Urea derivatives which can be used to treat cancer

Abstract

The present disclosure provides compounds of formulas (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), and pharmaceutically acceptable salts thereof. These chemical entities are useful for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Ka activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). The present disclosure also provides compositions containing the same, as well as methods for using and preparing the same. (I)

Description

Technology Field

[0001] Cross-reference regarding related applications

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

[0003] Technology field

[0004] The present disclosure provides compounds of formulas (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), and pharmaceutically acceptable salts thereof. These chemical entities are useful for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). The present disclosure also provides compositions containing the same, as well as methods for using and preparing the same. Background Technology

[0005] PIK3CAPhosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by genes, is part of the PI3K / AKT / TOR signaling network and is altered in various human cancers. Several researchers have demonstrated that the role of PI3K / AKT signaling is involved in physiological and pathophysiological functions that promote tumor progression, such as metabolism, cell growth, proliferation, angiogenesis, and metastasis. (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 a headway? (See 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 regression of tumor growth.

[0006] The PI3K path is, for example, PIK3CA Through point mutation(s) of the gene or phosphatase and tensin homologues ( PTEN : It can be activated through the inactivation of genes (phosphatase and tensin homolog). Activation of this pathway occurs in approximately 30–50% of human cancers and contributes to resistance to various anticancer therapies. (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.(See Pharmacol. Ther. 2015, 146, 53-60.) PI3K consists of three subunits: a p85 regulatory subunit, a p55 regulatory subunit, and a p110 catalytic subunit. Based on their different structures and specific substrates, PI3K is classified into three classes: Class I, II, and III. Class I PI3K includes Class IA and Class IB PI3K. Class IA PI3K, a heterodimer of the p85 regulatory subunit and the p110 catalytic subunit, is the type most clearly associated with human cancer. Class IA PI3K consists of different genes (respectively, PIK3CA, PIK3CB and PIK3CD While including p110α, p110β, and p110δ catalytic subunits generated in ), PIK3CG generated by p110γ is It represents the only catalytic subunit of class IB PI3K. The gene encoding the p110α subunit, PIK3CA It is frequently mutated or amplified in many human cancers, such as breast, colon, stomach, cervical, prostate, and lung cancer. (Samuels Y et al. High frequency of mutations of the PIK3CA See gene in human cancers. Science. 2004;304:554.)

[0007] However, the development of PI3K inhibitors has been problematic for several reasons, including (i) adaptive molecular mechanisms of therapeutic inhibition of PI3K, (ii) the inability to specifically inhibit signaling induced by PIK3CA mutations while preserving endogenous p110α, (iii) the limited use of these therapies in reasonable combinations, including those involving strong mechanical support, and (iv) dose-limiting toxicities that prevent sustained inhibition of the PI3K pathway. (Hanker et al. Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors,(See Cancer Discovery, April 2019;9: 482-491.) For example, alpelisib is an alpha-selective PI3K inhibitor equivalent to the wild-type and mutant forms of PI3Kα. However, the therapeutic benefits of alpelisib are limited due to the inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities including hyperglycemia.

[0008] Furthermore, there exist other factors and compensatory pathways derived from clinical and in vitro laboratory studies that affect PI3K signaling, such as HRAS and KRAS mutations that reduce sensitivity to PI3K inhibitors (and their knockdown has been shown to improve sensitivity to PI3K inhibitors). (Misrha, R.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. See Int. J. Mol. Sci. 2021, 22, 3464.)

[0009] PIK3CA Deletion of the 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 an approach for the treatment of proliferative disorders such as cancer. means of solving the problem

[0010] Some embodiments are compounds of chemical formula (I):

[0011] (I)

[0012] or provides a pharmaceutically acceptable salt thereof, wherein:

[0013] Z is O or NR x And;

[0014] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0015] Each R1 silver Independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl;

[0016] m is 0, 1, 2, or 3, and;

[0017] R 2 is a halogen, hydroxyl, a C1-C6 alkyl optionally substituted with a hydroxyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0018] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0019] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0020] Each R 4 is independently selected from a group consisting of:

[0021] (i) Halogen,

[0022] (ii) 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl alkyl arbitrarily substituted with

[0023] (iii) A C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0024] (iv) C1-C6 haloalkyl,

[0025] (v) hydroxyl,

[0026] (vi) cyano,

[0027] (vii) -CO2H,

[0028] (viii) -NR A RB ,

[0029] (ix) =NR A2 ,

[0030] (x) -C(=O)NR C R D ,

[0031] (xi) -SO2(NR E R F ),

[0032] (xii) -SO2(C1-C6 alkyl),

[0033] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0034] (xiv) -C(=O)(C1-C6 alkyl),

[0035] (xv) -CO2(C1-C6 alkyl),

[0036] (xvi) 5-6 member heteroaryl optionally substituted with C1-C6 alkyl,

[0037] (xvii) 1 or 2 independently selected R G A 3-9 member heterocyclile arbitrarily substituted with , and

[0038] (xviii) One or two independently selected R G 3-6 member cycloalkyl arbitrarily substituted with;

[0039] n is 0, 1, or 2, and;

[0040] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is doing it independently or

[0041] (i) hydrogen,

[0042] (ii) Hydroxyl,

[0043] (iii) 4-6-membered heterocyclil,

[0044] (iv) C1-C6 haloalkyl,

[0045] (v) -C(=O)(C1-C6 alkyl),

[0046] (vi) -C(=O)O(C1-C6 alkyl),

[0047] (vii) -SO2(C1-C6 alkyl),

[0048] (viii) a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or

[0049] (ix) Hydroxyl, -C(=O)NR B2 R C2 , C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0050] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[0051] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[0052] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H; and

[0053] Here, the compound is not a compound selected from the group consisting of the following:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] Some embodiments are compounds of chemical formula (I):

[0065] (I)

[0066] or provides a pharmaceutically acceptable salt thereof, wherein:

[0067] Each R 1 silver Independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl;

[0068] m is 0, 1, 2, or 3, and;

[0069] R 2is a halogen, hydroxyl, a C1-C6 alkyl optionally substituted with a hydroxyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0070] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0071] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0072] Each R 4 Is Independently selected from a group consisting of:

[0073] (i) Halogen,

[0074] (ii) 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl alkyl arbitrarily substituted with

[0075] (iii) A C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0076] (iv) C1-C6 haloalkyl,

[0077] (v) hydroxyl,

[0078] (vi) cyano,

[0079] (vii) -CO2H,

[0080] (viii) -NR A R B ,

[0081] (ix) =NR A2 ,

[0082] (x) -C(=O)NR C R D ,

[0083] (xi) -SO2(NRE R F ),

[0084] (xii) -SO2(C1-C6 alkyl),

[0085] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0086] (xiv) -C(=O)(C1-C6 alkyl),

[0087] (xv) -CO2(C1-C6 alkyl),

[0088] (xvi) 5-6 member heteroaryl optionally substituted with C1-C6 alkyl,

[0089] (xvii) 1 or 2 independently selected R G A 3-9 member heterocyclile arbitrarily substituted with , and

[0090] (xviii) One or two independently selected R G 3-6 member cycloalkyl arbitrarily substituted with;

[0091] n is 0, 1, or 2, and;

[0092] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is doing it independently or

[0093] (i) hydrogen,

[0094] (ii) Hydroxyl,

[0095] (iii) 4-6-membered heterocyclil,

[0096] (iv) C1-C6 haloalkyl,

[0097] (v) -C(=O)(C1-C6 alkyl),

[0098] (vi) -C(=O)O(C1-C6 alkyl),

[0099] (vii) -SO2(C1-C6 alkyl),

[0100] (viii) a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or

[0101] (ix) Hydroxyl, -C(=O)NR B2 R C2 , C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0102] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[0103] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[0104] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H; and

[0105] Here, the compound is not a compound selected from the group consisting of the following:

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116] Some embodiments are compounds of chemical formula (I):

[0117] (I)

[0118] or provides a pharmaceutically acceptable salt thereof, wherein:

