, the excluded compounds have a planar structure, 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 R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, one or more excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

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

[0072] In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for or .

[0073] In some implementation schemes, each R 1The halogen is selected independently. In some embodiments, each R... 1 The groups are independently selected from fluorine and chlorine groups. In some embodiments, each R... 1 The groups are independently selected from fluorine and bromine groups. In some embodiments, each R... 1 It is fluorine-based. In some embodiments, at least one R 1 Halogens are selected independently. In some embodiments, at least one R 1 Independently selected from fluorine and chlorine groups. In some embodiments, at least one R 1 It is fluorine-based.

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

[0075] In some implementations, m is 2; an R 1 It is a halogen; and another R 1 It is a C1-C6 alkyl group. In some embodiments, m is 2; one R 1 It is fluorine-based; and another R 1 Methyl. In some embodiments, m is 2; one R 1 It is a halogen; and another R 1 It is a C3-C6 cycloalkyl group. In some embodiments, m is 2; one R 1 It is a halogen; and another R 1 Cyclopropyl. In some embodiments, m is 2; one R 1 It is fluorine-based; and another R 1 It is a cyano group. In some embodiments, m is 2; one R 1 It is a halogen; and another R 1 It is a halogen. In some implementations, m is 2; one R1 It is fluorine-based; and another R 1 It is fluorine-based.

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

[0077] In some implementation schemes, R 2 It is a C1-C6 haloalkyl group. In some embodiments, R 2 It is a C1-C3 haloalkyl group. In some embodiments, R 2 It is a difluoromethyl group. In some embodiments, R 2 It is trifluoromethyl.

[0078] In some implementation schemes, R 2 It is a halogen. In some implementations, R 2 It is fluorine-based. In some embodiments, R 2 It is a chlorine group.

[0079] In some implementation schemes, R 2 It is a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. In some embodiments, R 2 It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups. In some embodiments, R 2 It is a C3-C6 cycloalkyl group substituted with one fluorine group. In some embodiments, R 2 It is a C3-C6 cycloalkyl group substituted with two fluorine groups. In some embodiments, R 2 It is a C3-C4 cycloalkyl group substituted with one fluorine group. In some embodiments, R 2 It is a C3-C4 cycloalkyl group substituted with two fluorine groups. In some embodiments, R 2 It is an unsubstituted C3-C6 cycloalkyl group.

[0080] In some implementation schemes, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3It is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl, ethyl, tert-butyl, or isopropyl. In some embodiments, R 3 It is methyl, ethyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is isopropyl.

[0081] In some implementation schemes, R 3 It is a C1-C6 haloalkyl group. In some embodiments, R 3 It is a C1-C3 haloalkyl group. In some embodiments, R 3 It is a difluoromethyl group. In some embodiments, R 3 It is trifluoromethyl.

[0082] In some implementation schemes, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group substituted with one fluorine group. In some embodiments, R 3 This refers to a C3-C6 cycloalkyl group that is substituted with a fluorine group at the C3-C6 cycloalkyl position bonded to the methine group of formula (I). In some embodiments, R 3 It is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 Optionally, the C3-C6 cycloalkyl group is replaced by one or two methyl groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group substituted with one or two methyl groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group substituted with one methyl group. In some embodiments, R 3 This refers to a C3-C6 cycloalkyl group that is substituted with one methyl group at the position of the C3-C6 cycloalkyl group bonded to the methine group of formula (I). In some embodiments, R 3 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 It is cyclopropyl. In some embodiments, R 3 It is cyclobutyl. In some embodiments, R 3It is cyclopentyl. In some embodiments, R 3 It is a cyclohexyl group.

[0083] In some embodiments, ring A is a 6-10 aryl group. In some embodiments, ring A is phenyl, naphthyl, or tetrahydronaphthyl. In some embodiments, ring A is phenyl.

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

[0085] In some embodiments, ring A is a 5-10 membered heteroaryl group. In some embodiments, ring A is a 9-10 membered heteroaryl group. In some embodiments, ring A is a 9 membered heteroaryl group. In some embodiments, ring A is a 9 membered heteroaryl group, wherein the attachment point with 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 group, wherein the attachment point with the urea nitrogen atom in formula (I) is on the 5-membered ring of ring A.

[0086] In some embodiments, ring A is benzimidazolyl, indazole, indolyl, quinazolone, isobenzofuranone, isoindolone, imidazo[1,2-a]pyridyl, or imidazo[1,2-a]pyrimidinyl. In some embodiments, ring A is benzimidazolyl, indazole, indolyl, quinazolone, isobenzofuranone, isoindolone, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-6-yl, or imidazo[1,2-a]pyridyl. In some embodiments, ring A is benzimidazolyl, indazole, indolyl, or imidazo[1,2-a]pyridyl. In some embodiments, ring A is 2-benzimidazolyl, 5-indazole, 2-indolyl, 7-imidazo[1,2-a]pyridyl, In some implementation schemes, ring A is selected freely. and The group consists of a symbol, where “*” indicates the attachment point to the urea nitrogen atom in formula (I).

[0087] In some embodiments, ring A is a 5-6 membered heteroaryl group. In some embodiments, ring A is selected from the group consisting of pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, thiazolyl, furazolyl, oxadiazolyl, thiazolyl, oxtriazolyl, and thiazolyl. In some embodiments, ring A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, ring A is pyrimidinyl, pyridinyl, thiazolyl, thiophene, or pyrazolyl. In some embodiments, ring A is pyrimidinyl, pyridinyl, or pyrazolyl. In some embodiments, ring A is 5-pyrimidinyl, 3-pyridinyl, or 4-pyrazolyl. In some embodiments, ring A is selected from the group consisting of pyrimidinyl, pyridinyl, pyridinyl, and thiazolyl. The group consists of elements, where "*" indicates the attachment point to the urea nitrogen atom in formula (I). In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is 5-pyrimidinyl. In some embodiments, ring A is... The asterisk (*) indicates the attachment point to the urea nitrogen atom in formula (I). In some embodiments, ring A is a 4-10 membered heterocyclic group. In some embodiments, ring A is a 6-9 membered heterocyclic group. In some embodiments, ring A is piperidinyl, isoindolineone, or tetrahydro-2H-thiopyranyl-1,1-dioxide.

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

[0089] In some implementations, ring A is selected from 3-piperidinyl, A group that is formed.

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

[0091] In some implementations, an R 4 It is a C1-C6 alkyl group. In some embodiments, one R 4 It is an unsubstituted C1-C6 alkyl group. In some embodiments, one R 4 It is a C1-C4 alkyl group. In some embodiments, one R 4 For tert-butyl. In some implementations, an R 4 It is a methyl group.

[0092] In some implementations, an R4 The C1-C6 alkoxy group is optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups. In some embodiments, an R 4 It is a C1-C6 alkoxy group substituted with 1-2 independently selected substituents chosen from hydroxyl and C3-C6 cycloalkyl groups. In some embodiments, one R 4 It is a C1-C6 alkoxy group substituted with 1-2 independently selected substituents chosen from hydroxyl and cyclopropyl. In some embodiments, one R 4 It is a C1-C6 alkoxy group substituted with a hydroxyl group. In some embodiments, an R 4 It is a C1-C6 alkoxy group substituted with a C3-C6 cycloalkyl group. In some embodiments, an R 4 It is a C1-C6 alkoxy group substituted with a cyclopropyl group. In some embodiments, R 4 It is a C1-C6 alkoxy group. In some embodiments, R 4 It is a C1-C3 alkoxy group. In some embodiments, an R 4 It is a methoxy group.

[0093] In some implementations, an R 4 It is a C1-C6 haloalkyl group. In some embodiments, one R 4 It is a C1-C3 haloalkyl group. In some embodiments, one R 4 It is a difluoromethyl group. In some embodiments, an R 4 It is trifluoromethyl.

[0094] In some implementations, an R 4 It is a hydroxyl group. In some embodiments, an R 4 It is cyano. In some embodiments, an R 4 For -CO2H. In some implementations, an R 4 For halogens. In some implementations, an R 4 It is fluorine-based. In some embodiments, an R 4 It is a chlorine group.

[0095] In some implementations, an R 4 It is a C1-C6 alkyl group optionally substituted with 1-2 hydroxyl groups. In some embodiments, one R 4 It is a C1-C6 alkyl group substituted with 1-2 hydroxyl groups. In some embodiments, one R 4 It is a C1-C6 alkyl group substituted with one hydroxyl group. In some embodiments, one R 4 It is a C1-C6 alkyl group substituted with two hydroxyl groups. In some embodiments, one R 4It is a C1-C3 alkyl group substituted with two hydroxyl groups. In some embodiments, one R 4 For optional land use -NR A R B Substituted C1-C6 alkyl groups. In some embodiments, one R 4 For -NR A R B Substituted C1-C6 alkyl groups. In some embodiments, one R 4 For -NR A R B Substituted methyl or ethyl. In some embodiments, an R 4 It is an unsubstituted C1-C6 alkyl group. In some embodiments, one R 4 It is a methyl group.

[0096] In some implementations, an R 4 For -NR A R B .

[0097] In some implementation schemes, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R A and R B Another one is optionally hydroxyl or -C(=O)NR B2 R C2 Substituted C1-C6 alkyl groups. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group or -C(=O)NH2. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is -C(=O)O (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is -C(=O)OCH3. In some implementations, R A and R B One of them is hydrogen and R A and R B Another component is a 4-6 membered heterocyclic group (e.g., oxetane), and in some embodiments, R A and RB One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a butyl group substituted with a hydroxyl group (e.g., 2-hydroxy-2-methyl-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R BEach is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, R A and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0098] In some implementation schemes, R B2 and R C2 Both are hydrogen. In some implementations, R B2 and R C2 One of them is hydrogen and R B2 and R C2 Another component is a C1-C6 alkyl group. In some embodiments, R B2 and R C2 One of them is hydrogen and R B2 and R C2 The other one is methyl. In some embodiments, R B2 and R C2 Both are methyl groups.

[0099] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R BAnother one is a C1-C3 haloalkyl group. In some embodiments, R A and R B Each is a C1-C6 haloalkyl group. In some embodiments, R A and R B Each is a C1-C3 haloalkyl group.

[0100] In some implementation schemes, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group.

[0101] In some implementations, an R 4 -C(=O)NR C R D .

[0102] In some implementation schemes, R C and R D Each is hydrogen. In some implementations, R C and R D One of them is hydrogen and R C and R D Another component is a C1-C6 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is a C1-C3 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D Each is a C1-C6 alkyl group. In some embodiments, R C and R D Each is a C1-C3 alkyl group. In some embodiments, R C and R D Each is a methyl group. In some embodiments, R C and R D One of them is a C1-C6 alkyl group and R C and R D The other one is a C1-C3 alkyl group.

[0103] In some implementation schemes, R C and R D One of them is hydrogen and R C and R DAnother one is a C1-C6 haloalkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D Another one is a C1-C3 haloalkyl group. In some embodiments, R C and R D Each is a C1-C6 haloalkyl group. In some embodiments, R C and R D One of them is a C1-C6 alkyl group and R C and R D Another one is a C1-C6 haloalkyl group.

[0104] In some implementation schemes, R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl groups. In some embodiments, R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group, which is substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups.

[0105] In some implementation schemes, R B1 and R C1 Each is hydrogen. In some implementations, R B1 and R C1 One of them is hydrogen and R B1 and R C1 Another component is a C1-C6 alkyl group. In some embodiments, R B1 and R C1 One of them is hydrogen and R B1 and R C1 The other one is methyl. In some embodiments, R B1 and R C1 Each is an independently selected C1-C6 alkyl group. In some embodiments, R B1 and R C1 Each is a methyl group.

[0106] In some implementation schemes, R C and R D Together with the attached nitrogen atom, it forms a 4-6 membered heterocyclic group. In some embodiments, R C and R D Together with the nitrogen atom attached to it, it forms azacyclobutane or piperazine.

[0107] In some implementations, an R 4 -SO2(NR) E R F In some implementations, R E and R F Each is hydrogen. In some implementations, R E and R F One of them is hydrogen and R E and R F Another component is a C1-C6 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is a C1-C3 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is methyl. In some embodiments, R E and R F Each is a C1-C6 alkyl group. In some embodiments, R E and R F Each is a C1-C3 alkyl group. In some embodiments, R E and R F Each is a methyl group.

[0108] In some implementation schemes, R E and R F One of them is hydrogen and R E and R F Another one is a C1-C6 haloalkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F Another one is a C1-C3 haloalkyl group. In some embodiments, R E and R F Each is a C1-C6 haloalkyl group. In some embodiments, R E and R F One of them is a C1-C6 alkyl group and R E and R FAnother one is a C1-C6 haloalkyl group.

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

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

[0111] In some implementations, an R 4 It is -C(=O)(C1-C6 alkyl). In some embodiments, an R 4 It is -C(=O)(C1-C3 alkyl). In some embodiments, an R 4 It is -C(=O)Me.

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

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

[0114] In some implementations, an R 4 R can be optionally selected by one or two independent choices G Replaced 3-9 membered heterocyclic groups. In some embodiments, an R 4 R can be optionally selected by one or two independent choices G The substituted 3-membered heterocyclic group. In some embodiments, an R 4 R can be optionally selected by one or two independent choices G The substituted 4-membered heterocyclic group. In some embodiments, an R 4 R can be optionally selected by one or two independent choices G The substituted 5-membered heterocyclic group. In some implementations, an R 4 R can be optionally selected by one or two independent choices G The 7-9 membered heterocyclic group is replaced. In some embodiments, R 4 The heterocyclic group is a spirocyclic group. In some embodiments, an R 4 R can be optionally selected by one or two independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, an R 4 For R selected by 1 or 2 independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, an R 4 For 1 R G Substituted 3-6 membered heterocyclic groups. In some embodiments, an R 4 For R, which is selected by two independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, an R 4 It is an unsubstituted 3-6 membered heterocyclic group.

[0115] In some implementations, an R 4 R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups. In some embodiments, one R 4 For R selected by 1 or 2 independent choices G Substituted 3-6 membered cycloalkyl groups. In some embodiments, one R 4 For 1 R G Substituted 3-6 membered cycloalkyl groups. In some embodiments, one R 4 For R, which is selected by two independent choices G Substituted 3-6 membered cycloalkyl groups. In some embodiments, one R 4 It is an unsubstituted 3-6 membered cycloalkyl group.

[0116] In some implementations, one or two independently selected R G For 1 R G In some implementations, one or two independently selected R G For 2 independently chosen R G In some implementations, when there are 2 R... G When the valence allows, they can bond to the same atom. In some implementations, when there are 2 R atoms... G When the valence allows, it can bond to adjacent atoms. In some implementations, when there are 2 R atoms... G At that time, 2 R G They are different. In some implementations, when there are 2 Rs... G At that time, 2 R G They are the same. In some implementations, an R G It is fluorine-based. In some embodiments, an R G It is cyano. In some embodiments, an R G It is a hydroxyl group. In some embodiments, an R G It is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, one R G It is 2-hydroxy-2-propyl. In some embodiments, an R G It is a C1-C6 alkyl group. In some embodiments, one R G It is a C1-C3 alkyl group. In some embodiments, one R G It is methyl. In some embodiments, an R G It is an ethyl group.