[0119] Each R 1 silver Independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl;

[0120] m is 0, 1, 2, or 3, and;

[0121] R 2 is a halogen, hydroxyl, a C1-C6 alkyl optionally substituted with a hydroxyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0122] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0123] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0124] Each R 4 Is Independently selected from a group consisting of:

[0125] (i) Halogen,

[0126] (ii) 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl alkyl arbitrarily substituted with

[0127] (iii) A C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0128] (iv) C1-C6 haloalkyl,

[0129] (v) hydroxyl,

[0130] (vi) cyano,

[0131] (vii) -CO2H,

[0132] (viii) -NR A R B ,

[0133] (ix) =NR A2 ,

[0134] (x) -C(=O)NR C R D ,

[0135] (xi) -SO2(NR E R F ),

[0136] (xii) -SO2(C1-C6 alkyl),

[0137] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0138] (xiv) -C(=O)(C1-C6 alkyl),

[0139] (xv) -CO2(C1-C6 alkyl),

[0140] (xvi) 5-6 member heteroaryl optionally substituted with C1-C6 alkyl,

[0141] (xvii) 1 or 2 independently selected R G A 3-9 member heterocyclile arbitrarily substituted with , and

[0142] (xviii) One or two independently selected R G 3-6 member cycloalkyl arbitrarily substituted with;

[0143] n is 0, 1, or 2, and;

[0144] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is doing it independently or

[0145] (i) hydrogen,

[0146] (ii) Hydroxyl,

[0147] (iii) 4-6-membered heterocyclil,

[0148] (iv) C1-C6 haloalkyl,

[0149] (v) -C(=O)(C1-C6 alkyl),

[0150] (vi) -C(=O)O(C1-C6 alkyl),

[0151] (vii) -SO2(C1-C6 alkyl),

[0152] (viii) a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or

[0153] (ix) Hydroxyl, -C(=O)NR B2 R C2, C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0154] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[0155] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[0156] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 It is independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H.

[0157] Some embodiments have the chemical formula (X):

[0158] (X)

[0159] Provides a compound of formula (I) having , or a pharmaceutically acceptable salt thereof, wherein:

[0160] Z is O or NR x And;

[0161] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0162] Each R 1 silver It is an independently selected halogen;

[0163] m is 0, 1, 2, or 3, and;

[0164] R 2 is a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0165] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0166] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0167] Each R 4 is a halogen, one or two hydroxyl groups, or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils or 3-6 member cycloalkyls each arbitrarily substituted;

[0168] n is 0, 1, or 2, and;

[0169] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently a 3-6-membered cycloalkyl optionally substituted with hydrogen, a 4-6 member heterocyclyl, a C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), or a hydroxyl, or -C(=O)NR B2 R C2 , 5-6 member heteroaryl, 3-6 member cycloalkyl, SO2(C1-C6 alkyl), -SO2(from NH2 It is a C1-C6 alkyl optionally substituted with 1-2 independently selected substituents; or

[0170] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0171] Each R G - fluoro, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and

[0172] Here, the compound is not a compound selected from the group consisting of the following:

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] Additionally, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients is provided herein.

[0184] A method for treating cancer in a subject in need is provided herein, 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.

[0185] Also, (a) cancer PIK3CA A method for treating cancer in a subject in need is provided herein, comprising the steps of: determining whether there is a dysregulation of the expression or activity or level of a gene, PI3Kα protein, or any of these; and (b) administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein to the subject.

[0186] A method for treating a PI3Kα-associated disease or disorder in a subject is provided herein, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject identified or diagnosed as having a PI3Kα-associated disease or disorder.

[0187] The present disclosure also provides a method for treating a PI3Kα-associated disease or disorder in a subject, comprising the steps of: determining whether the cancer of the subject is a PI3Kα-associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0188] A method for treating PI3Kα-associated cancer in a subject is further provided herein, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject identified or diagnosed with PI3Kα-associated cancer.

[0189] The present disclosure also provides a method for treating PI3Kα-associated cancer in a subject, comprising the steps of: determining whether the cancer of the subject is PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0190] The object PIK3CA A method for treating a subject is provided herein, comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein to a subject having a clinical record indicating dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these.

[0191] The present disclosure also provides a method for inhibiting PI3Kα in mammalian cells, comprising contacting mammalian cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0192] Some embodiments of the method and composition described herein are compounds of formula (II):

[0193] (II)

[0194] or comprising a pharmaceutically acceptable salt thereof, wherein:

[0195] Z is O or NR x And;

[0196] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0197] Each R 1 silver It is an independently selected halogen;

[0198] m is 0, 1, 2, or 3, and;

[0199] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0200] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0201] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0202] Each R 4 Is 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -NR optionally substituted 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-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0203] n is 0, 1, or 2, and;

[0204] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently a 3-6-membered cycloalkyl optionally substituted with hydrogen, a 4-6 member heterocyclyl, a C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), C(=O)O(C1-C6 alkyl), -SO2(C1-C6 alkyl), or a hydroxyl, or -C(=O)NR B2 R C2 , optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0205] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[0206] Each R A2 , R B2 , and RC2 Is Independently hydrogen or C1-C6 alkyl;

[0207] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 It is independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H.

[0208] Additionally, a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided herein.

[0209] A method for treating cancer in a subject in need is provided herein, 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.

[0210] Also (a) cancer PIK3CA A method for treating cancer in a subject in need is provided herein, comprising the steps of: determining whether there is a dysregulation of the expression or activity or level of a gene, PI3Kα protein, or any of these; and (b) administering a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein to the subject.

[0211] A method for treating a PI3Kα-associated disease or disorder in a subject is provided herein, comprising administering a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject identified or diagnosed with a PI3Kα-associated disease or disorder.

[0212] The present disclosure also provides a method for treating a PI3Kα-associated disease or disorder in a subject, comprising the steps of: determining whether the cancer of the subject is a PI3Kα-associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0213] A method for treating PI3Kα-associated cancer in a subject is further provided herein, comprising administering a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject identified or diagnosed with PI3Kα-associated cancer.

[0214] The present disclosure also provides a method for treating PI3Kα-associated cancer in a subject, comprising the steps of: determining whether the cancer of the subject is PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0215] The object PIK3CAA method for treating a subject is provided herein, comprising administering a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein to a subject having a clinical record indicating dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these.

[0216] The present disclosure also provides a method for inhibiting PI3Kα in mammalian cells, comprising contacting mammalian cells with an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0217] Other embodiments include those described in the detailed description and / or claims.

[0218] Additional definition

[0219] To facilitate understanding of the disclosures presented herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are those 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 a person skilled in the art to which this disclosure pertains. Each patent, application, published application, and other publication mentioned throughout this specification and the attached appendix is ​​incorporated herein by reference in its entirety.

[0220] When referring to a number or numerical range, the term "approximately" means that the referred number or numerical range is an approximation, for example, within experimental variability and / or statistical experimental error, and therefore the number or numerical range may vary by up to ±10% of the specified number or numerical range.

[0221] As used herein, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a sustained adverse effect on the overall health of the subject being treated.

[0222] The term "to suppress" or "suppression of" means to reduce by a measurable amount or to prevent completely (e.g., 100% suppression).

[0223] "API" refers to an active pharmaceutical ingredient.

[0224] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to a sufficient amount of a chemical entity administered to alleviate, to some extent, one or more of the symptoms of the disease or condition being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desirable alteration of the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing a compound as disclosed herein that is necessary to provide a clinically significant reduction in the symptoms of the disease. In any individual case, the appropriate “effective” dose is determined using any suitable technique, such as a dose escalation study.