[0117] In some implementations, an R G It is a C1-C6 alkoxy group. In some embodiments, an R G It is a C1-C3 alkoxy group. In some embodiments, an R G It is a methoxy group.

[0118] In some implementations, an R G For -NR A1 R B1 In some implementations, R A1 and R B1 Each is hydrogen. In some implementations, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another component is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and RA1 and R B1 The other one is a C1-C3 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is methyl. In some embodiments, R A1 and R B1 Each is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 Each is a methyl group.

[0119] In some implementation schemes, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another one is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another one is a C1-C3 haloalkyl group. In some embodiments, R A1 and R B1 Each is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl group and R A1 and R B1 Another one is a C1-C6 haloalkyl group.

[0120] In some implementations, an R G =NR A2 In some implementations, an R G =NH. In some implementations, R A2 It is hydrogen. In some implementations, R A2 It is a C1-C6 alkyl group. In some embodiments, R A2 It is a methyl group.

[0121] In some implementations, an R G -C(=O)NR C1 R D1 In some implementations, an R G For -CO2NH2. In some implementations, an R G For -CO2NHCH3. In some implementations, R C1 and R D1 Each is hydrogen. In some implementations, R C1 and R D1 One of them is hydrogen and RC1 and R D1 Another component is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is a C1-C3 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is methyl. In some embodiments, R C1 and R D1 Each is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 Each is a C1-C3 alkyl group. In some embodiments, R C1 and R D1 Each is a methyl group.

[0122] In some implementation schemes, R C1 and R D1 One of them is hydrogen and R C1 and R D1 Another one is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 Another one is a C1-C3 haloalkyl group. In some embodiments, R C1 and R D1 Each is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 One of them is a C1-C6 alkyl group and R C1 and R D1 Another one is a C1-C6 haloalkyl group.

[0123] In some implementations, an R G It is -CO2 (C1-C6 alkyl). In some embodiments, an R G For -CO2CH3. In some implementations, an R G It is a C1-C6 haloalkyl group. In some embodiments, one R G It is trifluoromethyl. In some embodiments, an R G It is a difluoromethyl group. In some embodiments, an R G It is a C3-C6 cycloalkyl group. In some embodiments, one R G It is cyclopropyl. In some embodiments, an R G It is -CO2H.

[0124] In some implementations, an R G It is a C1-C6 haloalkoxy group. In some embodiments, an R G It is a C1-C3 haloalkoxy group. In some embodiments, an R G It is a difluoromethoxy group. In some embodiments, an R... G It is trifluoromethoxy.

[0125] In some implementations, an R G It is -SO2 (C1-C6 alkyl). In some embodiments, an R G It is -SO2CH3.

[0126] In some implementation schemes, R 4 The 3-9 membered heterocyclic group is a 3-6 membered heterocyclic group. In some embodiments, R 4 The 3-6 membered heterocyclic group is a 5-6 membered heterocyclic group. In some embodiments, R 4 The 3-6 membered heterocyclic group is an azirrobutyl, azirrobutyl-2-one, morpholino, piperazine, or tetrahydropyranoyl group. In some embodiments, R 4 The 3-6 membered heterocyclic group is 1-azacyclobutane, 1-azacyclobut-2-one, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. In some embodiments, R 4 The 3-9 membered heterocyclic groups are selected from the following groups: , In some implementations, R 4 3-9 membered heterocyclic groups (e.g., R) 4 (3-6 membered heterocyclic group) is Wherein Q is a C1-C3 alkylene group in which one or more carbon atoms are optionally replaced by -C(=O)-, NH, O, or S. In some embodiments, Q is a C1-C3 alkylene group in which one or more carbon atoms are optionally replaced by -C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene group in which one or more carbon atoms are optionally replaced by -C(=O)- or NH. In some embodiments, R... 4 The 3-9 membered heterocyclic groups are selected from the following groups: .

[0127] In some implementations, an R 4 It is an unsubstituted 3-6 membered heterocyclic group. In some embodiments, R 4 The 3-6 membered heterocyclic group is a 5-6 membered heterocyclic group. In some embodiments, R 4It is a nitrogen-containing heterocyclic butyl, morpholino, or tetrahydropyranoyl group. In some embodiments, R... 4 Choose from the following groups: .

[0128] In some implementation schemes, for Where: X is selected from N and CR 4A2 ;R 4A1 and R 4A2 Independently selected from hydrogen, optionally by -NR A R B Substituted C1-C3 alkyl, methoxy, C1-C3 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F ), -SO2 (C1-C6 alkyl) and optionally R selected independently G The substituted 3-6-membered heterocyclic group and optionally one or two independently selected R G Substituted 3-6 membered cycloalkyl groups. In some embodiments, X is N. In some embodiments, X is CR. 4A2 In some implementations, R 4A1 and R when it exists 4A2 Independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2Me, and nitrogen-containing heterocyclic butyl groups optionally substituted with 1-2 independently selected fluorine, hydroxyl, or methyl groups. In some embodiments, R C and R D Together with the attached nitrogen atom, it forms a 4-6 membered heterocyclic group. In some embodiments, X is N and R 4A1 R can be optionally selected by one or two independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, R C and R D Together with the nitrogen atom attached to it, it forms azacyclobutane or piperazine.

[0129] In some implementations, X is N; and R 4A1 Selected from amino groups or optionally substituted with one or two independently chosen fluorine, hydroxyl, or methyl groups.

[0130] In some implementation schemes, for , where: R 4BSelected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 Selected from fluorinated, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl groups. In some embodiments, R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0131] In some implementation schemes, for , where: R 4B Selected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 The group is selected from fluorinated, hydroxyl, methoxy, methyl, ethyl, amino, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, R G1 The group is selected from fluorinated, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0132] In some implementation schemes, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and RB The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B Each is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, RA and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0133] In some implementation schemes, R 4B It is an amino group or has one nitrogen atom and is optionally composed of 1-2 independently selected R atoms. G Substituted 4-6 membered heterocyclic groups; wherein R G Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0134] In some implementation schemes, R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group, each optionally containing 1-2 =O groups, and each optionally being composed of 1-2 R groups independently selected from the following groups. G Substitution: fluorinated, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. In some embodiments, R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group, each optionally being represented by one or two independently selected R groups from the following groups. G Substitution: fluorinated, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and C1-C6 alkyl. In some embodiments, R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group, each optionally being represented by one or two independently selected R groups from the following groups. G Substitution: fluorinated, hydroxyl, trifluoromethyl, and C1-C6 alkyl. In some embodiments, R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, or piperidinyl group, each optionally constituting one or two independently selected R groups from the following groups. G Substitution: fluorine, hydroxyl, and C1-C6 alkyl. In some embodiments, ring B is a nitrogen-containing butyl ring.

[0135] In some implementations, ring B is not replaced.

[0136] In some implementations, ring B is divided by 1 R G Replacement. In some implementations, R G It is fluorine-based. In some embodiments, R G It is cyano. In some embodiments, R G For amino groups, in some embodiments, R GIt is a hydroxyl group. In some embodiments, R G It is a C1-C3 alkyl group. In some embodiments, R G It is methyl. In some embodiments, R G It is ethyl. In some embodiments, R G For -CO2CH3. In some implementations, R G It is methoxylated. In some embodiments, R G It is a methoxy group.

[0137] In some implementations, ring B is divided by 2 R G Replacement. In some implementations, each R G It is fluorine-based. In some embodiments, each R... G It is a C1-C3 alkyl group. In some embodiments, each R... G It is methyl. In some embodiments, an R G For hydroxyl and another R G It is methyl. In some embodiments, an R G For hydroxyl and another R G It is ethyl. In some embodiments, an R G For amino and another R G It is methyl. In some embodiments, an R G For hydroxyl and another R G It is cyclopropyl. In some embodiments, an R G It is fluorine-based and another R G1 It is methyl. In some embodiments, an R G For hydroxyl and another R G It is fluorine-based. In some embodiments, an R G For hydroxyl and another R G It is trifluoromethyl. In some embodiments, each R G The position of nitrogen bonded to ring B at the para position of nitrogen bonded to ring A.

[0138] In some implementation schemes, for One or two independently selected R G It is attached at the 3-position of azahexacyclic butane. In some embodiments, Freedom of choice and The group that makes up the composition. In some implementations, Freedom of choice The group that makes up the composition. In some implementations, Freedom of choice A group that is formed.

[0139] In some implementations, Z is O.

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

[0141] In some implementation schemes, R x It is hydrogen.

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

[0143] In some implementation schemes, R x It is a C3-C6 cycloalkyl group. In some embodiments, R x It is a C3-C4 cycloalkyl group. In some embodiments, R x It is cyclopropyl. In some embodiments, R x It is cyclobutyl.

[0144] In some implementation schemes, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R 3 It is a C1-C6 alkyl group. In some embodiments, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 Selected from methyl, ethyl, isopropyl or tert-butyl.

[0145] In some implementation schemes, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R 3 It is a C1-C6 haloalkyl group. In some embodiments, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 It is trifluoromethyl.

[0146] In some implementations, m is 2, and an R 4 It is a halogen, and another R 4 It is -SO2 (C1-C6 alkyl). In some embodiments, m is 2, and one R4 It is a chlorine group, and another R 4 It is -SO2CH3.

[0147] In some implementations, m is 2, and an R 4 It is a C1-C6 alkoxy group, and another R 4 -C(=O)NR C R D .

[0148] In some implementations, m is 2, and an R 4 It is methoxylated, and another R 4 The form is -C(O)NHCH3. In some embodiments, ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 Independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0149] In some implementation schemes, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heterocyclic groups; and n is 1 or 2.

[0150] In some implementation schemes, each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heteroaryl, and optionally R, which is independently selected by one or two. G Substituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0151] In some implementation schemes, each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heterocyclic groups; and n is 1 or 2.

[0152] In some implementation schemes, each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 Independently select from the following groups: -NHR B and optionally by 1-2 R G Substituted 4-6 membered heterocyclic groups; and n is 1 or 2.

[0153] In some implementations, Z is O; each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R3 It is a C1-C6 alkyl group. In some embodiments, Z is O; each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 Selected from methyl, ethyl, isopropyl or tert-butyl.

[0154] In some implementations, Z is O; each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R 3 It is a C1-C6 haloalkyl group. In some embodiments, Z is O; each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 It is trifluoromethyl.

[0155] In some implementations, Z is 0; m is 2, and an R 4 It is a halogen, and another R 4 It is -SO2 (C1-C6 alkyl). In some embodiments, m is 2, and one R 4 It is a chlorine group, and another R 4 It is -SO2CH3.

[0156] In some implementations, Z is 0; m is 2, and an R 4 It is a C1-C6 alkoxy group, and another R 4 -C(=O)NR C R D .

[0157] In some implementations, Z is 0; m is 2, and an R 4 It is methoxylated, and another R 4 The form is -C(O)NHCH3. In some embodiments, ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 Independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0158] In some implementations, Z is O; Each R 1 It is fluorine-based; m is 1 or 2; R2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heterocyclic groups; and n is 1 or 2.

[0159] In some implementations, Z is O; Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heteroaryl, and optionally R, which is independently selected by one or two. G Substituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0160] In some implementations, Z is O; Each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4Independently 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 heterocyclic groups; and n is 1 or 2.

[0161] In some implementations, Z is O; Each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 Independently select from the following groups: -NHR B and optionally by 1-2 R G Substituted 4-6 membered heterocyclic groups; and n is 1 or 2.

[0162] In some implementations, Z is NR x Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R 3 It is a C1-C6 alkyl group. In some embodiments, Z is NR. x Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 Selected from methyl, ethyl, isopropyl or tert-butyl.

[0163] In some implementations, Z is NR x Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; and R 3 It is a C1-C6 haloalkyl group. In some embodiments, Z is O; each R 1 It is fluorine-based; m is 1 or 2; R 2 It is methyl; and R 3 It is trifluoromethyl.

[0164] In some implementations, Z is NR x m is 2, and one R 4 It is a halogen, and another R4 It is -SO2 (C1-C6 alkyl). In some embodiments, m is 2, and one R 4 It is a chlorine group, and another R 4 It is -SO2CH3.

[0165] In some implementations, Z is NR x m is 2, and one R 4 It is a C1-C6 alkoxy group, and another R 4 -C(=O)NR C R D .

[0166] In some implementations, Z is NR x m is 2, and one R 4 It is methoxylated, and another R 4 The form is -C(O)NHCH3. In some embodiments, ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 Independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6 membered heteroaryl and unsubstituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0167] In some implementations, Z is NR x ; Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heterocyclic groups; and n is 1 or 2.

[0168] In some implementations, Z is NR x ; Each R 1 It is fluorine-based; m is 1 or 2; R 2 It is a C1-C6 alkyl group; R 3 It is a C1-C6 alkyl group; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heteroaryl, and optionally R, which is independently selected by one or two. G Substituted 3-6 membered heterocyclic groups; and n is 1 or 2.

[0169] In some implementations, Z is NR x ; Each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R 4 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 heterocyclic groups; and n is 1 or 2.

[0170] In some implementations, Z is NR x ; Each R 1 It can be fluorinated, cyano, or methyl; m is 1 or 2; R 2 It is a C1-C3 alkyl group; R 3 It is a C1-C3 alkyl or a C1-C3 haloalkyl; Ring A is phenyl or a 5-6 membered heteroaryl group; Each R4 Independently select from the following groups: -NHR B and optionally by 1-2 R G Substituted 4-6 membered heterocyclic groups; and n is 1 or 2.

[0171] In some embodiments, the compound of formula (I) has formula (IA): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl group; R 4 Independently select from the following groups: Optional - NR A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups optionally substituted with C1-C6 alkyl, or R groups optionally substituted with one or two independently selected R groups. G The substituted 3-6 membered heterocyclic group and optionally one or two independently selected R G Substituted 3-6 membered cycloalkyl groups; Where R 4 The position of the N atom in the urea moiety bonded to ring A1; Each R A R A1 R B R B1 R C R C1 R D RD1 R E and R F Independently hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2); or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0172] In some embodiments, ring A1 is pyrimidinyl, pyridinyl, or pyrazolyl. In some embodiments, ring A1 is pyrimidinyl. In some embodiments, ring A1 is pyridinyl. In some embodiments, ring A1 is pyrazolyl.

[0173] In some embodiments, ring A1 is 5-pyrimidinyl, 3-pyridinyl, or 4-pyrazolyl. In some embodiments, ring A1 is 5-pyrimidinyl. In some embodiments, ring A1 is 3-pyridinyl. In some embodiments, ring A1 is 4-pyrazolyl.

[0174] In some implementations of formula (IA), for , where: R 4B Selected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0175] In some implementations of formula (IA), R A and R B Each is hydrogen.

[0176] In some implementations of formula (IA), R A and R B Each is a 4-6 member heterocyclic group. In some embodiments of formula (IA), R A and R BOne of them is hydrogen and R A and R B Another one is a 4-6 membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a 4-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a 5-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is 1,1-dioxane-3-tetrahydrothiophene-3-yl. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a 6-membered heterocyclic group.