[0225] The term “pharmaceuticalally acceptable excipient” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of a pharmaceutical formulation and is suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic reaction, immunogenicity, or other problems or complications corresponding to a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed. .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. See ; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0226] The term “pharmaceuticalally acceptable salt” refers to a formulation of a compound that does not impair the biological activity and properties of the compound without causing significant irritation to the organism being administered. In certain cases, the pharmaceutically acceptable salt is obtained by reacting the compound described herein with an acid such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, the pharmaceutically acceptable salt is obtained by reacting the compound having an acidic group described herein with a base to obtain an ammonium salt, an alkali metal salt, e.g., a sodium or potassium salt, an alkaline earth metal salt, e.g., a calcium or magnesium salt, a salt of an organic base, e.g., dicyclohexylamine, N- Methyl-D-glucarmine, tris(hydroxymethyl)methylamine, and forms salts with amino acids, e.g., arginine, lysine, etc., or are obtained by other previously determined methods. Pharmacologically acceptable salts are not particularly limited as long as they can be used in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include the following: salts with inorganic bases, e.g., sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases, e.g., methylamine, ethylamine, and ethanolamine; salts with basic amino acids, e.g., lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, which is specifically exemplified by the following acid addition salts: inorganic acids, e.g., hydrochloric acid, hydrobromide, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids, e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids, e.g., aspartic acid and glutamic acid.

[0227] The term “pharmaceutical composition” refers to a mixture of the compound described herein and other chemical components (collectively referred to herein as “pharmaceutically acceptable excipients”), such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. A pharmaceutical composition facilitates the administration of the compound to an organism. Various techniques for administering the compound exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0228] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including primates (e.g., human), mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject experiences and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented.

[0229] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desirable clinical outcomes include, but are not limited to, the whole or partly remission of symptoms associated with a disease, disorder, or condition, whether or not they are detectable; a reduction in the severity of the disease; a stabilized (i.e., non-deteriorating) state of the disease; a delay or slowing of disease progression; improvement or alleviation of the disease state (e.g., one or more symptoms of the disease); and remission (partial or whole). “Treatment” may also mean extending survival time compared to the survival time expected without treatment.

[0230] The term "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodo(I).

[0231] The term "oxo" refers to an oxygen atom with a divalent double bond (i.e., "=O"). As used herein, the oxo group is attached to a carbon atom to form a carbonyl.

[0232] The term "hydroxyl" refers to the -OH radical.

[0233] The term "cyano" refers to the -CN radical.

[0234] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be straight-chain or branched and contains the indicated number of carbon atoms. For example, C1-10 silver Indicates that the group may have 1 to 10 (inclusive) carbon atoms. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso -profile, tert -butyl, n - Includes hexyl. The term "saturated" as used herein means only a single bond existing between a constituent carbon atom and other available atoms occupied by hydrogen and / or other substituents as defined herein.

[0235] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halos.

[0236] The term "alkoxy" refers to -O-alkyl radicals (e.g., -OCH3).

[0237] The term “aryl” is a 6- to 20-carbon mono-, bi-, tri-, or polycyclic group in which at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring systems); 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.

[0238] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 cyclic carbons, preferably 3 to 16 cyclic carbons, and more preferably 3 to 12 cyclic carbons or 3 to 10 cyclic carbons or 3 to 6 cyclic carbons, wherein the cycloalkyl group may optionally be substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl may comprise multiple fused and / or cross-linked rings. Non-limiting examples of fused / crosslinked cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2,2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[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" refers only to single bonds existing between constituent carbon atoms.

[0239] As used herein, the term “heteroaryl” means a mono-, bi-, tri-, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not need to be a ring containing heteroatoms, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazoyl, pyrrolyl, imidazoyl, triazolyl, thiodiazoyl, pyrazolyl, isooxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazoyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazoyl, indolyl, isoquinolinyl, isothiazoyl, naftiridinyl, furinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinil, quinolinil, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ bIncludes ][1,4]oxathiine (2,3-dihydrobenzo[b][1,4]oxathiine), isoindoline, etc. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarification, the heteroaryl also includes an aromatic lactam, an aromatic cyclic element, or a vinyl analog thereof, wherein each ring nitrogen adjacent to the carbonyl is one or more pyridones (e.g., , , , or ), pyrimidon (for example, or ), Piridazinon (for example, or ), pyrazinone (for example, or ), and imidazolone (e.g., As in ), it is tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group of the present invention (i.e., "=O") is a component of the heteroaryl ring).

[0240] The term "heterocyclile" refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system (e.g., 5-8-membered monocyclic, 8-12-membered bicyclic, or 11-14-membered tricyclic ring system) comprising 3-16 ring atoms, having 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic, or 1-9 heteroatoms in the case of tricyclic or polycyclic, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S, respectively, in the case of monocyclic, bicyclic, or tricyclic), wherein, as far as valence allows, one or more ring atoms may be substituted with 1-3 oxos (e.g., lactam-forming) and one or more N or S atoms It may be substituted with 1-2 oxides (e.g., forming N-oxide, S-oxide, or S,S-dioxide); and wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclil groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, etc. The heterocyclil may comprise multiple fused and cross-linked rings. Non-limiting examples of fused / crosslinked heterocyclies include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1] Includes 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. Heterocyclils also contain spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through only one atom). Non-limiting examples of spirocyclic heterocyclils include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, and 1-oxaspiro[3.5]nonane. Includes 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.

[0241] Examples of aromatic rings as used herein include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazol, oxazole, thioazole, isooxazole, isothiazol, etc.

[0242] Where a ring is described as "partially unsaturated" as used herein, this means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0243] To avoid doubt, and unless otherwise specified, in the case of ring and cyclic groups (e.g., aryl, heteroaryl, heterocyclil, cycloalkyl, etc. described herein) containing a sufficient number of ring atoms to form a bicyclic or higher-order ring system (e.g., tricyclic, polycyclic ring system), such ring and cyclic groups have fusion sites where (i) adjacent ring atoms (e.g., [xx0] ring system, where 0 indicates zero atom bridging (e.g., )); (ii) single ring atom (spiro-fused ring system) (e.g., , , or ), or (iii) a contiguous arrangement of ring atoms (a cross-linked ring system in which all bridge lengths are greater than 0) (e.g., , , or It is understood to encompass things having fused rings, including those located on )

[0244] Additionally, the atoms constituting the compound of the present embodiment are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon are 13 C and 14 Includes C.

[0245] Additionally, compounds disclosed herein generally or specifically are intended to include all tautomeric forms. Thus, for example, moiety: Compounds containing are moiety: It encompasses tautomeric forms containing. Similarly, pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0246] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a result of structural asymmetry of a particular compound. Unless otherwise indicated, if the disclosed compound is named or illustrated by a structure (e.g., a "flat" structure) without specifying stereochemistry and has one or more chiral centers, it is understood that this represents all possible stereoisomers of the compound. Likewise, unless otherwise indicated, if the disclosed compound is named or illustrated by a structure that specifies stereochemistry (e.g., a structure having "wedge" and / or "dotted" bonds) and has one or more chiral centers, it is understood that this represents the stereoisomers of the indicated compound.

[0247] Details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the following description. Other features and advantages of the present disclosure will become apparent from the description, drawings, and claims. Specific details for implementing the invention

[0248] The present disclosure provides compounds of formulas (I) and (II) that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), and pharmaceutically acceptable salts thereof. These chemical entities are useful for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., cancer) in a subject (e.g., human). The present disclosure also provides compositions containing the same, as well as methods for using and preparing the same.