[0177] In some implementations of formula (IA), R A and R B Each is a C1-C6 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group.

[0178] In some implementations of formula (IA), R A and R B Each is an optional 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R BThe other is a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is an unsubstituted 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 3-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 4-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is cis- or trans-3-hydroxycyclobutyl. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 5-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 6-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a 3-6 membered cycloalkyl group substituted with a hydroxyl group.

[0179] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R BThe other is a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 alkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 alkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is methyl.

[0180] In some implementations of formula (IA), R A and R B Each is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments of formula (IA), R A and R B Each is a C1-C6 alkyl group. In some embodiments of formula (IA), R A and R B Each is a C1-C3 alkyl group. In some embodiments of formula (IA), R A and R B Each is a methyl group.

[0181] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group. In some embodiments of formula (IA), RA and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group and a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with cyclopropyl and hydroxyl groups. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is an ethyl group substituted with both cyclopropyl and hydroxyl groups, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B All are C1-C6 alkyl groups substituted with 3-6 membered cycloalkyl groups.

[0182] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2 (C1-C3 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2CH3, such as 1-(methylsulfonyl)propyl-2-yl. In some embodiments of formula (IA), RA and R B One of them is a C1-C6 alkyl group and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B All are C1-C6 alkyl groups substituted with -SO2 (C1-C6 alkyl).

[0183] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with -SO2(NH2), such as 1-aminosulfonylpropyl-2-yl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group, hydrogen, and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments of formula (IA), R A and R B All are C1-C6 alkyl groups substituted with -SO2(NH2). In some embodiments of formula (IA), R 4B For R, which includes a nitrogen ring member and is optionally selected by 1-2 independently chosen members. G Substituted 4-6 membered heterocyclic groups; wherein R G Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0184] In some implementations of formula (IA), R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, or piperidinyl group, each optionally surrounded by 1-2 R groups independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups. G Substitution. In some embodiments of formula (IA), ring B is a nitrogen-containing heterocyclic butyl group.

[0185] In some implementations of formula (IA), ring B is unsubstituted.

[0186] In some implementations of formula (IA), ring B is surrounded by 1 R GReplacement. In some implementations of formula (IA), R G It is fluorinated. In some embodiments of formula (IA), R G It is a cyano group. In some embodiments of formula (IA), R G It is a hydroxyl group. In some embodiments of formula (IA), R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), R G It is methyl. In some embodiments of formula (IA), R G It is -CO2CH3.

[0187] In some implementations of equation (IA), ring B is formed by two independently chosen R... G Replacement. In some implementations of formula (IA), each R G It is fluorinated. In some embodiments of formula (IA), each R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), each R G It is methyl. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), one R G For hydroxyl and another R G It is methyl. In some embodiments of formula (IA), an R G It is fluorine-based and another R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), one R G It is fluorine-based and another R G It is methyl. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is fluorinated. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is trifluoromethyl.

[0188] In some implementations of formula (IA), for One or two independently selected R G At the 3-position of the azahexacyclic butane. In some embodiments of formula (IA), Choose from the following groups: and In some implementations of formula (IA), Choose from the following groups: .

[0189] In some embodiments, the compound of formula (I) is of formula (IB): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; R 4 Independently select from the following groups: Optional - NR A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups optionally substituted with C1-C6 alkyl, or R groups optionally substituted with one or two independently selected R groups. G The substituted 3-6 membered heterocyclic group and optionally one or two independently selected R G Substituted 3-6 membered cycloalkyl groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently composed of hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2); or R C and RD Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0190] In some implementation schemes, R 1A and R 1B Each is a fluorine group; In some implementation schemes, R 2 It is a C1-C6 alkyl group. In some embodiments, R 2 It is a C1-C3 alkyl group. In some embodiments, R 2 It is a methyl group.

[0191] In some implementation schemes, R 2 It is a C1-C6 haloalkyl group. In some embodiments, R 2 It is a C1-C3 haloalkyl group. In some embodiments, R 2 It is trifluoromethyl.

[0192] In some implementation schemes, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl, ethyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is isopropyl.

[0193] In some implementation schemes, R 3 It is a C1-C6 haloalkyl group. In some embodiments, R 3 It is a C1-C3 haloalkyl group. In some embodiments, R 3 It is trifluoromethyl.

[0194] In some implementation schemes, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. In some embodiments, R 3It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups. In some embodiments, R 3 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 It is cyclopropyl.

[0195] In some implementation schemes, R 4 For optional land use -NR A R B Substituted C1-C6 alkyl groups. In some embodiments, R 4 For optional land use -NR A R B Substituted C1-C3 alkyl groups. In some embodiments, R 4 For optional land use -NR A R B Substituted methyl groups. In some embodiments, R 4 It is a C1-C4 alkyl group. In some embodiments, R 4 It is a methyl group.

[0196] In some implementation schemes, R 4 It is a C1-C6 alkoxy group. In some embodiments, R 4 It is a C1-C3 alkoxy group. In some embodiments, R 4 It is a methoxy group.

[0197] In some implementation schemes, R 4 It is a C1-C6 haloalkyl group. In some embodiments, R 4 It is a C1-C3 haloalkyl group. In some embodiments, R 4 It is trifluoromethyl.

[0198] In some implementation schemes, R 4 It is a hydroxyl group. In some embodiments, R 4 It is cyano. In some embodiments, R 4 For -CO2H. In some implementations, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R BAnother component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B Each is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R BThe other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, R A and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0199] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments, R A and R B Each is a C1-C6 haloalkyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 haloalkyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group.

[0200] In some implementation schemes, R A and R B Each is a 4-6 member heterocyclic group. In some implementations, R A and R B One of them is hydrogen and R A and R B Another component is a 4-6 membered heterocyclic group. In some implementations, R A and R B One of them is hydrogen and R A and R B Another one is a 4-membered heterocyclic group. In some implementations, R A and RB One of them is hydrogen and R A and R B Another component is a 5-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is 1,1-dioxo-tetrahydrothiophene-3-yl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a 6-membered heterocyclic group.

[0201] In some implementation schemes, R A and R B Each is an optional 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is an unsubstituted 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a 3-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a four-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is cis- or trans-3-hydroxycyclobutyl. In some embodiments, R A and R B One of them is hydrogen and R A and R BThe other is a 5-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a 6-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a 3-6 membered cycloalkyl group substituted with a hydroxyl group.

[0202] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl) and -SO2 (NH2).

[0203] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group and a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with cyclopropyl and hydroxyl groups. In some embodiments, R A and R B One of them is hydrogen and R A and R BAnother is an ethyl group substituted with cyclopropyl and hydroxyl groups, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another component is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with 3-6 membered cycloalkyl groups.

[0204] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2 (C1-C3 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with -SO2CH3, such as 1-(methylsulfonyl)propyl-2-yl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments, R A and R B One of them is hydrogen and R A and RB Another component is a C1-C3 alkyl group substituted with -SO2(NH2), such as 1-aminosulfonylpropyl-2-yl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group, hydrogen, and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with -SO2(NH2).

[0205] In some implementations, an R 4 -C(=O)NR C R D In some implementations, R C and R D Each is hydrogen. In some implementations, R C and R D One of them is hydrogen and R C and R D Another component is a C1-C6 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is a C1-C3 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D Each is a C1-C6 alkyl group. In some embodiments, R C and R D Each is a C1-C3 alkyl group. In some embodiments, R C and R D Each is a methyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D Another one is a C1-C6 haloalkyl group. In some embodiments, R C and R D Each is a C1-C6 haloalkyl group. In some embodiments, R C and R D One of them is a C1-C6 alkyl group and R C and R DAnother one is a C1-C6 haloalkyl group. In some embodiments, R C and R D Together with the attached nitrogen atom, it forms a 4-6 membered heterocyclic group. In some embodiments, R C and R D Together with the nitrogen atom attached to it, it forms azacyclobutane or piperazine.

[0206] In some implementations, an R 4 -SO2(NR) E R F In some implementations, R E and R F Each is hydrogen. In some implementations, R E and R F One of them is hydrogen and R E and R F Another component is a C1-C6 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one is methyl. In some embodiments, R E and R F Each is a C1-C6 alkyl group. In some embodiments, R E and R F Each is a C1-C3 alkyl group. In some embodiments, R E and R F Each is a methyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F Another one is a C1-C6 haloalkyl group. In some embodiments, R E and R F Each is a C1-C6 haloalkyl group. In some embodiments, R E and R F One of them is a C1-C6 alkyl group and R E and R F Another one is a C1-C6 haloalkyl group.

[0207] In some implementation schemes, R 4 It is -SO2 (C1-C6 alkyl). In some embodiments, R 4 It is -SO2 (C1-C3 alkyl). In some embodiments, R 4 For -SO2Me. In some implementations, R 4 It is -SO2Et.

[0208] In some implementation schemes, R 4 It is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 It is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 For -S(=O)(=NH)Me.

[0209] In some implementation schemes, R 4 It is a -C(=O)(C1-C6 alkyl). In some embodiments, R 4 It is a -C(=O)(C1-C3 alkyl). In some embodiments, R 4 It is -C(=O)Me.

[0210] In some implementation schemes, R 4 It is -CO2 (C1-C6 alkyl). In some embodiments, R 4 It is -CO2 (C1-C3 alkyl). In some embodiments, R 4 It is -CO2Me.

[0211] In some implementations, an R 4 It is a 5-6 membered heteroaryl group optionally substituted with a C1-C6 alkyl group. In some embodiments, an R 4 It is a 5-6 membered heteroaryl group substituted with a C1-C6 alkyl group. In some embodiments, R 4 It is a 5-6 membered heteroaryl group. In some implementations, R 4 The group is selected from the group consisting of pyrrole, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxtriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R 4 It is a pyrazolyl group. In some embodiments, an R 4 It is a tetrazolium group substituted with a methyl group. In some embodiments, an R 4 It is a pyrazolyl group. In some embodiments, an R 4 It is an unsubstituted pyrazolyl group. In some embodiments, an R 4 It is 1-pyrazolyl.

[0212] In some implementation schemes, R 4 R can be optionally selected by one or two independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, R 4 For R selected by 1 or 2 independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, R4 For 1 R G Substituted 3-6 membered heterocyclic groups. In some embodiments, R 4 For R, which is selected by two independent choices G Substituted 3-6 membered heterocyclic groups.

[0213] In some implementation schemes, R G It is fluorine-based. In some embodiments, R G It is cyano. In some embodiments, R G It is a hydroxyl group. In some embodiments, R G It is a C1-C6 alkyl group. In some embodiments, R G It is a C1-C3 alkyl group. In some embodiments, R G It is a methyl group.

[0214] In some implementation schemes, R G It is a C1-C6 alkoxy group. In some embodiments, R G It is a C1-C3 alkoxy group. In some embodiments, R G It is a methoxy group.

[0215] In some implementations, an R G For -NR A1 R B1 In some implementations, R A1 and R B1 Each is hydrogen. In some implementations, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another component is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is a C1-C3 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is methyl. In some embodiments, R A1 and R B1 Each is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 Each is a C1-C3 alkyl group. In some embodiments, R A1 and R B1 Each is a methyl group.

[0216] In some implementation schemes, R A1 and RB1 One of them is hydrogen and R A1 and R B1 Another one is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 Each is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl group and R A1 and R B1 Another one is a C1-C6 haloalkyl group.

[0217] In some implementations, an R G -C(=O)NR C1 R D1 In some implementations, R C1 and R D1 Each is hydrogen. In some implementations, R C1 and R D1 One of them is hydrogen and R C1 and R D1 Another component is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is a C1-C3 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is methyl. In some embodiments, R C1 and R D1 Each is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 Each is a methyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 Another one is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 Each is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 One of them is a C1-C6 alkyl group and R C1 and R D1 Another one is a C1-C6 haloalkyl group.

[0218] In some implementations, an R GIt is -CO2 (C1-C6 alkyl). In some embodiments, an R G It is -CO2CH3.

[0219] In some implementations, an R G It is a C1-C6 haloalkyl group. In some embodiments, one R G It is trifluoromethyl.

[0220] In some implementations, an R G It is a C3-C6 cycloalkyl group. In some embodiments, one R G It is cyclopropyl.

[0221] In some implementation schemes, R G It is -CO2H.

[0222] In some implementation schemes, R 4 The 3-6 membered heterocyclic group is a 5-6 membered heterocyclic group. In some embodiments, R 4 The 3-6 membered heterocyclic group is an azirrobutyl, azirrobutyl-2-one, morpholino, piperazine, or tetrahydropyranoyl group. In some embodiments, R 4 The 3-6 membered heterocyclic group is 1-azacyclobutane, 1-azacyclobut-2-one, 1-piperazinyl, 1-morpholinyl or 4-tetrahydropyranyl.

[0223] In some implementation schemes, R 4 It is an unsubstituted 3-6 membered heterocyclic group. In some embodiments, R 4 It is a 5-6 membered heterocyclic group. In some implementations, R 4 It is a nitrogen-containing heterocyclic butyl, morpholino, or tetrahydropyranoyl.

[0224] In some implementation schemes, R 4 Choose from the following groups: and .

[0225] In some implementation schemes, R 4 Selected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0226] In some implementation schemes, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R Aand R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B Each is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R BThe other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, R A and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0227] In some implementation schemes, R 4 For R, which includes a nitrogen ring member and is optionally selected by 1-2 independently chosen members. G Substituted 4-6 membered heterocyclic groups; wherein R G Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0228] In some embodiments, the compound of formula (I) is of formula (IC): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F-SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 and -CO2H.

[0229] In some embodiments, the compound of formula (I) is of formula (ID): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F-SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0230] In some implementations, the compound of formula (I) is of formula (IE): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR)E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0231] In some embodiments, the compound of formula (I) is of formula (IF): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR CR D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and the compounds therein are not .

[0232] Some embodiments provide a compound of formula (IF) wherein the compound is not a compound selected from the group consisting of: .

[0233] In some embodiments, the compound of formula (I) is of formula (IG): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0234] In some embodiments, the compound of formula (I) is of formula (IH): Or its pharmaceutically acceptable salt, wherein: R 1A It is a halogen; R 1B It is halogenated, cyano, cyclopropyl or absent (the benzene ring is replaced by R). 1A (single substitution); R 2It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. A R B and R, which can be optionally selected by one or two independent choices G Substituted 3-9 membered heterocyclic groups; Each R A R B R C1 and R D1 Independently hydrogen, 4-6 membered heterocyclic group, optionally surrounded by hydroxyl or -C(=O)NR B2 R C2 Substituted C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine group, hydroxyl group, C1-C6 alkyl group optionally substituted with hydroxyl group, C1-C6 alkoxy group, =NR group A2 -C(=O)NR C1 R D1 -C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H.

[0235] In some embodiments, the compound of formula (I) is of formula (IJ): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A1 is a 6-membered heteroaryl group; R 4 Independently select from the following groups: Optional - NR A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups optionally substituted with C1-C6 alkyl, or R groups optionally substituted with one or two independently selected R groups. G The substituted 3-6 membered heterocyclic group and optionally one or two independently selected R G Substituted 3-6 membered cycloalkyl groups; Where R 4 The position of the N atom in the urea moiety bonded to ring A1; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently composed of hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2); or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0236] In some embodiments, ring A1 is pyrimidinyl, pyridinyl, or pyrazolyl. In some embodiments, ring A1 is pyrimidinyl. In some embodiments, ring A1 is pyridinyl. In some embodiments, ring A1 is pyrazolyl.