[0249] Chemical formula (I) compound

[0250] Some embodiments are compounds of chemical formula (I):

[0251] (I)

[0252] or provides a pharmaceutically acceptable salt thereof, wherein:

[0253] Z is O or NR x And;

[0254] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0255] Each R 1 silver Independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl;

[0256] m is 0, 1, 2, or 3, and;

[0257] R 2 is a halogen, hydroxyl, a C1-C6 alkyl optionally substituted with a hydroxyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0258] R 3is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0259] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0260] Each R 4 Is Independently selected from a group consisting of:

[0261] (i) Halogen,

[0262] (ii) 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl alkyl arbitrarily substituted with

[0263] (iii) A C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[0264] (iv) C1-C6 haloalkyl,

[0265] (v) hydroxyl,

[0266] (vi) cyano,

[0267] (vii) -CO2H,

[0268] (viii) -NR A R B ,

[0269] (ix) =NR A2 ,

[0270] (x) -C(=O)NR C R D ,

[0271] (xi) -SO2(NR E R F ),

[0272] (xii) -SO2(C1-C6 alkyl),

[0273] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[0274] (xiv) -C(=O)(C1-C6 alkyl),

[0275] (xv) -CO2(C1-C6 alkyl),

[0276] (xvi) 5-6 member heteroaryl optionally substituted with C1-C6 alkyl,

[0277] (xvii) 1 or 2 independently selected R G A 3-9 member heterocyclile arbitrarily substituted with , and

[0278] (xviii) One or two independently selected R G 3-6 member cycloalkyl arbitrarily substituted with;

[0279] n is 0, 1, or 2, and;

[0280] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is doing it independently or

[0281] (i) hydrogen,

[0282] (ii) Hydroxyl,

[0283] (iii) 4-6-membered heterocyclil,

[0284] (iv) C1-C6 haloalkyl,

[0285] (v) -C(=O)(C1-C6 alkyl),

[0286] (vi) -C(=O)O(C1-C6 alkyl),

[0287] (vii) -SO2(C1-C6 alkyl),

[0288] (viii) a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or

[0289] (ix) Hydroxyl, -C(=O)NRB2 R C2 , C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[0290] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[0291] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[0292] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1 Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H; and

[0293] Here, the compound is not a compound selected from the group consisting of the following:

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] In some embodiments, Z is NR x and R 3 In the case of this methyl group, ring A is not phenyl.

[0305] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound is not a compound selected from the group consisting of:

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound is not a compound selected from the group consisting of:

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] Some embodiments provide a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound is not a compound selected from the group consisting of:

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] Some embodiments have the chemical formula (X):

[0339] (X)

[0340] Provides a compound of formula (I) having , or a pharmaceutically acceptable salt thereof, wherein:

[0341] Z is O or NR x And;

[0342] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0343] Each R 1 silver It is an independently selected halogen;

[0344] m is 0, 1, 2, or 3, and;

[0345] R 2 is a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0346] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0347] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[0348] Each R 4 is halogen, 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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 member heteroaryls optionally substituted with C1-C6 alkyl, and one or two independently selected Rs each. G Independently selected from the group consisting of a 3-6-membered heterocyclile or a 3-6-membered cycloalkyl optionally substituted with;

[0349] n is 0, 1, or 2, and;

[0350] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently a 3-6-membered cycloalkyl optionally substituted with hydrogen, a 4-6 member heterocyclyl, a C1-C6 haloalkyl, -C(=O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), or a hydroxyl, or -C(=O)NR B2 R C2 , 5-6-membered heteroaryl, 3-6-membered cycloalkyl, SO2(C1-C6 alkyl), C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from -SO2(NH2); or

[0351] R C and R D Is, They form 4-6 member heterocyclies together with the attached nitrogen atoms;

[0352] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and

[0353] Here, the compound is not a compound selected from the group consisting of the following:

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364] Some embodiments provide a compound of formula (X) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound is not a compound selected from the group consisting of:

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375] Some embodiments provide a compound of formula (X) or a pharmaceutically acceptable salt thereof as described herein, wherein the compound is not a compound selected from the group consisting of:

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386] In some embodiments, the compounds described herein are not compounds selected from the group described above (i.e., "excluded compounds"). In some embodiments, the excluded compounds have a flat structure as described above. In some embodiments, the excluded compounds are specific stereoisomers, e.g., specific enantiomers or diastereomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, the excluded compounds are S isomers. In some embodiments, one or more of the excluded compounds are R isomers, and the remaining excluded compounds are S isomers. In some embodiments, the excluded compounds are R isomers. In some embodiments, one or more of the excluded compounds are S isomers, and the remaining excluded compounds are S isomers.

[0387] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0388] In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is is. In some embodiments, Is or am.

[0389] In some embodiments, each R 1 is a halogen selected independently. In some embodiments, each R 1 is independently selected from fluoro and chloro. In some embodiments, each R 1 is independently selected from fluoro and bromo. In some embodiments, each R 1 is a fluoro. In some embodiments, at least one R 1 silver It is a halogen that is independently selected. In some embodiments, at least one R 1is independently selected from fluoro and chloro. In some embodiments, at least one R 1 It is a fluoro.

[0390] In some embodiments, at least one R 1 It is cyano. In some embodiments, at least one R 1 is a hydroxyl. In some embodiments, at least one R 1 is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, at least one R 1 is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, at least one R 1 is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, at least one R 1 is hydroxymethyl. In some embodiments, at least one R 1 silver It is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 1 It is methyl. In some embodiments, at least one R 1 is a C3-C6 cycloalkyl. In some embodiments, at least one R 1 is cyclopropyl.

[0391] In some embodiments, m is 2; and one R 1 is a halogen; and other R 1 is a C1-C6 alkyl. In some embodiments, m is 2; and one R 1 silver It is fluoro; and other R 1 is methyl. In some embodiments, m is 2; and one R 1 is a halogen; and other R 1 is a C3-C6 cycloalkyl. In some embodiments, m is 2; and one R 1 silver It is a halogen; and other R 1is a cyclopropyl. In some embodiments, m is 2; and one R 1 silver It is fluoro; and other R 1 silver It is cyano. In some embodiments, m is 2; and one R 1 silver It is a halogen; and other R 1 is a halogen. In some embodiments, m is 2; and one R 1 is fluoro; and other R 1 It is a fluoro.

[0392] In some embodiments, R 2 is a hydroxyl. In some embodiments, R 2 is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R 2 hydroxyl It is a substituted C1-C6 alkyl. In some embodiments, R 2 is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R 2 is hydroxymethyl. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl. In some embodiments, R 2 is an unsubstituted C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0393] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 Is It is a C1-C3 haloalkyl. In some embodiments, R 2 is difluoromethyl. In some embodiments, R 2 is trifluoromethyl.

[0394] In some embodiments, R 2 is a halogen. In some embodiments, R 2 is a fluoro. In some embodiments, R2 is chloro.

[0395] In some embodiments, R 2 is a C3-C6 cycloalkyl optionally substituted with one or two fluoro groups. In some embodiments, R 2 is a C3-C6 cycloalkyl substituted with one or two fluoro groups. In some embodiments, R 2 is a C3-C6 cycloalkyl substituted with one fluoro group. In some embodiments, R 2 is a C3-C6 cycloalkyl substituted with two fluoro groups. In some embodiments, R 2 is a C3-C4 cycloalkyl substituted with one fluoro group. In some embodiments, R 2 is a C3-C4 cycloalkyl substituted with two fluoro groups. In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.

[0396] In some embodiments, R 3 silver It is a C1-C6 alkyl. In some embodiments, R 3 silver It is a C1-C3 alkyl. In some embodiments, R 3 silver It is methyl, ethyl, t-butyl, or isopropyl. In some embodiments, R 3 silver It is methyl, ethyl, or isopropyl. In some embodiments, R 3 silver It is methyl. In some embodiments, R 3 silver It is ethyl. In some embodiments, R 3 silver It is isopropyl.

[0397] In some embodiments, R 3 silver It is a C1-C6 haloalkyl. In some embodiments, R 3 silver It is a C1-C3 haloalkyl. In some embodiments, R 3 silver It is difluoromethyl. In some embodiments, R 3 It is trifluoromethyl.

[0398] In some embodiments, R 3 silver It is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl optionally substituted with one or two fluoro groups. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl substituted with one or two fluoro groups. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl substituted with one fluoro group. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl group substituted with one fluoro group at the position of the C3-C6 cycloalkyl group bonded to the methine of formula (I). In some embodiments, R 3 silver It is 2,2-difluorocyclopropyl or 3,3-difluorocyclopropyl. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl optionally substituted with one or two methyl groups. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl substituted with one or two methyl groups. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl substituted with one methyl group. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl in which one methyl group is substituted at the position of the C3-C6 cycloalkyl bonded to the methine of formula (I). In some embodiments, R3 silver It is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 silver It is a cyclopropyl. In some embodiments, R 3 silver It is cyclobutyl. In some embodiments, R 3 silver It is cyclopentyl. In some embodiments, R 3 silver It is cyclohexyl.