[0237] In some embodiments, ring A1 is 5-pyrimidinyl, 3-pyridinyl, or 4-pyrazolyl. In some embodiments, ring A1 is 5-pyrimidinyl. In some embodiments, ring A1 is 3-pyridinyl. In some embodiments, ring A1 is 4-pyrazolyl.

[0238] In some implementations of formula (IA), for , where: R 4B Selected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0239] In some implementations of formula (IA), R A and R B Each is hydrogen.

[0240] In some implementations of formula (IA), R A and R B Each is a 4-6 member heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a 4-6 membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a 4-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a 5-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is 1,1-dioxane-3-tetrahydrothiophene-3-yl. In some embodiments of formula (IA), R A and R B One of them is hydrogen and RA and R B The other one is a 6-membered heterocyclic group.

[0241] In some implementations of formula (IA), R A and R B Each is a C1-C6 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 haloalkyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group.

[0242] In some implementations of formula (IA), R A and R B Each is an optional 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is an unsubstituted 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 3-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R BThe other is a 4-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is cis- or trans-3-hydroxycyclobutyl. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 5-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a 6-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a 3-6 membered cycloalkyl group substituted with a hydroxyl group.

[0243] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 alkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R BThe other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 alkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is methyl.

[0244] In some implementations of formula (IA), R A and R B Each is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is methyl and R A and R BThe other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments of formula (IA), R A and R B Each is a C1-C6 alkyl group. In some embodiments of formula (IA), R A and R B Each is a C1-C3 alkyl group. In some embodiments of formula (IA), R A and R B Each is a methyl group.

[0245] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group and a hydroxyl group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with cyclopropyl and hydroxyl groups. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is an ethyl group substituted with both cyclopropyl and hydroxyl groups, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B Another is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments of formula (IA), RA and R B All are C1-C6 alkyl groups substituted with 3-6 membered cycloalkyl groups.

[0246] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another is a C1-C3 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2 (C1-C3 alkyl). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2CH3, such as 1-(methylsulfonyl)propyl-2-yl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments of formula (IA), R A and R B All are C1-C6 alkyl groups substituted with -SO2 (C1-C6 alkyl).

[0247] In some implementations of formula (IA), R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R BAnother component is a C1-C3 alkyl group substituted with -SO2(NH2), such as 1-aminosulfonylpropyl-2-yl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl group, hydrogen, and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments of formula (IA), R A and R B All are C1-C6 alkyl groups substituted with -SO2(NH2). In some embodiments of formula (IA), R 4B For R, which includes a nitrogen ring member and is optionally selected by 1-2 independently chosen members. G Substituted 4-6 membered heterocyclic groups; wherein R G Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0248] In some implementations of formula (IA), R 4B for ; wherein ring B is an azacyclic butyl, pyrrolidinyl, or piperidinyl group, each optionally surrounded by 1-2 R groups independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups. G Substitution. In some embodiments of formula (IA), ring B is a nitrogen-containing heterocyclic butyl group.

[0249] In some implementations of formula (IA), ring B is unsubstituted.

[0250] In some implementations of formula (IA), ring B is surrounded by 1 R G Replacement. In some implementations of formula (IA), R G It is fluorinated. In some embodiments of formula (IA), R G It is a cyano group. In some embodiments of formula (IA), R G It is a hydroxyl group. In some embodiments of formula (IA), R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), R G It is methyl. In some embodiments of formula (IA), R G It is -CO2CH3.

[0251] In some implementations of equation (IA), ring B is formed by two independently chosen R... G Replacement. In some implementations of formula (IA), each R G It is fluorinated. In some embodiments of formula (IA), each R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), each RG It is methyl. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), one R G For hydroxyl and another R G It is methyl. In some embodiments of formula (IA), an R G It is fluorine-based and another R G It is a C1-C3 alkyl group. In some embodiments of formula (IA), one R G It is fluorine-based and another R G It is methyl. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is fluorinated. In some embodiments of formula (IA), an R G For hydroxyl and another R G It is trifluoromethyl.

[0252] In some implementations of formula (IA), for One or two independently selected R G At the 3-position of the azahexacyclic butane. In some embodiments of formula (IA), Choose from the following groups: and In some implementations of formula (IA), Choose from the following groups: .

[0253] In some embodiments, the compound of formula (I) is of formula (IK): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; R4 Independently select from the following groups: Optional - NR A R B Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups optionally substituted with C1-C6 alkyl, or R groups optionally substituted with one or two independently selected R groups. G The substituted 3-6 membered heterocyclic group and optionally one or two independently selected R G Substituted 3-6 membered cycloalkyl groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently composed of hydrogen, a 4-6 membered heterocyclic group, a C1-C6 haloalkyl group, a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group, or a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), and -SO2 (NH2); or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0254] In some implementation schemes, R 1A and R 1B Each is a fluorine group; In some implementation schemes, R 2 It is a C1-C6 alkyl group. In some embodiments, R2 It is a C1-C3 alkyl group. In some embodiments, R 2 It is a methyl group.

[0255] In some implementation schemes, R 2 It is a C1-C6 haloalkyl group. In some embodiments, R 2 It is a C1-C3 haloalkyl group. In some embodiments, R 2 It is trifluoromethyl.

[0256] In some implementation schemes, R 3 It is a C1-C6 alkyl group. In some embodiments, R 3 It is a C1-C3 alkyl group. In some embodiments, R 3 It is methyl, ethyl, or isopropyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is isopropyl.

[0257] In some implementation schemes, R 3 It is a C1-C6 haloalkyl group. In some embodiments, R 3 It is a C1-C3 haloalkyl group. In some embodiments, R 3 It is trifluoromethyl.

[0258] In some implementation schemes, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. In some embodiments, R 3 It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups. In some embodiments, R 3 It is an unsubstituted C3-C6 cycloalkyl group. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 It is cyclopropyl.

[0259] In some implementation schemes, R 4 For optional land use -NR A R B Substituted C1-C6 alkyl groups. In some embodiments, R 4 For optional land use -NR A R B Substituted C1-C3 alkyl groups. In some embodiments, R 4 For optional land use -NR A R BSubstituted methyl groups. In some embodiments, R 4 It is a C1-C4 alkyl group. In some embodiments, R 4 It is a methyl group.

[0260] In some implementation schemes, R 4 It is a C1-C6 alkoxy group. In some embodiments, R 4 It is a C1-C3 alkoxy group. In some embodiments, R 4 It is a methoxy group.

[0261] In some implementation schemes, R 4 It is a C1-C6 haloalkyl group. In some embodiments, R 4 It is a C1-C3 haloalkyl group. In some embodiments, R 4 It is trifluoromethyl.

[0262] In some implementation schemes, R 4 It is a hydroxyl group. In some embodiments, R 4 It is cyano. In some embodiments, R 4 For -CO2H. In some implementations, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and RB Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B Each is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, R A and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0263] In some implementation schemes, R A and R B One of them is hydrogen and R A and R BAnother one is a C1-C6 haloalkyl group. In some embodiments, R A and R B Each is a C1-C6 haloalkyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is a C1-C3 haloalkyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a C1-C6 haloalkyl group.

[0264] In some implementation schemes, R A and R B Each is a 4-6 member heterocyclic group. In some implementations, R A and R B One of them is hydrogen and R A and R B Another component is a 4-6 membered heterocyclic group. In some implementations, R A and R B One of them is hydrogen and R A and R B Another one is a 4-membered heterocyclic group. In some implementations, R A and R B One of them is hydrogen and R A and R B Another component is a 5-membered heterocyclic group. In some embodiments of formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is 1,1-dioxo-tetrahydrothiophene-3-yl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a 6-membered heterocyclic group.

[0265] In some implementation schemes, R A and R B Each is an optional 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments, R A and R BOne of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a 3-6 membered cycloalkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is an unsubstituted 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a 3-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a four-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is cis- or trans-3-hydroxycyclobutyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a 5-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a 6-membered cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another one is a 3-6 membered cycloalkyl group substituted with a hydroxyl group.

[0266] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C6 alkyl group optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl) and -SO2 (NH2).

[0267] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with a 3-4 membered cycloalkyl group and a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with cyclopropyl and hydroxyl groups. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with cyclopropyl and hydroxyl groups, such as 1-cyclopropyl-2-hydroxyethyl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B Another component is a C1-C6 alkyl group substituted with a 3-6 membered cycloalkyl group. In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with 3-6 membered cycloalkyl groups.

[0268] In some implementation schemes, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and RB The other is a C1-C3 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with -SO2 (C1-C3 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with -SO2CH3, such as 1-(methylsulfonyl)propyl-2-yl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group and R A and R B The other is a C1-C6 alkyl group substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with -SO2 (C1-C6 alkyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C3 alkyl group substituted with -SO2(NH2), such as 1-aminosulfonylpropyl-2-yl. In some embodiments, R A and R B One of them is a C1-C6 alkyl group, hydrogen, and R A and R B Another component is a C1-C6 alkyl group substituted with -SO2(NH2). In some embodiments, R A and R B All are C1-C6 alkyl groups substituted with -SO2(NH2).

[0269] In some implementations, an R 4 -C(=O)NR C R D In some implementations, R C and R D Each is hydrogen. In some implementations, R C and R DOne of them is hydrogen and R C and R D Another component is a C1-C6 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is a C1-C3 alkyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D Each is a C1-C6 alkyl group. In some embodiments, R C and R D Each is a C1-C3 alkyl group. In some embodiments, R C and R D Each is a methyl group. In some embodiments, R C and R D One of them is hydrogen and R C and R D Another one is a C1-C6 haloalkyl group. In some embodiments, R C and R D Each is a C1-C6 haloalkyl group. In some embodiments, R C and R D One of them is a C1-C6 alkyl group and R C and R D Another one is a C1-C6 haloalkyl group. In some embodiments, R C and R D Together with the attached nitrogen atom, it forms a 4-6 membered heterocyclic group. In some embodiments, R C and R D Together with the nitrogen atom attached to it, it forms azacyclobutane or piperazine.

[0270] In some implementations, an R 4 -SO2(NR) E R F In some implementations, R E and R F Each is hydrogen. In some implementations, R E and R F One of them is hydrogen and R E and R F Another component is a C1-C6 alkyl group. In some embodiments, R E and R F One of them is hydrogen and R Eand R F The other one is methyl. In some embodiments, R E and R F Each is a C1-C6 alkyl group. In some embodiments, R E and R F Each is a C1-C3 alkyl group. In some embodiments, R E and R F Each is a methyl group. In some embodiments, R E and R F One of them is hydrogen and R E and R F Another one is a C1-C6 haloalkyl group. In some embodiments, R E and R F Each is a C1-C6 haloalkyl group. In some embodiments, R E and R F One of them is a C1-C6 alkyl group and R E and R F Another one is a C1-C6 haloalkyl group.

[0271] In some implementation schemes, R 4 It is -SO2 (C1-C6 alkyl). In some embodiments, R 4 It is -SO2 (C1-C3 alkyl). In some embodiments, R 4 For -SO2Me. In some implementations, R 4 It is -SO2Et.

[0272] In some implementation schemes, R 4 It is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 It is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 For -S(=O)(=NH)Me.

[0273] In some implementation schemes, R 4 It is a -C(=O)(C1-C6 alkyl). In some embodiments, R 4 It is a -C(=O)(C1-C3 alkyl). In some embodiments, R 4 It is -C(=O)Me.

[0274] In some implementation schemes, R 4 It is -CO2 (C1-C6 alkyl). In some embodiments, R 4 It is -CO2 (C1-C3 alkyl). In some embodiments, R 4 It is -CO2Me.

[0275] In some implementations, an R 4 It is a 5-6 membered heteroaryl group optionally substituted with a C1-C6 alkyl group. In some embodiments, an R 4 It is a 5-6 membered heteroaryl group substituted with a C1-C6 alkyl group. In some embodiments, R 4 It is a 5-6 membered heteroaryl group. In some implementations, R 4 The group is selected from the group consisting of pyrrole, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxtriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R 4 It is a pyrazolyl group. In some embodiments, an R 4 It is a tetrazolium group substituted with a methyl group. In some embodiments, an R 4 It is a pyrazolyl group. In some embodiments, an R 4 It is an unsubstituted pyrazolyl group. In some embodiments, an R 4 It is 1-pyrazolyl.

[0276] In some implementation schemes, R 4 R can be optionally selected by one or two independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, R 4 For R selected by 1 or 2 independent choices G Substituted 3-6 membered heterocyclic groups. In some embodiments, R 4 For 1 R G Substituted 3-6 membered heterocyclic groups. In some embodiments, R 4 For R, which is selected by two independent choices G Substituted 3-6 membered heterocyclic groups.

[0277] In some implementation schemes, R G It is fluorine-based. In some embodiments, R G It is cyano. In some embodiments, R G It is a hydroxyl group. In some embodiments, R G It is a C1-C6 alkyl group. In some embodiments, R G It is a C1-C3 alkyl group. In some embodiments, R G It is a methyl group.

[0278] In some implementation schemes, R G It is a C1-C6 alkoxy group. In some embodiments, R G It is a C1-C3 alkoxy group. In some embodiments, R GIt is a methoxy group.

[0279] In some implementations, an R G For -NR A1 R B1 In some implementations, R A1 and R B1 Each is hydrogen. In some implementations, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another component is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is a C1-C3 alkyl group. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is methyl. In some embodiments, R A1 and R B1 Each is a C1-C6 alkyl group. In some embodiments, R A1 and R B1 Each is a C1-C3 alkyl group. In some embodiments, R A1 and R B1 Each is a methyl group.

[0280] In some implementation schemes, R A1 and R B1 One of them is hydrogen and R A1 and R B1 Another one is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 Each is a C1-C6 haloalkyl group. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl group and R A1 and R B1 Another one is a C1-C6 haloalkyl group.

[0281] In some implementations, an R G -C(=O)NR C1 R D1 In some implementations, R C1 and R D1 Each is hydrogen. In some implementations, R C1 and R D1 One of them is hydrogen and R C1 and R D1Another component is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is a C1-C3 alkyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 The other one is methyl. In some embodiments, R C1 and R D1 Each is a C1-C6 alkyl group. In some embodiments, R C1 and R D1 Each is a methyl group. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and R D1 Another one is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 Each is a C1-C6 haloalkyl group. In some embodiments, R C1 and R D1 One of them is a C1-C6 alkyl group and R C1 and R D1 Another one is a C1-C6 haloalkyl group.

[0282] In some implementations, an R G It is -CO2 (C1-C6 alkyl). In some embodiments, an R G It is -CO2CH3.

[0283] In some implementations, an R G It is a C1-C6 haloalkyl group. In some embodiments, one R G It is trifluoromethyl.

[0284] In some implementations, an R G It is a C3-C6 cycloalkyl group. In some embodiments, one R G It is cyclopropyl.

[0285] In some implementation schemes, R G It is -CO2H.

[0286] In some implementation schemes, R 4 The 3-6 membered heterocyclic group is a 5-6 membered heterocyclic group. In some embodiments, R 4 The 3-6 membered heterocyclic group is an azirrobutyl, azirrobutyl-2-one, morpholino, piperazine, or tetrahydropyranoyl group. In some embodiments, R4 The 3-6 membered heterocyclic group is 1-azacyclobutane, 1-azacyclobut-2-one, 1-piperazinyl, 1-morpholinyl or 4-tetrahydropyranyl.

[0287] In some implementation schemes, R 4 It is an unsubstituted 3-6 membered heterocyclic group. In some embodiments, R 4 It is a 5-6 membered heterocyclic group. In some implementations, R 4 It is a nitrogen-containing heterocyclic butyl, morpholino, or tetrahydropyranoyl.

[0288] In some implementation schemes, R 4 Choose from the following groups: and .

[0289] In some implementation schemes, R 4 Selected from -NR A R B and includes a nitrogen ring member and is optionally selected by 1-2 independently chosen R G1 Substituted 4-6 membered heterocyclic groups; wherein R G1 Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0290] In some implementation schemes, R A and R B Each is hydrogen. In some implementations, R A and R B One of them is hydrogen and R A and R B The other is a C1-C6 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another component is a C1-C6 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group optionally substituted with a hydroxyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, RA and R B One of them is hydrogen and R A and R B Another is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other is a propyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl group. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is methyl. In some embodiments, R A and R B Each is an optional C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B Each is a C1-C6 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is a C1-C3 alkyl group and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is a C1-C3 alkyl group substituted with a hydroxyl group. In some embodiments, R A and R B One of them is methyl and R A and R B The other is an ethyl group substituted with a hydroxyl group (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Each is a C1-C6 alkyl group. In some embodiments, R A and R B Each is a C1-C3 alkyl group. In some embodiments, R A and R B Each is a methyl group.

[0291] In some implementation schemes, R 4For R, which includes a nitrogen ring member and is optionally selected by 1-2 independently chosen members. G Substituted 4-6 membered heterocyclic groups; wherein R G Selected from fluorinated, hydroxyl, and C1-C6 alkyl groups.

[0292] In some embodiments, the compound of formula (I) is of formula (IL): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each RG Independently selected from the group consisting of: fluorine, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 and -CO2H.

[0293] In some embodiments, the compound of formula (I) is of formula (IM): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or C1-C6 alkyl, C1-C6 haloalkyl; or R C and R DTogether with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0294] In some embodiments, the compound of formula (I) is of formula (IN): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R FIndependently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0295] In some embodiments, the compound of formula (I) is of formula (IO): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each R A R A1 R B R B1 R C RC1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0296] In some embodiments, the compound of formula (I) is of formula (IP): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B Halogen or absent (benzene ring is replaced by R) 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluorine groups; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, cyano, -CO2H, -NR A R B -C(=O)NR C R D -SO2(NR) E R F -SO2 (C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2 (C1-C6 alkyl), 5-6 heteroaryl groups, and optionally R groups selected independently by one or two other groups. G Substituted 3-6 membered heterocyclic groups; Each RA R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently hydrogen or optionally substituted with a hydroxyl group, C1-C6 alkyl or C1-C6 haloalkyl; or R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl and -CO2H.

[0297] In some embodiments, the compound of formula (I) is of formula (IQ): Or its pharmaceutically acceptable salt, wherein: R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R 1A It is a halogen; R 1B It is halogenated, cyano, cyclopropyl or absent (the benzene ring is replaced by R). 1A (single substitution); R 2 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 3 It is a C1-C6 alkyl or a C1-C6 haloalkyl; R 4 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. A R B and R, which can be optionally selected by one or two independent choices G Substituted 3-9 membered heterocyclic groups; Each R A R B R C1 and R D1Independently hydrogen, 4-6 membered heterocyclic group, optionally surrounded by hydroxyl or -C(=O)NR B2 R C2 Substituted C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine group, hydroxyl group, C1-C6 alkyl group optionally substituted with hydroxyl group, C1-C6 alkoxy group, =NR group A2 -C(=O)NR C1 R D1 -C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl) and -CO2H.

[0298] In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described herein; and wherein the compound is not selected from the group consisting of: .

[0299] In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described herein; and wherein the compound is not selected from the group consisting of: .

[0300] In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described herein; and wherein the compound is not selected from the group consisting of: In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described in this article.

[0301] In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described in this article.

[0302] In some implementations, the compound of formula (I) is Or a pharmaceutically acceptable salt thereof, wherein R 3 R 4 And ring A as described in this article.

[0303] Non-limiting exemplary compounds In some embodiments, the compounds are selected from the group consisting of the compounds in Examples 1-195 (e.g., compounds 1-276) or pharmaceutically acceptable salts thereof.

[0304] In some embodiments, the compounds are selected from the group consisting of the compounds described in Table A or their pharmaceutically acceptable salts.

[0305] Table A In some embodiments, the compounds are selected from the group consisting of the compounds described in Table B or their pharmaceutically acceptable salts.

[0306] Table B In some embodiments, the compounds are selected from the group consisting of the compounds described in Table C or pharmaceutically acceptable salts thereof.

[0307] Table C In some embodiments, the compounds are selected from the group consisting of the compounds described in Table D or their pharmaceutically acceptable salts.

[0308] Pharmaceutical composition and administration General Rules In some embodiments, the 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 pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0309] In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; and lanolin. Cyclodextrins such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing from 0.005% to 100% of the chemical entities described herein, with the remainder consisting of pharmaceutically acceptable excipients, can be prepared. The compositions covered may contain from 0.001% to 100% of the chemical entities provided herein, in one embodiment 0.1%-95%, in another embodiment 75%-85%, and in yet another embodiment 20%-80%. Practical methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; for example, see [link to relevant documentation]. Remington: The Science and Practice of Pharmacy , 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0310] Application route and composition components In some implementations, the chemical entities described herein or their pharmaceutical compositions may be administered to subjects in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intranasal, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisional, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratestinal, intrasheath, intracanal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric tube, oral, extraintestinal, percutaneous, epidural, rectal, respiratory tract (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some implementations, the preferred route of administration is parenteral (e.g., intratumoral).

[0311] The compositions can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared in injectable forms, such as liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions by adding liquid prior to injection; and the formulations can be emulsified. The preparation of such formulations will be known to those skilled in the art based on this disclosure.

[0312] Suitable injectable drug forms include sterile aqueous solutions or dispersions; formulations including aqueous solutions of sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be a fluid to the extent that it is readily injectable. It should also be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria and fungi.

[0313] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. For example, appropriate flowability can be maintained by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial activity can be prevented by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars or sodium chloride, will be preferred. The absorption of the injectable composition can be prolonged by using a delayed absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0314] Sterile injectable solutions are prepared as follows: the desired amount of the active compound, along with various other components listed above, is incorporated into a suitable solvent, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating multiple sterile active ingredients into a sterile medium containing a basic dispersion medium and desired other components from those listed above. When sterile powders are used to prepare sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any other desired components from a previously sterile filtered solution.

[0315] Intratumoral injections are discussed, for example, by Lammers et al. "Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems"Neoplasia 2006, 10 , 788-795.

[0316] Pharmaceutically acceptable excipients that can be used as gels, creams, enemas, or rectal suppositories in rectal compositions include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, p-hydroxybenzoates in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol hexadecyl octadecyl ether, cocoyl caprylocaprate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonyl methane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0317] In some embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable, non-irritating, pharmaceutically acceptable excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0318] In other embodiments, the compounds or pharmaceutical compositions thereof described herein are suitable for local delivery to the digestive tract or gastrointestinal tract via oral administration (e.g., solid or liquid dosage forms).

[0319] Solid dosage forms intended for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or expanders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) dissolution delayers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) humectants, 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 contain a buffer. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using pharmaceutically acceptable excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0320] In one embodiment, the composition will be in the form of a unit dosage form such as a pill or tablet, and therefore, in addition to containing the chemical entities provided herein, the composition may also contain a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose capsule). Also covered are unit dosage forms in which one or more chemical entities or other active agents provided herein are physically separated; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; double-chamber gel caps, etc. Also covered are enteric-coated or delayed-release oral dosage forms.

[0321] Other physiologically acceptable compounds include humectants, emulsifiers, dispersants, or preservatives particularly suited to preventing the growth or action of microorganisms. Various preservatives are well-known and include, for example, phenol and ascorbic acid.

[0322] In some implementations, pharmaceutically acceptable excipients are sterile and generally free of unwanted substances. These compositions can be sterilized using conventional, well-known sterilization techniques. For various oral dosage forms, pharmaceutically acceptable excipients, such as tablets and capsules, do not require sterility. USP / NF standards are generally sufficient.

[0323] In some embodiments, the solid oral dosage form may also include one or more components that are chemically and / or structurally conducive to the delivery of the chemical entity to the stomach or lower gastrointestinal tract, such as the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are described, for example, by Filipski, KJ, et al. Current Topics in Medicinal Chemistry 2013 ,13,776-802 Its full text is incorporated into this article.

[0324] Examples include upper gastrointestinal targeting technologies such as Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0325] Other examples include lower gastrointestinal targeting technologies. Several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available for targeting various regions of the intestine. These materials are typically polymers designed to dissolve or corrode within a specific pH range, selected based on the gastrointestinal region where drug release is desired. These materials are also used to protect acid-labile drugs from gastric acid degradation or limit exposure in cases where the active ingredient might irritate the upper gastrointestinal tract (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to local gut microbiota, pressure-controlled colonic delivery capsules, and pulsed capsules (Pulsincap).

[0326] The ophthalmic composition may include, but is not limited to, any one or more of the following: a thickener (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); a stabilizer (e.g., Pluronic (a triblock copolymer), cyclodextrin); and a preservative (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (a stable oxychloride complex; Allergan, Inc.)).

[0327] Topical compositions may include ointments and creams. Ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil emulsions. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, generally includes petrolatum and fatty alcohols such as cetyl alcohol or octadecyl alcohol; although not essential, the aqueous phase usually exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. As with other carriers or mediators, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0328] In any of the foregoing embodiments, the pharmaceutical composition described herein may include one or more of the following: lipids, interlayer cross-linked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA] or polyanhydride nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0329] dose Dosage may vary depending on patient needs, the severity of the condition being treated, and the specific compound used. The appropriate dosage for a particular situation can be determined by a physician in the medical field. The total daily dose may be divided into multiple doses and administered throughout the day, or administered via continuous delivery.

[0330] In some embodiments, the compounds described herein are administered at doses of about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg; about 0.01 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). 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.

[0331] plan The aforementioned dosage may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0332] In some embodiments, the application period of the compound described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In another embodiment, the discontinuation 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 longer. In one embodiment, a therapeutic compound is administered to an individual for a specified period of time, followed by a period of interval. In another embodiment, the therapeutic compound is administered during a first period of time, followed by a second period of time, during which administration is stopped, followed by administration of the therapeutic compound for a third period of time, and then administration is stopped in a fourth period of time following the third period of time. In one aspect of this embodiment, the therapeutic compound administration period, followed by the cessation of administration period, is repeated for a defined or undefined period of time. In another embodiment, the 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 longer. In another implementation, the period of discontinuation of application may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0333] Treatment Indications This article provides methods for suppressing [the problem]. PIK3CAMethods for gene-encoded phosphatidylinositol 4,5-bisphosphate 3-kinase isoform α (PI3Kα). For example, this article provides PI3Kα inhibitors that can be used to treat or prevent [therapeutic / prophylactic / complex] phosphatidylinositol isoform α (PI3Kα). PIK3CA Diseases or conditions associated with dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of them (i.e., PI3Kα-related diseases or conditions), such as PIK3CA-associated overgrowth syndrome ((PROS), see, for example, Venot et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., malformed macrocephaly-capillary malformation (MCAP) and hemimacentemsis), congenital lipomas (e.g., vascular malformation overgrowth), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibrolipodystrophy (FH) or cancer (e.g., PI3Kα-related cancer).

[0334] As used herein, "PI3Kα inhibitor" includes any compound that exhibits PI3Kα inactivation activity (e.g., inhibition or reduction). In some embodiments, the PI3Kα inhibitor may be selective for PI3Kα having one or more mutations.

[0335] The ability of a test compound to act as a PI3Kα inhibitor can be confirmed by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays to determine kinase inhibition. Alternative in vitro assays quantify the ability of an inhibitor to bind a protein kinase and can be measured by radiolabeling the compound prior to binding, isolating the compound / kinase complex and determining the amount of radiolabeled material bound, or by performing a competition experiment in which a novel compound is incubated with a kinase bound to a known radioligand.

[0336] Available via EC 50 The value was used to determine the potency of PI3Kα inhibitors as presented in this paper. As determined under substantially similar conditions, relative to those with higher EC50 values... 50 Compounds with low EC values 50 The compound with the value is a more effective inhibitor. In some embodiments, substantially similar conditions include determining the PI3Kα-dependent phosphorylation level in vitro or in vivo (e.g., in tumor cells, A594 cells, U2OS cells, A431 cells, Ba / F3 cells, or 3T3 cells expressing wild-type PI3Kα, mutant PI3Kα, or fragments thereof).

[0337] The efficacy of PI3Kα inhibitors, as described in this article, can also be assessed by IC50. 50 The value is determined. As determined under substantially similar conditions, relative to having a higher IC.50 Compounds with low IC50 values 50 The compound with the value is a more effective inhibitor. In some embodiments, substantially similar conditions include determining the level of PI3Kα-dependent phosphorylation in vitro or in vivo (e.g., in tumor cells expressing fragments of wild-type PI3Kα, mutant PI3Kα, or any of them, 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).

[0338] The selectivity between wild-type PI3Kα and PI3Kα containing one or more mutations as described herein can also be measured using in vitro assays, such as surface plasmon resonance and fluorescence-based binding assays; and cellular assays, such as pAKT levels, biomarkers of PI3Kα activity, or proliferation assays, wherein cell proliferation depends on the activity of the mutant PI3Kα kinase.

[0339] In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of PI3Kα. For example, the compounds provided herein may bind to the catalytic domain of the helical phosphatidylinositol kinase homology domain of PI3Kα. In some embodiments, the compounds provided herein may exhibit nanomolar potency against PI3Kα kinases including one or more mutations, such as those in Tables 1 and 2.

[0340] In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of mutant PI3Kα. For example, the compounds provided herein may bind to allosteric sites in the kinase domain. In some embodiments, the compounds provided herein may exhibit nanomolar potency against PI3Kα proteins, including activating mutants, with minimal activity against the associated kinase (e.g., wild-type PI3Kα). Inhibition of wild-type PI3Kα may cause adverse side effects (e.g., hyperglycemia and rash), which may affect quality of life and compliance. In some cases, inhibition of wild-type PI3Kα may cause dose-limiting toxicities. 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).

[0341] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα rather than another kinase or non-kinase target.