[0399] In some embodiments, ring A is a 6-10 aryl. In some embodiments, ring A is phenyl, naphthyl, or tetrahydronaphthyl. In some embodiments, ring A is phenyl.

[0400] In some embodiments, ring A is a C3-C8 cycloalkyl. In some embodiments, ring A is a C5-C6 cycloalkyl. In some embodiments, ring A is a cyclohexyl.

[0401] In some embodiments, ring A is a 5-10-membered heteroaryl. In some embodiments, ring A is a 9-10-membered heteroaryl. In some embodiments, ring A is a 9-membered heteroaryl. In some embodiments, ring A is a 9-membered heteroaryl, wherein the attachment point for the elemental nitrogen atom of formula (I) is on the 6-membered ring of ring A. In some embodiments, ring A is a 9-membered heteroaryl, wherein the attachment point for the elemental nitrogen atom of formula (I) is on the 5-membered ring of ring A.

[0402] In some embodiments, ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinyl, imidazo[1,2-a]pyridinyl, or imidazo[1,2-a]pyridinyl. In some embodiments, ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-6-yl, or imidazo[1,2-a]pyridinyl. In some embodiments, ring A is benzimidazolyl, indazolyl, indolyl, or imidazo[1,2-a]pyridinyl. In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, , or is. In some embodiments, ring A is and It is selected from the group consisting of, where "*" indicates the attachment point to the element nitrogen atom of chemical formula (I).

[0403] In some embodiments, ring A is a 5-6-membered heteroaryl. In some embodiments, ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isooxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl. In some embodiments, ring A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl. In some embodiments, ring A is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A is , , and It is selected from the group consisting of, where "*" indicates an attachment site to the element nitrogen atom of chemical formula (I). In some embodiments, ring A is pyrimidinyl. In some embodiments, ring A is 5-pyrimidinyl. In some embodiments, ring A is , where "*" indicates the attachment site to the element nitrogen atom of chemical formula (I). In some embodiments, ring A is a 4-10-membered heterocyclile. In some embodiments, ring A is a 6-9-membered heterocyclile. In some embodiments, ring A is piperidinyl, isoindolinone, or tetrahydro-2H-thiopyranyl-1,1-dioxide.

[0404] In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, , , , , , or is. In some embodiments, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, , , am.

[0405] In some embodiments, ring A is 3-piperidinyl, , , , and It is selected from a group consisting of.

[0406] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0407] In some embodiments, one R 4 is a C1-C6 alkyl. In some embodiments, one R 4 is an unsubstituted C1-C6 alkyl. In some embodiments, one R 4is a C1-C4 alkyl. In some embodiments, one R 4 is t-butyl. In some embodiments, one R 4 is methyl.

[0408] In some embodiments, one R 4 is a C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is a C1-C6 alkoxy substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl. In some embodiments, one R 4 is a C1-C6 alkoxy substituted with one or two substituents independently selected from hydroxyl and cyclopropyl. In some embodiments, one R 4 is a hydroxyl-substituted C1-C6 alkoxy. In some embodiments, one R 4 is a C1-C6 alkoxy substituted with a C3-C6 cycloalkyl. In some embodiments, one R 4 is a C1-C6 alkoxy substituted with cyclopropyl. In some embodiments, one R 4 is a C1-C6 alkoxy. In some embodiments, one R 4 is a C1-C3 alkoxy. In some embodiments, one R 4 is methoxy.

[0409] In some embodiments, one R 4 is a C1-C6 haloalkyl. In some embodiments, one R 4 is a C1-C3 haloalkyl. In some embodiments, one R 4 is difluoromethyl. In some embodiments, one R 4 is trifluoromethyl.

[0410] In some embodiments, one R 4is a hydroxyl. In some embodiments, one R 4 is cyano. In some embodiments, one R 4 is -CO2H. In some embodiments, one R 4 is a halogen. In some embodiments, one R 4 is a fluoro. In some embodiments, one R 4 is chloro.

[0411] In some embodiments, one R 4 is a C1-C6 alkyl optionally substituted with 1-2 hydroxyl groups. In some embodiments, one R 4 is a C1-C6 alkyl substituted with 1-2 hydroxyl groups. In some embodiments, one R 4 is a C1-C6 alkyl substituted with one hydroxyl. In some embodiments, one R 4 is a C1-C6 alkyl substituted with two hydroxyl groups. In some embodiments, one R 4 is a C1-C3 alkyl substituted with two hydroxyl groups. In some embodiments, one R 4 is -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, one R 4 is -NR A R B It is a C1-C6 alkyl substituted with . In some embodiments, one R 4 is -NR A R B It is methyl or ethyl substituted with . In some embodiments, one R 4 is an unsubstituted C1-C6 alkyl. In some embodiments, one R 4 is methyl.

[0412] In some embodiments, one R 4 is -NR A R B am.

[0413] In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one is hydroxyl or -C(=O)NR B2 R C2 as It is an optionally substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is hydroxyl or is a C1-C6 alkyl optionally substituted with -C(=O)NH2. In some embodiments, R A and R B One of them is It is hydrogen and R A and R B The other one among them 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 The other one among them is -C(=O)OCH3. In some implementations, R A and R B One of them is hydrogen and R A and R B Another one is a 4-6-membered heterocyclile (e.g., oxetanyl). 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-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one among them is It is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. 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 optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R BAnother one is a hydroxyl-substituted propyl (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 Another one is hydroxyl-substituted butyl (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 among them is It is a C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is methyl. In some embodiments, R A and R B Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B Is Each is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is C1-C3 alkyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is It is methyl and R A and R BThe other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Is Each is a C1-C6 alkyl. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B are methyl respectively.

[0414] In some embodiments, R B2 and R C2 Is Both are hydrogen. In some embodiments, R B2 and R C2 One of them is hydrogen and R B2 and R C2 The other one is a C1-C6 alkyl. 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 Is Both are methyl.

[0415] In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one among them is It is a C1-C6 haloalkyl. In some embodiments, R A and R B One of them is hydrogen and RA and R B The other one among them is It is a C1-C3 haloalkyl. In some embodiments, R A and R B are each a C1-C6 haloalkyl. In some embodiments, R A and R B Is They are each C1-C3 haloalkyls.

[0416] In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl.

[0417] In some embodiments, one R 4 is -C(=O)NR C R D am.

[0418] In some embodiments, R C and R D are each hydrogen. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C6 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C3 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D are each C1-C6 alkyls. In some embodiments, R C and R D are each C1-C3 alkyls. In some embodiments, RC and R D are each methyl. In some embodiments, R C and R D One of them is C1-C6 alkyl and R C and R D Another one is a C1-C3 alkyl.

[0419] In some embodiments, R C and R D One of them is It is hydrogen and R C and R D Another one is a C1-C6 haloalkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D Another one is a C1-C3 haloalkyl. In some embodiments, R C and R D are each a C1-C6 haloalkyl. In some embodiments, R C and R D One of them is C1-C6 alkyl and R C and R D Another one is a C1-C6 haloalkyl.

[0420] In some embodiments, R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, forms a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl. In some embodiments, R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1, -SO2(C1-C6 alkyl), -CO2H, forms a 4-10-membered heterocyclile substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl.

[0421] In some embodiments, R B1 and R C1 Each is hydrogen. In some embodiments, R B1 and R C1 One of them is hydrogen and R B1 and R C1 The other one is a C1-C6 alkyl. In some embodiments, R B1 and R C1 One of them is It is hydrogen and R B1 and R C1 The other one is methyl. In some embodiments, R B1 and R C1 is a C1-C6 alkyl that is independently selected. In some embodiments, R B1 and R C1 Each is methyl.

[0422] In some embodiments, R C and R D They form a 4-6 member heterocyclile together with the nitrogen atoms to which they are attached. In some embodiments, R C and R D They form azetidine or piperazine together with the nitrogen atoms to which they are attached.

[0423] In some embodiments, one R 4 Is -SO2(NR E R F ) is. In some embodiments, R E and R F Is Each is hydrogen. In some embodiments, R E and R F One of them is hydrogen and R E and R FThe other one among them is It is a C1-C6 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C3 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is methyl. In some embodiments, R E and R F Is Each is a C1-C6 alkyl. In some embodiments, R E and R F Is Each is a C1-C3 alkyl. In some embodiments, R E and R F Is Each is methyl.

[0424] In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C6 haloalkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C3 haloalkyl. In some embodiments, R E and R F are each a C1-C6 haloalkyl. In some embodiments, R E and R F One of them is C1-C6 It is alkyl and R E and R F The other one is C1-C6 It is a haloalkyl.

[0425] In some embodiments, one R 4is -SO2(C1-C6 alkyl). In some embodiments, one R 4 is -SO2(C1-C3 alkyl). In some embodiments, one R 4 is -SO2Et. In some implementations, one R 4 is -SO2Me.

[0426] In some embodiments, one R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, one R 4 is -S(=O)(=NH)(C1-C3 alkyl). In some embodiments, one R 4 is -S(=O)(=NH)Me.

[0427] In some embodiments, one R 4 is -C(=O)(C1-C6 alkyl). In some embodiments, one R 4 is -C(=O)(C1-C3 alkyl). In some embodiments, one R 4 is -C(=O)Me.

[0428] In some embodiments, one R 4 is -CO2(C1-C6 alkyl). In some embodiments, one R 4 is -CO2(C1-C3 alkyl). In some embodiments, one R 4 is -CO2Me.

[0429] In some embodiments, one R 4 is a 5-6-membered heteroaryl optionally substituted with a C1-C6 alkyl group. In some embodiments, one R 4 is a 5-6-membered heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, one R 4 is a 5-6-membered heteroaryl. In some embodiments, one R 4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isooxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, one R 4 is a methyl-substituted tetrazolyl. In some embodiments, one R 4 is pyrazolil. In some embodiments, one R 4 is an unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolil.

[0430] In some embodiments, one R 4 is one or two independently selected Rs G It is a 3-9 binary heterocyclile arbitrarily substituted with . In some embodiments, one R 4 is one or two independently selected Rs G It is a ternary heterocyclile arbitrarily substituted with . In some embodiments, one R 4 is one or two independently selected Rs G It is a quaternary heterocyclile arbitrarily substituted with . In some embodiments, one R 4 is one or two independently selected Rs G It is a 5-membered heterocyclile arbitrarily substituted with . In some embodiments, one R 4 is one or two independently selected Rs G It is a 7-9 member heterocyclile arbitrarily substituted with . In some embodiments, R 4 Heterocycliles are spirocycles. In some embodiments, one R 4 is one or two independently selected Rs G It is a 3-6 binary heterocyclile arbitrarily substituted with . In some embodiments, one R4 is one or two independently selected Rs G It is a 3-6-membered heterocyclile substituted with . In some embodiments, one R 4 is 1 R G It is a 3-6-membered heterocyclile substituted with . In some embodiments, one R 4 is 2 independently selected R G It is a 3-6-membered heterocyclile substituted with . In some embodiments, one R 4 is an unsubstituted 3-6 member heterocyclile.

[0431] In some embodiments, one R 4 is one or two independently selected Rs G It is a 3-6-membered cycloalkyl optionally substituted with R. In some embodiments, one R 4 Is One or two independently selected Rs G It is a 3-6-membered cycloalkyl substituted with . In some embodiments, one R 4 is 1 R G It is a 3-6-membered cycloalkyl substituted with . In some embodiments, one R 4 is 2 independently selected R G It is a 3-6-membered cycloalkyl substituted with . In some embodiments, one R 4 is an unsubstituted 3-6 member cycloalkyl.

[0432] In some embodiments, one or two independently selected Rs G is 1 R G is. In some embodiments, one or two independently selected Rs G is 2 independently selected R G is. In some embodiments, 2 R G When are present, they are bonded to the same atom as long as the valence allows. In some embodiments, two R GWhen are present, they bond to adjacent atoms to the extent that their valence allows. In some embodiments, two R G go When they exist, 2 Rs G is different. In some embodiments, 2 R G go When they exist, 2 Rs G is identical. In some embodiments, one R G is a fluoro. In some embodiments, one R G is cyano. In some embodiments, one R G is a hydroxyl. In some embodiments, one R G is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, one R G Is It is 2-hydroxy-2-propyl. In some embodiments, one R G is a C1-C6 alkyl. In some embodiments, one R G is a C1-C3 alkyl. In some embodiments, one R G is methyl. In some embodiments, one R G is ethyl.

[0433] In some embodiments, one R G is a C1-C6 alkoxy. In some embodiments, one R G is a C1-C3 alkoxy. In some embodiments, one R G is methoxy.

[0434] In some embodiments, one R G is -NR A1 R B1 is. In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 One of them is hydrogen. R A1 and R B1 The other one among them is It is a C1-C6 alkyl. In some embodiments, R A1 and R B1 One of them is hydrogen. R A1 and R B1 The other one among them is C1-C3 It is an alkyl. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one among them is It is methyl. In some embodiments, R A1 and R B1 are each C1-C6 alkyls. In some embodiments, R A1 and R B1 Each is methyl.

[0435] In some embodiments, R A1 and R B1 One of them is hydrogen. R A1 and R B1 The other one is C1-C6 It is a haloalkyl. In some embodiments, R A1 and R B1 One of them is hydrogen. R A1 and R B1 The other one is C1-C3 It is a haloalkyl. In some embodiments, R A1 and R B1 are each a C1-C6 haloalkyl. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl and RA1 and R B1 The other one is C1-C6 It is a haloalkyl.

[0436] In some embodiments, one R G Is =NR A2 is. In some embodiments, one R G Is =NH. In some implementations, R A2 Is It is hydrogen. In some embodiments, R A2 Is It is a C1-C6 alkyl. In some embodiments, R A2 Is It is methyl.

[0437] In some embodiments, one R G Is -C(=O)NR C1 R D1 is. In some embodiments, one R G Is -CO2NH2. In some embodiments, one R G Is -CO2NHCH3. In some implementations, R C1 and R D1 Each is hydrogen. 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-C6 alkyl. In some embodiments, R C1 and R D1 middle One is hydrogen and R C1 and R D1 The other one is a C1-C3 alkyl. In some embodiments, R C1 and R D1 middle One is hydrogen and R C1 and R D1 The other one is methyl. In some embodiments, R C1and R D1 are each C1-C6 alkyls. In some embodiments, R C1 and R D1 are each C1-C3 alkyls. In some embodiments, R C1 and R D1 Each is methyl.

[0438] In some embodiments, R C1 and R D1 middle One is hydrogen and R C1 and R D1 Another one is a C1-C6 haloalkyl. In some embodiments, R C1 and R D1 middle One is hydrogen and R C1 and R D1 Another one is a C1-C3 haloalkyl. In some embodiments, R C1 and R D1 are each a C1-C6 haloalkyl. In some embodiments, R C1 and R D1 middle One is a C1-C6 alkyl and R C1 and R D1 Another one is a C1-C6 haloalkyl.

[0439] In some embodiments, one R G Is It is -CO2(C1-C6 alkyl). In some embodiments, one R G Is It is -CO2CH3. In some implementations, one R G Is It is a C1-C6 haloalkyl. In some embodiments, one R G Is It is trifluoromethyl. In some embodiments, one R G Is It is difluoromethyl. In some embodiments, one R G Is It is a C3-C6 cycloalkyl. In some embodiments, one RG Is It is a cyclopropyl. In some embodiments, one R G Is It is CO2H.