[0342] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit greater inhibition of PI3Kα containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1 or Table 2) relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit at least 2-, 3-, 5-, 10-, 25-, 50-, or 100-fold inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit up to 1000-fold inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit up to 10000-fold inhibition of PI3Kα having a combination of mutations as described herein relative to inhibition of wild-type PI3Kα.

[0343] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits approximately 2 to approximately 10 times inhibition of PI3Kα containing one or more mutations as described herein, relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits approximately 10 to approximately 100 times inhibition of PI3Kα containing one or more mutations as described herein, relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits approximately 100 to approximately 1000 times inhibition of PI3Kα containing one or more mutations as described herein, relative to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits approximately 1000 to approximately 10000 times inhibition of PI3Kα containing one or more mutations as described herein, relative to inhibition of wild-type PI3Kα.

[0344] Compounds of formula (I) or pharmaceutically acceptable salts thereof may be used to treat diseases and conditions that can be treated with PI3Kα inhibitors, such as PI3Kα-related diseases and conditions, such as PIK3CA-associated overgrowth syndrome (PROS) and proliferative conditions, such as cancers, including hematologic malignancies and solid tumors (e.g., advanced or metastatic solid tumors).

[0345] In some implementation schemes, the subjects have been identified or diagnosed with... PIK3CA Cancers with dysregulated expression, activity, or level of the gene, PI3Kα protein, or either of these (PI3Kα-related cancers) (e.g., determined using a regulatory-approved (e.g., FDA-approved) assay or kit). In some implementations, the subject has a predisposition to... PIK3CA A tumor that is positive for dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these (e.g., determined using a regulatory-approved assay or kit). For example, the subject has a tumor that is positive for mutations as described in Table 1 or Table 2. The subject may be a tumor with mutations that are positive for... PIK3CA Subjects with tumors that are positive for dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of these (e.g., identified using a regulatory-approved (e.g., FDA-approved) assay or kit). Subjects may have tumors that are positive for dysregulation. PIK3CA Subjects with dysregulation of the gene, PI3Kα protein, or its expression, activity, or level (e.g., where a tumor is identified using a regulatory-approved (e.g., FDA-approved) kit or assay). In some embodiments, the subject is suspected of having PI3Kα-related cancer. In some embodiments, the subject's clinical record indicates that the subject has... PIK3CA Tumors with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of them (and optionally, clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0346] In some implementation schemes, the subjects are pediatric subjects.

[0347] As used in this article, “pediatric subject” refers to a subject under 21 years of age at diagnosis or treatment. The term “pediatric” can be further subdivided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (until, but not including, their twenty-second birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed., Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st ed., New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd ed., Baltimore: Williams & Wilkins; 1994.) In some implementation schemes, pediatric subjects are defined as those 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 implementation schemes, pediatric subjects are defined as those from birth to the first 28 days of life, from 29 days of age to less than one year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than one year of age, from one year of age to less than two years of age, from two years of age to less than three years of age, from two years of age to less than seven years of age, from three years of age to less than five years of age, from five years of age to less than ten years of age, from six years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0348] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to prevent diseases and conditions 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 its symptoms as described herein.

[0349] As used in this article, the term "PI3Kα-related disease or condition" refers to... PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them (e.g., one or more) (e.g., as described herein). PIK3CAA disease or condition associated with or having any type of dysregulation of the expression, activity, or level of a gene or PI3Kα protein or either of these. Non-limiting examples of PI3Kα-related diseases or conditions include, for example, PIK3CA-associated overgrowth syndrome (PROS), brain disorders (e.g., malformed macrocephaly-capillary malformation (MCAP) and hemimacentemsis), congenital lipomas (e.g., vascular malformation overgrowth), epidermal nevi and skeletal / spinal abnormalities (e.g., CLOVES syndrome), and fibrolipodystrophy (FH) or cancer (e.g., PI3Kα-associated cancer).

[0350] As used in this article, the term "PI3Kα-associated cancer" refers to cancers associated with... PIK3CA Cancers associated with or having dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of them. Non-limiting examples of PI3Kα-related cancers are described herein.

[0351] phrase" PIK3CA "Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either thereof" refers to a gene mutation (e.g., causing a deficiency of at least one amino acid in the expression of PI3Kα compared to wild-type PI3Kα) resulting from abnormal cell signaling and / or dysregulation of autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). PIK3CA Gene mutation; causing the expression of PI3Kα with one or more point mutations compared to wild-type PI3Kα. PIK3CA Gene mutation; causing the expression of PI3Kα with at least one inserted amino acid compared to wild-type PI3Kα. PIK3CA Gene mutations; gene duplication that increases PI3Kα levels in cells; or mutations in regulatory sequences (e.g., promoters and / or enhancers) that increase PI3Kα levels in cells; alternative splicing patterns of PI3Kα mRNA that produce PI3Kα with at least one amino acid missing compared to wild-type PI3Kα; or increased expression (e.g., increased levels) of wild-type PI3Kα in mammalian cells. As another example, PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of them can affect the expression of PI3Kα. PIK3CA A mutation in the gene, wherein the PI3Kα is constitutively active, or associated with a gene that does not contain the mutation. PIK3CA The protein encoded by the gene exhibits increased activity. Non-restrictive examples of PI3Kα point mutations / substitutions / insertions / deletions are described in Tables 1 and 2.

[0352] The term "activation mutation" for PI3Kα is described. PIK3CAA mutation in a gene that causes, for example, increased kinase activity (e.g., when measured under identical conditions) in the expression of PI3Kα compared to wild-type PI3Kα. For example, an activating mutation could be a mutation in the PIK3CA gene that causes increased kinase activity (e.g., when measured under identical conditions) in the expression of PI3Kα having one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any amino acid substitutions described herein) compared to wild-type PI3Kα. In another example, an activating mutation could be a mutation in PIK3CA that causes the expression of PI3Kα with one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid deletions compared to wild-type PI3Kα (e.g., when measured under identical conditions). In another example, the activating mutation may be a mutation in the PIK3CA gene that causes the expression of PI3Kα with at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20) amino acid insertion (e.g., when measured under the same conditions) compared to wild-type PI3Kα (e.g., the exemplary wild-type PI3Kα described herein). Further examples of activating mutations are known in the art.

[0353] The term “wild type” or “wild-type” describes a nucleic acid (e.g., PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) sequence that is typically found in subjects who do not have a disease or condition associated with the mentioned nucleic acid or protein.

[0354] The terms "wild-type PI3Kα" or "wild-type PI3Kα" describe normal PI3Kα nucleic acid (e.g., found in subjects who do not have PI3Kα-related diseases, such as PI3Kα-related cancers (and optionally have no increased risk of developing PI3Kα-related diseases and / or are not suspected of having PI3Kα-related diseases) or in cells or tissues from subjects who do not have PI3Kα-related diseases, such as PI3Kα-related cancers (and optionally have no increased risk of developing PI3Kα-related diseases and / or are not suspected of having PI3Kα-related diseases). PIK3CA (or PI3Kα mRNA) or protein.

[0355] This article provides a method for treating a subject with cancer (e.g., PI3Kα-related cancer) requiring such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. For example, this article provides a method for treating a subject with PI3Kα-related cancer requiring such treatment, the method comprising a) detecting in a sample from the subject... PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them; and b) administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them includes 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.

[0356] In some embodiments, the PI3Kα protein substitution / insertion / deletion is selected from the group consisting of: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid.

[0357] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-related cancers) is selected from hematologic malignancies and solid tumors.

[0358] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-related cancer) is selected from breast cancer (including HER2-related cancer). + With HER2 - Breast cancer, ER + Breast cancer and triple-negative breast cancer), endometrial cancer, lung cancer (including lung adenocarcinoma and squamous cell lung cancer), 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 oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumor (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[0359] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-related cancer) is selected from breast cancer (including HER2-related cancer). + With HER2 - Breast cancer, ER + Breast cancer and triple-negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumor (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including lung adenocarcinoma and squamous cell lung cancer), and endometrial cancer.

[0360] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-related cancer) is selected from breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0361] In some embodiments of any of the methods or uses described herein, PI3Kα-related cancer is breast cancer. In some embodiments of any of the methods or uses described herein, PI3Kα-related cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, PI3Kα-related cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, PI3Kα-related cancer is lung cancer.

[0362] In some embodiments of any of the methods or uses described herein, PI3Kα-related cancers are selected from the cancers described in Tables 1 and 2.

[0363] Table 1. Amino acid substitutions / insertions / deletions in PI3Kα protein A A Unless otherwise noted, the mutations in Table 1 are available from the cBioPortal database, Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data Cancer Discovery. May 2012; 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

[0364] † 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 PIK3CAmutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0365] Table 2. Other PI3Kα protein amino acid substitutions / insertions / deletions A A Unless otherwise noted, the mutations in Table 2 are available from the cBioPortal database, as described by Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data Cancer Discovery. May 2012; 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

[0366] † 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 PIK3CAmutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0367] In some implementation schemes, PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of them includes splicing variations of PI3Kα mRNA such that the expressed protein is an alternative splicing variant of PI3Kα with at least one residue missing (compared to wild-type PI3Kα protein), thereby causing constitutive activity of the PI3Kα protein domain.

[0368] In some implementation schemes, PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or either of these includes PIK3CA At least one point mutation in the gene leads to the production of PIK3CA A PI3Kα protein with one or more amino acid substitutions, insertions, or deletions in its gene results in a PI3Kα protein with one or more amino acid insertions or removals compared to the wild-type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein exhibits increased activity compared to the wild-type PI3Kα protein or a PI3Kα protein without the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to the wild-type PI3Kα protein or a PI3Kα protein without the same mutation.

[0369] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform α (UniProtKB entry P42336) (SEQ ID NO:1) In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to treat cancers identified as having one or more PI3Kα mutations. Therefore, this document provides a method for treating a subject diagnosed with (or identified as having) cancer, comprising administering to the subject a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0370] This article also provides methods for treating subjects identified or diagnosed with PI3Kα-related cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the cancer is identified in the subject or from a biopsy sample by using a regulatory-approved (e.g., FDA-approved) test or assay. PIK3CA A subject is identified or diagnosed with PI3Kα-related cancer by dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of the above, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is PI3Kα-related cancer.

[0371] The term "regulatory agency" refers to a national agency that approves the medical use of a drug within a country. A non-restrictive example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0372] Methods for treating cancer in subjects in need are also provided, the methods comprising: (a) detecting PI3Kα-related cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods also include administering another anticancer agent (e.g., immunotherapy) to the subject. In some embodiments, the subject has previously been treated with another anticancer therapy, such as at least partial resection of the tumor or radiation therapy. In some embodiments, the subject or a biopsy sample from the subject is identified using a test or assay approved by a regulatory agency (e.g., FDA approval). PIK3CA A subject is identified to have PI3Kα-related cancer by dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of the above, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is PI3Kα-related cancer.

[0373] Methods for treating subjects are also provided, which include measuring samples obtained from the subjects to determine whether the subjects have [certain conditions]. PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or either of these, and directed toward a known... PIK3CASubjects with dysregulated expression, activity, or level of a gene, PI3Kα protein, or any of these genes are administered (e.g., specifically or selectively) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods also include administration of another anticancer agent (e.g., immunotherapy) to the subject. In some embodiments of these methods, the subject has previously received another anticancer treatment, such as at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having PI3Kα-related cancer, a subject presenting with one or more symptoms of PI3Kα-related cancer, or a subject at elevated risk of developing PI3Kα-related cancer. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is a regulatory-approved assay, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Other assays are also known in the art.

[0374] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating PI3Kα-related cancer in a subject, said subject being identified or diagnosed with PI3Kα-related cancer by the following steps: measuring a sample obtained from the subject (e.g., in vitro assay) to determine whether the subject has PI3Kα-related cancer. PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of them, PIK3CA The presence of dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these is used to identify a subject as having PI3Kα-related cancer. Use is also provided for the manufacture of an agent for treating a subject with PI3Kα-related cancer by means of the following steps: measuring a sample obtained from the subject to determine whether the subject has PI3Kα-related cancer. PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of them, PIK3CA The presence of dysregulation in the expression, activity, or level of a gene, PI3Kα protein, or any of these is used to identify PI3Kα-related cancer in a subject. Some embodiments of any of the methods or uses described herein also include recording in the subject's clinical record (e.g., a computer-readable medium) the determination of the subject's presence of PI3Kα-related cancer by performing a assay. PIK3CAFor dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof should be administered. In some embodiments, the assay uses next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is a regulatory-approved assay, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0375] Also provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a subject in need or a subject identified or diagnosed with PI3Kα-related cancer. Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for manufacturing an agent for treating a subject identified or diagnosed with PI3Kα-related cancer. In some embodiments, the cancer is identified in a subject or from a biopsy sample obtained from a subject using a regulatory-approved (e.g., FDA-approved) kit. PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these will identify or diagnose a subject with PI3Kα-related cancer. As provided herein, PI3Kα-related cancer includes cancers described herein and known in the art.

[0376] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed with... PIK3CA Cancer characterized by dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these. In some embodiments of any of the methods or uses described herein, the subject suffers from cancer for which... PIK3CA A tumor that is positive for dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these. In some embodiments of any of the methods or uses described herein, the subject may be a tumor with [a condition that is not specified in the original text]. PIK3CA Subjects with tumors that are positive for dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these. In some embodiments of any of the methods or uses described herein, the subject may be a tumor with... PIK3CA A subject with dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. In some embodiments of any of the methods or uses described herein, the subject is suspected of having PI3Kα-related cancer. In some embodiments, this document provides a method for treating PI3Kα-related cancer in a subject requiring such treatment, the method comprising a) detecting in a sample from the subject... PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them; and b) administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, PIK3CADysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them includes 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 implementations, a regulatory-approved (e.g., FDA-approved) assay or kit is used to determine... PIK3CA Cancer characterized by dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of these. In some embodiments, a regulatory-approved (e.g., FDA-approved) assay or kit is used to determine... PIK3CA Tumors with dysregulation of the expression, activity, or level of genes, PI3Kα protein, or any of them.

[0377] In some embodiments of any of the methods or uses described herein, the subject's clinical record indicates that the subject suffers from... PIK3CA Tumors with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of these. Methods for treating subjects are also provided, including informing clinical records of the subject's... PIK3CA Subjects with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of these genes are given a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0378] In some implementations, the methods provided herein include measuring samples obtained from a subject to determine whether the subject possesses [certain characteristics]. PIK3CA Dysregulation of the expression or level of a gene, PI3Kα protein, or any of them. In some such embodiments, the method further includes directing the expression of a gene determined to have... PIK3CA Subjects with dysregulated expression, activity, or level of the gene, PI3Kα protein, or any of these are administered a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, by assay of a sample obtained from the subject, that the subject has PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them. In such embodiments, the method further includes administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments,PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of them is PIK3CA One or more point mutations in a gene (e.g., any one or more of the PI3Kα point mutations described herein). PIK3CA One or more point mutations in the gene can cause translation of PI3Kα proteins 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. PIK3CA One or more mutations in the gene can cause translation of a PI3Kα protein, for example, having one or more of the following amino acids: 542, 545, 1043, 1047, and 1049. In some embodiments, PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them is caused by substitution of one or more PI3Kα amino acids (e.g., any of the PI3Kα amino acid substitutions described herein). Some embodiments of these methods also include administration of another anticancer agent (e.g., immunotherapy) to the subject.