[0440] In some embodiments, one R G Is It is a C1-C6 haloalkoxy. In some embodiments, one R G Is It is a C1-C3 haloalkoxy. In some embodiments, one R G Is It is difluoromethoxy. In some embodiments, one R G Is It is trifluoromethoxy.

[0441] In some embodiments, one R G Is It is -SO2(C1-C6 alkyl). In some embodiments, one R G Is It is SO2CH3.

[0442] In some embodiments, R 4 The 3-9-membered heterocyclile is a 3-6-membered heterocyclile. In some embodiments, R 4 The 3-6-membered heterocyclile is a 5-6-membered heterocyclile. In some embodiments, R 4 The 3-6-membered heterocyclile is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, R 4 The 3-6-membered heterocyclile is 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranyl. In some embodiments, R 4 3-9 won heterocyclil is , , , , , , , , , , , and It is selected from a group consisting of. In some embodiments, R 4 3-9 synergistic heterocyclil (e.g., R 4 3-6 prismatic heterocyclile) , wherein Q is a C1-C3 alkylene in which one or more carbons are optionally replaced with -C(=O)-, NH, O, or S. In some embodiments, Q is a C1-C3 alkylene in which one or more carbons are optionally replaced with -C(=O)- or NH. In some embodiments, Q is a C1-C2 alkylene in which one or more carbons are optionally replaced with -C(=O)- or NH. In some embodiments, R 4 3-9 won heterocyclil is , , It is selected from a group consisting of.

[0443] In some embodiments, one R 4 is an unsubstituted 3-6-membered heterocyclile. In some embodiments, R 4 The 3-6-membered heterocyclile is a 5-6-membered heterocyclile. In some embodiments, R 4 Is It is azetidinyl, morpholinyl, or tetrahydropyranil. In some embodiments, R 4 Is , , and It is selected from a group consisting of.

[0444] In some embodiments, Is and, where: X is N and CR 4A2 Selected from; R 4A1 and R 4A2 is hydrogen, -NR A R B C1-C3 alkyl, methoxy, C1-C3 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with A R B, -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), and one or two independently selected R G A 3-6 binary heterocyclile arbitrarily substituted with , and One or two independently selected Rs G It is independently selected from 3-6 member cycloalkyls optionally substituted with . In some embodiments, X is N. In some embodiments, X is CR 4A2 is. In some embodiments, R 4A1 and, if present, R 4A2 is independently selected from hydrogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2Me, and 1-2 independently selected azetidinyls optionally substituted with fluoro, hydroxyl, or methyl. In some embodiments, R C and R D They form a 4-6 member heterocyclile together with the nitrogen atom to which they are attached. In some embodiments, X is N and R 4A1 is one or two independently selected Rs G It is a 3-6 binary heterocyclile arbitrarily substituted with . In some embodiments, R C and R D They form azetidine or piperazine together with the nitrogen atoms to which they are attached.

[0445] In some embodiments, X is N; and R 4A1 It is selected from amino or 1-2 independently selected fluoro, hydroxyl, or methyl optionally substituted azetidinyl.

[0446] In some embodiments, Is and, here: R 4BIs -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 It is selected from fluoro, hydroxyl, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, R G1 silver It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0447] In some embodiments, Is and, here: R 4B is -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 fluoro, Selected from 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 It is selected from fluoro, hydroxyl, methoxy, methyl, ethyl, hydroxymethyl, 2-hydroxy-2-propyl, -C(O)Me, -C(O)NH2, =NH, difluoromethoxy, -S(O)2Me, -CO2H, C1-C6 haloalkyl, and C1-C6 alkyl. In some embodiments, R G1 It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0448] In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one among them is It is a C1-C6 alkyl. 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 optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B middle Another is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B One of them is hydrogen and R A and R BAnother one is a hydroxyl-substituted propyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one among them is It is a C1-C3 alkyl. 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 Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B Is Each is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is C1-C3 alkyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is It is methyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R BThe other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Is Each is a C1-C6 alkyl. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B Is Each is methyl.

[0449] In some embodiments, R 4B is an amino or has one nitrogen atom and 1-2 independently selected R G It is a 4-6 binary heterocyclile arbitrarily substituted with; where R G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0450] In some embodiments, R 4B Is and; where ring B optionally contains 1-2 =O groups, and each fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, and 1-2 R independently selected from C1-C6 alkyls G It is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl arbitrarily substituted with . In some embodiments, R 4B Is and; where ring B is fluoro, hydroxyl, trifluoromethyl, amino, cyclopropyl, -CO2CH3, respectively and 1-2 R independently selected from C1-C6 alkyls G as It is optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R 4B Is and; where ring B is each 1-2 R groups independently selected from fluoro, hydroxyl, trifluoromethyl, and C1-C6 alkyl. G It is arbitrarily substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R 4B Is and; where ring B is each 1-2 R groups independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G It is azetidinyl, pyrrolidinyl, or piperidinyl optionally substituted with. In some embodiments, ring B is azetidinyl.

[0451] In some embodiments, ring B is not substituted.

[0452] In some embodiments, ring B is 1 R G It is replaced with. In some implementations, R G is a fluoro. In some embodiments, R G Is It is cyano. In some embodiments, R G is an amino. In some embodiments, R G is a hydroxyl. In some embodiments, R G is a C1-C3 alkyl. In some embodiments, R G is methyl. In some embodiments, R G is ethyl. In some embodiments, R G is -CO2CH3. In some implementations, R G is methoxy. In some embodiments, R G is methoxy.

[0453] In some embodiments, ring B is 2 R G It is replaced with. In some embodiments, each R G is a fluoro. In some embodiments, each R Gis a C1-C3 alkyl. In some embodiments, each R G is methyl. In some embodiments, one R G is a hydroxyl and the other R G is methyl. In some embodiments, one R G is a hydroxyl and the other R G is ethyl. In some embodiments, one R G is an amino and another R G is methyl. In some embodiments, one R G is a hydroxyl and the other R G is a cycloprofile. In some embodiments, one R G is fluoro and other R G1 is methyl. In some embodiments, one R G is a hydroxyl and the other R G is a fluoro. In some embodiments, one R G is a hydroxyl and the other R G is trifluoromethyl. In some embodiments, each R G is for the nitrogen bonded to ring A blue In ring It is combined at position B.

[0454] In some embodiments, Is and, where one or two independently selected R G It is attached to the 3-position of azetidine. In some embodiments, Is , , , , and It is selected from a group consisting of. In some embodiments, Is , , , , , , , , and It is selected from a group consisting of. In some embodiments, Is , , , , , , , , , , , , , , and It is selected from a group consisting of.

[0455] In some implementations, Z is O.

[0456] In some embodiments, Z is NR x am.

[0457] In some embodiments, R x Is It is hydrogen.

[0458] In some embodiments, R x Is It is a C1-C6 alkyl. In some embodiments, R x Is It is a C1-C3 alkyl. In some embodiments, R x Is It is methyl. In some embodiments, R x Is It is ethyl. In some embodiments, R x Is It is an n-profile. In some implementations, R x Is It is isopropyl.

[0459] In some embodiments, R x Is It is a C3-C6 cycloalkyl. In some embodiments, R x Is It is a C3-C4 cycloalkyl. In some embodiments, R x Is It is a cyclopropyl. In some embodiments, Rx Is It is cyclobutyl.

[0460] In some embodiments, each R 1 is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3 is a C1-C6 alkyl. In some embodiments, each R 1 is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0461] In some embodiments, each R 1 is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3 is a C1-C6 haloalkyl. In some embodiments, each R 1 is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is trifluoromethyl.

[0462] In some embodiments, m is 2 and one R 4 is a halogen, and other R 4 is -SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and other R 4 is -SO2CH3.

[0463] In some embodiments, m is 2 and one R 4 is a C1-C6 alkoxy, and other R 4 is -C(=O)NR C R D am.

[0464] In some embodiments, m is 2 and one R 4 is methoxy, and other R 4is -C(O)NHCH3. In some embodiments, ring A is phenyl or 5-6-membered heteroaryl;

[0465] Each R 4 is 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 Independently selected from the group consisting of unsubstituted 3-6 member heterocyclils; and

[0466] n is 1 or 2.