[0379] In some embodiments of any of the methods or uses described herein, a sample from the subject is used to determine whether the subject has [a specific condition / condition]. PIK3CA Assays of dysregulation of the expression, activity, or level of a gene or PI3Kα protein, or any of them, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, separation FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. Assays may be detected using other detection methods known in the art. PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them (see, for example, references cited herein). In some embodiments, the sample is a biological sample or biopsy sample from the subject (e.g., a paraffin-embedded biopsy sample). In some embodiments, the subject is a subject suspected of having PI3Kα-related cancer, a subject with one or more symptoms of PI3Kα-related cancer, and / or a subject with an increased risk of developing PI3Kα-related cancer.

[0380] In some implementations, liquid biopsy (also referred to as fluid biopsy or fluid phase biopsy) can be used for identification. PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or either of these. See, for example, 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 PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or either of these. Liquid biopsy can be performed on biological samples that are relatively easier to obtain from the subject (e.g., by a simple blood draw) and is used in conjunction with methods for detecting tumor burden and / or PIK3CA Liquid biopsies are generally less invasive than conventional methods for detecting dysregulation of gene expression, activity, or levels of PI3Kα protein or any of these. In some implementations, liquid biopsies can be used for detection at an earlier stage than conventional methods. PIK3CA The presence of dysregulation in the expression, activity, or level of a gene, PI3Kα protein, or any of these. In some embodiments, biological samples used for liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used for identification. PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them.

[0381] A method for inhibiting PI3Kα activity in cells is also provided, comprising contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having cells with aberrant PI3Kα activity. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer as described herein. In some embodiments, the cancer cells are PI3Kα-associated cancer cells. As used herein, the term “contact” means bringing the indicated portion into an in vitro or in vivo system. For example, “contacting” the PI3Kα protein with the compound provided herein includes administering the compound provided herein to a subject having the PI3Kα protein, such as a human, and, for example, introducing the compound provided herein into a sample containing a cell preparation or purified preparation containing the PI3Kα protein.

[0382] 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 a pharmaceutical composition thereof.

[0383] This document also provides a method for 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 pharmaceutical composition thereof. This document also provides a method for increasing tumor cell death in a subject. The method comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that effectively increases tumor cell death.

[0384] The phrase “therapeutic effective amount” means an amount of compound which, when administered to a subject requiring such treatment, is sufficient to (i) treat a PI3Kα protein-related disease or condition, (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or symptom, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or symptom described herein. The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof corresponding to this amount will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity (e.g., weight) of the subject requiring treatment, but can still be routinely determined by those skilled in the art.

[0385] When used as a pharmaceutical product, compounds of formula (I) (including their pharmaceutically acceptable salts) may be administered in the form of pharmaceutical compositions as described herein.

[0386] Combination In the field of medical oncology, routine practice is to treat each subject with cancer using a combination of different forms of treatment. In medical oncology, other components of such combined treatments or therapies besides the compositions presented herein can be, for example, surgical procedures, radiation therapy, and chemotherapy agents, such as other kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, surgery can be open or minimally invasive. Therefore, compounds of formula (I) or pharmaceutically acceptable salts thereof may also be used as adjuvants to cancer treatment, i.e., they can be used in combination with one or more other therapies or therapeutic agents, such as chemotherapy agents acting through the same or different mechanisms of action. In some embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof may be used prior to the administration of additional therapeutic agents or therapies. For example, one or more doses of compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered to a subject in need over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of compounds of formula (I) or pharmaceutically acceptable salts thereof reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, one or more doses of the (I) compound or a pharmaceutically acceptable salt thereof may be administered to a subject in need over a period of time and in one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of the (I) compound or a pharmaceutically acceptable salt thereof prior to one or more rounds of radiotherapy reduces tumor size (e.g., tumor burden).

[0387] In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is difficult to treat with standard therapy (e.g., administration of chemotherapy agents such as multiple kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)) or is intolerant to said standard therapy. In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is difficult to treat with previous therapy (e.g., administration of chemotherapy agents such as multiple kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)) or is intolerant to said previous therapy. In some embodiments, the subject has cancer for which there is no standard therapy (e.g., locally advanced or metastatic tumor). In some embodiments, the subject has not received PI3Kα inhibitor treatment. For example, the subject has not received selective PI3Kα inhibitor treatment. In some embodiments, the subject has not received PI3Kα inhibitor treatment. In some embodiments, the subject has not received kinase inhibitor treatment. In some embodiments, the subject has not received kinase inhibitor treatment. In some embodiments, the subject has undergone prior therapy.For example, treatment with multiple kinase inhibitors (MKIs) or another PI3K inhibitor, such as buparlisib (BKM120), apelixir (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), tacilisib (GDC-0032, RG7604), and sonolisib (PX- 866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK) 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319 or GSK2636771.

[0388] In some embodiments of any of the methods described herein, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more other therapies or treatments (e.g., chemotherapy).

[0389] Other non-limiting examples of therapeutic agents include: other PI3Kα-targeting agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, RAS-targeting agents (including mTOR inhibitors as described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeting agents (e.g., Trk inhibitors or multiple kinase inhibitors)), farnesyltransferase inhibitors, signal transduction pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERM / SERD), checkpoint inhibitors, apoptosis pathway modulators (e.g., obataclax); cytotoxic chemotherapy agents, angiogenesis-targeting therapies, immune-targeting agents (including immunotherapy), and radiotherapy.

[0390] In some implementations, EGFR inhibitors include osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA™, IMC-11F8), neratinib (HKI-272, NERLYNX®), and lapatinib (TYKERB®). Panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW) 2992, GILOTRIF®, dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806. Canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β-shikonin),β-Dimethacrylol Shikonin and Acetyl Shikonin), Poziotinib (NOV120101, HM781-36B), AV-412, Ibrutinib, WZ4002, Brigatinib (AP26113, ALUNBRIG®), Pelitinib (EKB-569), Tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, Tevasevatinib (KD019, XL647), YH25448, Epitinib ib)(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 implementations, the EGFR-targeting agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0391] Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), and trastuzumab mettansine. The following are listed as potential alternatives: emtansine (T-DM1 or trastuzumab-emtansine conjugate, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, peritinib, S-22261 1, and AEE-788.

[0392] As used herein, a "therapeutic agent targeting the RAS pathway" includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any protein 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, the RAS pathway modulator may be selective for proteins in the RAS pathway; for example, the RAS pathway modulator may be selective for RAS (also referred to as a RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the therapeutic agent targeting the RAS pathway is a "KRAS pathway modulator." A KRAS pathway modulator includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) 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., other PI3K inhibitors as described herein), AKT, and mTOR. In some embodiments, the KRAS pathway modulator may be selective for proteins in the RAS pathway; for example, the KRAS pathway modulator may be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0393] Non-limiting examples of KRAS-targeting therapeutics (e.g., KRAS inhibitors) include BI 1701963, AMG510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0394] Other non-limiting examples of therapeutic agents targeting RAS include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some implementations, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or combinations thereof.

[0395] In some implementations, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0396] In some implementations, the ERK inhibitors are FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcium diol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, and GDC-0994. (RG-7482), ASN007, FR148083, 5-7-Oxozeaenol, 5-iodotuberculin, GDC0994, ONC201 or combinations thereof.

[0397] In some implementations, the other PI3K inhibitor is another PI3Kα inhibitor. In some implementations, the other PI3K inhibitor is a pan-PI3K inhibitor. In some implementation schemes, other PI3K inhibitors are selected from buprazab (BKM120), apelis (BYL719), WX-037, cobancoxib (ALIQOPATM, BAY80-6946), dacrylolisad (NVP-BEZ235, BEZ-235), tacilisad (GDC-0032, RG7604), sonolithi (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pitilis (GDC-0941), piracelisad (XL147, SAR245408), gitolisad (PF-05212384, PKI-587), and threlisad (TAK-117, MLN1117, INK). 1117), BGT-226 (NVP-BGT226), PF-04691502, Atolis (GDC-0980), Omilixeira (GSK2126458, GSK458), Votacobib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, Wolman penicillin, LY294002, PI-103, Ligosetti, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771 or combinations thereof.

[0398] In some implementations, the AKT inhibitor is selected from miltefosine (IMPADIVO®), woumacil, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminopropyl-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edefosine (EDE) lfosine), mitefosine, perifosine, choline phosphate, 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, BAY1125976, 3-oxo-tirucallic acid acid), lactoquinomycin, boc-Phe-vinyl ketone, perifol (D-21266), TCN, TCN-P, GSK2141795, ONC201 or combinations thereof.

[0399] In some implementations, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or combinations thereof.

[0400] Non-restrictive examples of farnesyltransferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0401] In some implementations, chemotherapeutic agents include anthracycline, cyclophosphamide, taxane, platinum-based agents, mitomycin, gemcitabine, eribulin (HALAVEN) TM (or a combination thereof).

[0402] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0403] In some embodiments, anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0404] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatinium tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.

[0405] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0406] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testosterone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0407] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[0408] Non-limiting examples of immunotherapy include immune checkpoint therapy, atezolizumab (TECENTRIQ®), and albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapy include inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cimiprimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo et al. J Hematol Oncol. 11:39 (2018).

[0409] In some implementations, the additional therapy or treatment agent is selected from fulvestrant, capecitabine, trastuzumab, trastuzumab-metamexin conjugate, pertuzumab, paclitaxel, albumin-bound paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, buprazab, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG 479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, LGX818, acestrantraniliprole, and combinations thereof.

[0410] In some embodiments, additional therapeutic agents may also be administered to treat potential side effects of specific anticancer therapies and / or as palliative care, such as opioids and corticosteroids. In some embodiments, the 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.

[0411] Non-limiting examples of GLP-1 receptor agonists include liraglutide (VICTOZA®, NN2211), dulaglutide (LY2189265, TRULICITY®), exenatide (BYETTA®, BYDUREON®, exendin-4), taspoglutide, lixisenatide (LYXUMIA®), albiglutide (TANZEUM®), semaglutide (OZEMPIC®), ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0412] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI®), remogliflozin, serfliflozin, licofliglozin, and sotagliflozin (ZYNQUISTA). TM ) and tofogliflozin.

[0413] Non-limiting examples of DPP-4 inhibitors include sitagliptin (JANUVIA®), vildagliptin, saxagliptin (ONGLYZA®), linagliptin (TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (NESINA®), omarigliptin, evogliptin, and dutogliptin.

[0414] In some implementations, subjects are also instructed to maintain a specific diet and / or exercise regimen to control their blood sugar levels.

[0415] Therefore, this article also provides a method for treating cancer, comprising administering to a subject in need a combination of drugs for treating cancer, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential treatment of cancer, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together effectively treat cancer.

[0416] In some implementations, additional therapeutic agents include any of the above-listed therapies or therapeutic agents that are standard of cancer care, wherein the cancer has PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of them.

[0417] These additional therapeutic agents may be combined with one or more doses of a (I) compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, as part of the same or independent dosage form, via the same or different routes of administration, and / or according to the same or different administration regimens, in accordance with standard pharmaceutical practices known to those skilled in the art.

[0418] This document also provides (i) a pharmaceutical combination for treating cancer in a subject of need, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any exemplary additional therapeutic agent described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential treatment of cancer, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together effectively treat cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) use of such a combination for preparing a pharmaceutical agent for treating cancer; and (iv) a commercial package or product comprising such a combination as a combined formulation for simultaneous, separate, or sequential use; and a method of treating cancer in a subject of need. In some embodiments, the cancer is PI3Kα-related cancer.

[0419] As used herein, the term "drug combination" refers to a pharmaceutical therapy resulting from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are administered simultaneously to a subject 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 and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or dosage forms such that they can be administered simultaneously, in parallel, or sequentially to a subject in need, under different intervention time constraints, wherein such administration provides effective levels of two or more compounds in the subject. These combinations also apply to mixed therapies, such as the administration of three or more active ingredients.

[0420] Therefore, this document also provides a method for treating cancer, comprising administering to a subject in need a combination of drugs for treating cancer, said drug combination comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together effectively treat 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, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially in any order at a combined therapeutically effective amount as separate doses, such as daily or intermittent doses. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as a combined dose.

[0421] Implementation Plan Implementation Scheme 1: A compound of formula (I): Or its pharmaceutically acceptable salt, wherein: Z is O or NR x ; R x It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; Each R 1 Independently selected from halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups optionally substituted with hydroxyl groups, and C3-C6 cycloalkyl groups; m can be 0, 1, 2, or 3; R 2 It is a halogen, a hydroxyl group, a C1-C6 alkylalkyl group optionally substituted with a hydroxyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups. R 3 It is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl; Ring A is a 6-10 aryl, C3-C8 cycloalkyl, 5-10 heteroaryl, or 4-10 heterocyclic group; Each R 4 Choose independently from the following groups: (i) Halogens, (ii) Optionally surrounded by one or two hydroxyl groups or -NR A R B Substituted C1-C6 alkyl groups, (iii) A C1-C6 alkoxy group optionally substituted with one or two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups, (iv) C1-C6 haloalkyl groups, (v) Hydroxyl group, (vi) Cyano group, (vii) -CO2H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO2(NR E R F ), (xii)-SO2(C1-C6 alkyl), (xiii) -S(=O)(=NH)(C1-C6 alkyl), (xiv) -C(=O)(C1-C6 alkyl), (xv)-CO2(C1-C6 alkyl), (xvi) 5-6-membered heteroaryl groups optionally substituted with C1-C6 alkyl groups, (xvii) R can be optionally selected by one or two independent choices. G Substituted 3-9 membered heterocyclic groups, and (xviii) R can be optionally selected by one or two independent choices G Substituted 3-6 membered cycloalkyl groups; n is 0, 1, or 2; Each R A R A1 R B R B1 R C R C1 R D R D1 R E and R F Independently (i) Hydrogen, (ii) Hydroxyl group, (iii) 4-6 membered heterocyclic groups, (iv) C1-C6 haloalkyl groups, (v) -C(=O)(C1-C6 alkyl), (vi) -C(=O)O(C1-C6 alkyl), (vii) -SO2 (C1-C6 alkyl), (viii) Optionally hydroxyl-substituted 3- to 6-membered cycloalkyl groups, or (ix) C1-C6 alkyl groups optionally substituted with 1-2 substituents independently selected from the following: hydroxyl, -C(=O)NR B2 R C2 5-6 membered heteroaryl, 3-6 membered cycloalkyl, -SO2 (C1-C6 alkyl), -CO2H and -SO2 (NH2); or R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups; Each R A2 R B2 and R C2 Independently hydrogen or C1-C6 alkyl; Each R G Independently selected from the group consisting of: fluorine, cyano, hydroxyl, C1-C6 alkyl groups optionally substituted with hydroxyl, C1-C6 alkoxy groups, -NR A1 R B1 =NR A2 -C(=O)NR C1 R D1 -CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2 (C1-C6 alkyl), and -CO2H; and The compounds are not selected from the following groups: Implementation Scheme 2: The compound as described in Implementation Scheme 1, wherein m is 1.

[0422] Implementation Scheme 3: The compound as described in Implementation Scheme 1, wherein m is 2.

[0423] Implementation Scheme 4: The compound as described in Implementation Scheme 1 or 2, wherein for .

[0424] Implementation Scheme 5: The compound as described in Implementation Scheme 1 or 2, wherein for .

[0425] Implementation Scheme 6: The compound as described in Implementation Scheme 1 or 3, wherein for .

[0426] Implementation Scheme 7: The compound as described in any one of Implementation Schemes 1-6, wherein each R 1 It is a halogen.

[0427] Implementation Scheme 8: The compound as described in any one of Implementation Schemes 1-7, wherein each R 1 Selected from fluorine and chlorine groups.

[0428] Implementation Scheme 9: The compound as described in any one of Implementation Schemes 1-8, wherein each R 1 It is fluorine-based.

[0429] Implementation Scheme 10: A compound as described in any one of Implementation Schemes 1-6, wherein one of R 1 It is a cyano group.

[0430] Implementation Scheme 11: A compound as described in any one of Implementation Schemes 1-6, wherein one of R 1 It is a C1-C6 alkyl group.

[0431] Implementation Scheme 12: A compound as described in any one of Implementation Schemes 1-6, wherein one of R 1 It is a C3-C6 cycloalkyl group.

[0432] Implementation Scheme 13: The compound as described in Implementation Scheme 1, wherein m is 0.

[0433] Implementation Scheme 14: The compound as described in any one of Implementation Schemes 1-13, wherein R 2 It is a C1-C6 alkyl group.

[0434] Implementation Scheme 15: The compound as described in Implementation Scheme 14, wherein R 2 It is a methyl group.

[0435] Implementation Scheme 16: The compound as described in any one of Implementation Schemes 1-13, wherein R 2 It is a C1-C6 haloalkyl group.

[0436] Implementation Scheme 17: The compound as described in Implementation Scheme 16, wherein R 2 It is difluoromethyl.

[0437] Implementation Scheme 18: The compound as described in Implementation Scheme 16, wherein R 2 It is trifluoromethyl.

[0438] Implementation Scheme 19: The compound as described in any one of Implementation Schemes 1-13, wherein R 2 It is a halogen.

[0439] Implementation Scheme 20: The compound as described in any one of Implementation Schemes 1-13, wherein R 2 It is a C3-C6 cycloalkyl group optionally substituted with one or two fluorine groups.

[0440] Implementation Scheme 21: The compound as described in any one of Implementation Schemes 1-13 or 20, wherein R 2 It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups.

[0441] Implementation Scheme 22: The compound as described in any one of Implementation Schemes 1-13 or 21, wherein R 2 It is an unsubstituted C3-C6 cycloalkyl group.

[0442] Implementation Scheme 23: The compound as described in any one of Implementation Schemes 1-22, wherein R 3 It is a C1-C6 alkyl group.

[0443] Implementation Scheme 24: The compound as described in any one of Implementation Schemes 1-23, wherein R 3 It can be methyl, ethyl, or isopropyl.

[0444] Implementation Scheme 25: The compound as described in any one of Implementation Schemes 1-23, wherein R 3 It is a methyl group.

[0445] Implementation Scheme 26: The compound as described in any one of Implementation Schemes 1-23, wherein R 3 It is an ethyl group.

[0446] Implementation Scheme 27: The compound as described in any one of Implementation Schemes 1-23, wherein R 3 It is isopropyl.

[0447] Implementation Scheme 28: The compound as described in any one of Implementation Schemes 1-22, wherein R 3 It is a C1-C6 haloalkyl group.

[0448] Implementation Scheme 29: The compound as described in any one of Implementation Schemes 1-22 and 28, wherein R 3 It is trifluoromethyl.

[0449] Implementation Scheme 30: The compound as described in any one of Implementation Schemes 1-22, wherein R 3 It is a C3-C6 cycloalkyl group that is optionally substituted with one or two substituents independently selected from fluorine and C1-C6 alkyl groups.

[0450] Implementation Scheme 31: The compound as described in any one of Implementation Schemes 1-22 and 30, wherein R 3 It is a C3-C6 cycloalkyl group substituted with one or two fluorine groups.

[0451] Implementation Scheme 32: The compound as described in any one of Implementation Schemes 1-22 and 30, wherein R 3 It is an unsubstituted C3-C6 cycloalkyl group.

[0452] Implementation Scheme 33: The compound as described in any one of Implementation Schemes 1-22, 30 and 31, wherein R 3 The C3-C6 cycloalkyl group is cyclopropyl.

[0453] Implementation Scheme 34: The compound as described in any one of Implementation Schemes 1-33, wherein ring A is a 6-10 aryl group.

[0454] Implementation Scheme 35: The compound as described in any one of Implementation Schemes 1-34, wherein ring A is phenyl.

[0455] Implementation Scheme 36: The compound as described in any one of Implementation Schemes 1-33, wherein ring A is a C3-C8 cycloalkyl group.

[0456] Implementation Scheme 37: The compound as described in any one of Implementation Schemes 1-33 and 36, wherein ring A is a C5-C6 cycloalkyl group.

[0457] Implementation Scheme 38: The compound as described in any one of Implementation Schemes 1-33 and 36-37, wherein ring A is cyclohexyl.

[0458] Implementation Scheme 39: The compound as described in any one of Implementation Schemes 1-33, wherein ring A is a 5-10 member heteroaryl.

[0459] Implementation Scheme 40: The compound as described in any one of Implementation Schemes 1-33 and 39, wherein ring A is a 5-6 membered heteroaryl group.

[0460] Implementation Scheme 41: A compound as described in any one of Implementation Schemes 1-33 and 39-40, wherein ring A is pyrimidinyl, pyridinyl, thiazolyl, thiopheneyl or pyrazolyl.

[0461] Implementation Scheme 42: The compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is a pyrimidinyl group.

[0462] Implementation Scheme 43: The compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is pyridyl.

[0463] Implementation Scheme 44: The compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is a thiazolyl group.

[0464] Implementation Scheme 45: The compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is a thiophene group.

[0465] Implementation Scheme 46: The compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is a pyrazolyl group.

[0466] Implementation Scheme 47: A compound as described in any one of Implementation Schemes 1-33 and 39-41, wherein ring A is 5-pyrimidinyl, 3-pyridinyl or 4-pyrazolyl.

[0467] Implementation Scheme 48: The compound as described in any one of Implementation Schemes 1-33, 39-41 and 47, wherein ring A is 5-pyrimidinyl.

[0468] Implementation Scheme 49: The compound as described in any one of Implementation Schemes 1-33, 39-41 and 47, wherein ring A is 3-pyridyl.

[0469] Implementation Scheme 50: The compound as described in any one of Implementation Schemes 1-33, 39-41 and 47, wherein ring A is 4-pyrazolyl.

[0470] Implementation Scheme 51: The compound as described in any one of Implementation Schemes 1-33 and 39, wherein ring A is a 9-10 member heteroaryl.

[0471] Implementation Scheme 52: A compound as described in any one of Implementation Schemes 1-33, 39 and 51, wherein ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranone, isoindolone, or imidazo[1,2-a]pyridyl.

[0472] Implementation Scheme 53: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is a benzimidazole group.

[0473] Implementation Scheme 54: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is an indazole group.

[0474] Implementation Scheme 55: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is an indole group.

[0475] Implementation Scheme 56: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is an indole group.

[0476] Implementation Scheme 57: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is a quinazonone.

[0477] Implementation Scheme 58: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is an isobenzofuranone group.

[0478] Implementation Scheme 59: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is an isoindolinone group.

[0479] Implementation Scheme 60: The compound as described in any one of Implementation Schemes 1-33, 39 and 51-52, wherein ring A is imidazo[1,2-a]pyridyl.

[0480] Scheme 61: A compound as described in any one of Schemes 1-33, 39 and 51-52, wherein ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridyl, or .

[0481] Implementation Scheme 62: The compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is 2-benzimidazole.

[0482] Implementation Scheme 63: The compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is 5-indazole.

[0483] Implementation Scheme 64: The compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is 2-indole.

[0484] Implementation Scheme 65: A compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is 7-imidazo[1,2-a]pyridyl.

[0485] Implementation Scheme 66: A compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is .

[0486] Implementation Scheme 67: A compound as described in any one of Implementation Schemes 1-33, 39 and 61, wherein ring A is .

[0487] Implementation Scheme 68: A compound as described in any one of Implementation Schemes 1-33, wherein ring A is a 4-10 membered heterocyclic group.

[0488] Implementation Scheme 69: The compound as described in any one of Implementation Schemes 1-33 and 68, wherein ring A is a 6-9 membered heterocyclic group.

[0489] Implementation Scheme 70: A compound as described in any one of Implementation Schemes 1-33 and 68-69, wherein ring A is piperidinyl or 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide.

[0490] Implementation Scheme 71: The compound as described in any one of Implementation Schemes 1-33 and 68-70, wherein ring A is piperidinyl.

[0491] Implementation Scheme 72: The compound of any one of Implementation Schemes 1-33 and 68-70, wherein ring A is 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide.

[0492] Embodiment 73: A compound as described in any one of Embodiments 1-33 and 68-70, wherein ring A is 3-piperidinyl, 4-piperidinyl, or... .

[0493] Implementation Scheme 73: The compound of any one of Implementation Schemes 1-33 and 68-70, wherein ring A is 3-piperidinyl.

[0494] Implementation Scheme 74: The compound as described in any one of Implementation Schemes 1-33 and 68-70, wherein ring A is 4-piperidinyl.

[0495] Implementation Scheme 75: The compound as described in any one of Implementation Schemes 1-33 and 68-70, wherein ring A is .

[0496] Implementation Scheme 76: The compound as described in any one of Implementation Schemes 1-75, wherein n is 1.

[0497] Implementation Scheme 77: The compound as described in any one of Implementation Schemes 1-75, wherein n is 2.

[0498] Implementation Scheme 78: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is an unsubstituted C1-C6 alkyl group.

[0499] Implementation Scheme 79: A compound as described in any one of Implementation Schemes 1-78, wherein one of R 4 It is a methyl group.

[0500] Implementation Scheme 80: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4It is a C1-C6 alkoxy group optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups.

[0501] Implementation Scheme 81: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 alkoxy group that is substituted by 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups.

[0502] Implementation Scheme 82: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 alkoxy group substituted with a hydroxyl group or a C3-C6 cycloalkyl group.

[0503] Implementation Scheme 83: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 alkoxy group substituted with two substituents independently selected from hydroxyl and C3-C6 cycloalkyl groups.

[0504] Implementation Scheme 84: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 alkoxy group.

[0505] Implementation Scheme 85: A compound as described in any one of Implementation Schemes 1-77 and 84, wherein one of R 4 It is a methoxy group.

[0506] Implementation Scheme 86: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 haloalkyl group.

[0507] Implementation Scheme 87: A compound as described in any one of Implementation Schemes 1-77 and 86, wherein one of R 4 It is trifluoromethyl.

[0508] Implementation Scheme 88: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a hydroxyl group.

[0509] Implementation Scheme 89: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a cyano group.

[0510] Implementation Scheme 90: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is -CO2H.

[0511] Implementation Scheme 91: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a halogen.

[0512] Implementation Scheme 92: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is a C1-C6 alkyl group substituted with 1-2 hydroxyl groups.

[0513] Implementation Scheme 93: A compound as described in any one of Implementation Schemes 1-77 and 92, wherein one of R 4 It is a C1-C6 alkyl group substituted with a hydroxyl group.

[0514] Implementation Scheme 94: A compound as described in any one of Implementation Schemes 1-77 and 92, wherein one of R 4 It is a C1-C6 alkyl group substituted with two hydroxyl groups.

[0515] Implementation Scheme 95: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 For -NR A R B Substituted C1-C6 alkyl groups.

[0516] Implementation Scheme 96: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 For -NR A R B .

[0517] Implementation Scheme 97: The compound as described in any one of Implementation Schemes 1-77 and 95-96, wherein R A and R B Each is hydrogen.

[0518] Implementation Scheme 98: The compound as described in any one of Implementation Schemes 1-77 and 95-96, wherein R A and R B Each is a C1-C6 alkyl group.

[0519] Implementation Scheme 99: The compound as described in any one of Implementation Schemes 1-52, 95-96 and 98, wherein R A and R B Each is a methyl group.

[0520] Implementation Scheme 100: The compound as described in any one of Implementation Schemes 1-77 and 95-96, wherein R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl group.

[0521] Implementation Scheme 101: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 -C(=O)NR C RD .

[0522] Implementation Scheme 102: The compound as described in any one of Implementation Schemes 1-77 and 101, wherein R C and R D Each is hydrogen.

[0523] Implementation Scheme 103: The compound as described in any one of Implementation Schemes 1-77 and 101, wherein R C and R D Each is a C1-C6 alkyl group.

[0524] Implementation Scheme 104: The compound as described in any one of Implementation Schemes 1-77 and 101, wherein R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group optionally substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups.

[0525] Implementation Scheme 105: The compound as described in any one of Implementation Schemes 1-77 and 101, wherein R C and R D Together with the attached nitrogen atom, it forms a 4-10 membered heterocyclic group, which is substituted by 1-2 independent substituents selected from the following: hydroxyl, halogen, -C(=O)NR. B1 R C1 -SO2 (C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy optionally substituted with hydroxyl groups.

[0526] Implementation Scheme 106: The compound as described in any one of Implementation Schemes 1-77 and 101, wherein R C and R D Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0527] Implementation Scheme 107: The compound as described in any one of Implementation Schemes 1-77, 101 and 76, wherein R C and R D Together with the nitrogen atom attached to it, it forms azacyclobutane or piperazine.

[0528] Implementation Scheme 108: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 -SO2(NR) E R F).

[0529] Implementation Scheme 109: The compound as described in any one of Implementation Schemes 1-77 and 108, wherein R E and R F Each is hydrogen.

[0530] Implementation Scheme 110: The compound as described in any one of Implementation Schemes 1-77 and 208, wherein R E and R F Each is a C1-C6 alkyl group.

[0531] Implementation Scheme 111: A compound as described in any one of Implementation Schemes 1-77, wherein one of R 4 It is -SO2 (C1-C6 alkyl).

[0532] Implementation Scheme 112: A compound as described in any one of Implementation Schemes 1-77 and 111, wh...

Claims

1. Use of a pharmaceutical composition in the preparation of a medicament for treating breast cancer, said pharmaceutical composition comprising... The compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, having the following structure: Or its pharmaceutically acceptable salt; and One or more pharmaceutically acceptable excipients.

2. The use as claimed in claim 1, wherein the compound is (R)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

3. Use of the pharmaceutical composition in the preparation of a medicament for treating breast cancer, said pharmaceutical composition comprising... The compound is ;as well as One or more pharmaceutically acceptable excipients.

4. The use as described in any one of claims 1-3, wherein the breast cancer is PI3Kα-associated breast cancer.

5. The use as described in any one of claims 1-4, wherein the breast cancer is ER. + Breast cancer.

6. The use as described in any one of claims 1-5, wherein the breast cancer is HER2. - Breast cancer.

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