[0467] In some embodiments, each R 1 is fluoro, and;

[0468] m is 1 or 2 and;

[0469] R 2 is a C1-C6 alkyl;

[0470] R 3 is a C1-C6 alkyl;

[0471] Ring A is a phenyl or 5-6-membered heteroaryl;

[0472] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0473] n is 1 or 2.

[0474] In some embodiments, each R 1 is fluoro, and;

[0475] m is 1 or 2 and;

[0476] R 2 is a C1-C6 alkyl;

[0477] R 3 is a C1-C6 alkyl;

[0478] Ring A is a phenyl or 5-6-membered heteroaryl;

[0479] Each R 4 is a 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 one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with; and

[0480] n is 1 or 2.

[0481] In some embodiments, each R 1 is fluoro, cyano, or methyl;

[0482] m is 1 or 2 and;

[0483] R 2 is a C1-C3 alkyl;

[0484] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0485] Ring A is a phenyl or 5-6-membered heteroaryl;

[0486] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0487] n is 1 or 2.

[0488] In some embodiments, each R 1 is fluoro, cyano, or methyl;

[0489] m is 1 or 2 and;

[0490] R 2 is a C1-C3 alkyl;

[0491] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0492] Ring A is a phenyl or 5-6-membered heteroaryl;

[0493] Each R 4 -NHR B , and 1-2 R G Composed of 4-6 binary heterocyclies arbitrarily substituted with Selected independently from the military; and

[0494] n is 1 or 2.

[0495] In some embodiments, Z is O; and each R 1 silver It is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3 is a C1-C6 alkyl. In some embodiments, Z is O; and each R 1 silver It is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0496] In some embodiments, Z is O; and each R 1 silver It is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3is a C1-C6 haloalkyl. In some embodiments, Z is O; and each R 1 silver It is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is trifluoromethyl.

[0497] In some embodiments, Z is O; m is 2, and one R 4 is a halogen, and other R 4 Is It is -SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and other R 4 is -SO2CH3.

[0498] In some embodiments, Z is O; m is 2, and one R 4 is a C1-C6 alkoxy, and other R 4 is -C(=O)NR C R D am.

[0499] In some embodiments, Z is O; m is 2, and one R 4 is methoxy, and other R 4 is -C(O)NHCH3. In some embodiments, ring A is phenyl or 5-6-membered heteroaryl;

[0500] Each R 4 is 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 Independently selected from the group consisting of unsubstituted 3-6 member heterocyclils; and

[0501] n is 1 or 2.

[0502] In some embodiments, Z is O;

[0503] Each R 1 silver It is fluoro;

[0504] m is 1 or 2 and;

[0505] R 2 is a C1-C6 alkyl;

[0506] R 3 is a C1-C6 alkyl;

[0507] Ring A is a phenyl or 5-6-membered heteroaryl;

[0508] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0509] n is 1 or 2.

[0510] In some embodiments, Z is O;

[0511] Each R 1 silver It is fluoro;

[0512] m is 1 or 2 and;

[0513] R 2 is a C1-C6 alkyl;

[0514] R 3 is a C1-C6 alkyl;

[0515] Ring A is a phenyl or 5-6-membered heteroaryl;

[0516] Each R 4is a 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 one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with; and

[0517] n is 1 or 2.

[0518] In some embodiments, Z is O;

[0519] Each R 1 silver It is fluoro, cyano, or methyl;

[0520] m is 1 or 2 and;

[0521] R 2 is a C1-C3 alkyl;

[0522] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0523] Ring A is a phenyl or 5-6-membered heteroaryl;

[0524] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0525] n is 1 or 2.

[0526] In some embodiments, Z is O;

[0527] Each R 1 silver It is fluoro, cyano, or methyl;

[0528] m is 1 or 2 and;

[0529] R 2 is a C1-C3 alkyl;

[0530] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0531] Ring A is a phenyl or 5-6-membered heteroaryl;

[0532] Each R 4 Is -NHR B , and 1-2 R G Composed of 4-6 binary heterocyclies arbitrarily substituted with Selected independently from the military; and

[0533] n is 1 or 2.

[0534] In some embodiments, Z is NR x and; each R 1 silver It is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3 is a C1-C6 alkyl. In some embodiments, Z is NR x and; each R 1 silver It is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is selected from methyl, ethyl, isopropyl, or tert-butyl.

[0535] In some embodiments, Z is NR x and; each R 1 silver It is fluoro; m is 1 or 2; and R 2 is a C1-C6 alkyl; and R 3 is a C1-C6 haloalkyl. In some embodiments, Z is O; and each R 1 silver It is fluoro; m is 1 or 2; and R 2 Is It is methyl; and R 3 It is trifluoromethyl.

[0536] In some embodiments, Z is NR x and; m is 2, and one R 4 is a halogen, and other R 4 Is It is -SO2(C1-C6 alkyl). In some embodiments, m is 2 and one R 4 is chloro, and other R 4 is -SO2CH3.

[0537] In some embodiments, Z is NR x and; m is 2, and one R 4 is a C1-C6 alkoxy, and other R 4 Is -C(=O)NR C R D am.

[0538] In some embodiments, Z is NR x and; m is 2, and one R 4 is methoxy, and other R 4 is -C(O)NHCH3. In some embodiments, ring A is phenyl or 5-6-membered heteroaryl;

[0539] Each R 4 is 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 Independently selected from the group consisting of unsubstituted 3-6 member heterocyclils; and

[0540] n is 1 or 2.

[0541] In some embodiments, Z is NR x And;

[0542] Each R 1 silver It is fluoro;

[0543] m is 1 or 2 and;

[0544] R 2 is a C1-C6 alkyl;

[0545] R 3 is a C1-C6 alkyl;

[0546] Ring A is a phenyl or 5-6-membered heteroaryl;

[0547] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0548] n is 1 or 2.

[0549] In some embodiments, Z is NR x And;

[0550] Each R 1 silver It is fluoro;

[0551] m is 1 or 2 and;

[0552] R 2 is a C1-C6 alkyl;

[0553] R 3 is a C1-C6 alkyl;

[0554] Ring A is a phenyl or 5-6-membered heteroaryl;

[0555] Each R 4is a 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 one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with; and

[0556] n is 1 or 2.

[0557] In some embodiments, Z is NR x And;

[0558] Each R 1 silver It is fluoro, cyano, or methyl;

[0559] m is 1 or 2 and;

[0560] R 2 is a C1-C3 alkyl;

[0561] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0562] Ring A is a phenyl or 5-6-membered heteroaryl;

[0563] Each R 4 is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxyl, cyano, -NH2, -C(=O)NH2, -C(=O)NHMe, -SO2NH2, -SO2NHMe, -SO2Me, -S(=O)(=NH)Me, -C(=O)Me, 5-6-membered heteroaryls, and unsubstituted 3-6-membered heterocyclils; and

[0564] n is 1 or 2.

[0565] In some embodiments, Z is NR x And;

[0566] Each R 1 silver It is fluoro, cyano, or methyl;

[0567] m is 1 or 2 and;

[0568] R 2 is a C1-C3 alkyl;

[0569] R 3 is a C1-C3 alkyl or C1-C3 haloalkyl;

[0570] Ring A is a phenyl or 5-6-membered heteroaryl;

[0571] Each R 4 -NHR B , and 1-2 R G Composed of 4-6 binary heterocyclies arbitrarily substituted with Selected independently from the military; and

[0572] n is 1 or 2.

[0573] In some embodiments, the compound of formula (I) is formula (IA):

[0574] (IA)

[0575] or a pharmaceutically acceptable salt thereof, wherein:

[0576] R 1A Is It is a halogen;

[0577] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0578] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0579] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0580] Ring A1 is a 6-membered heteroaryl;

[0581] R 4 Is -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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 member heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G A 3-6 binary heterocyclile arbitrarily substituted with , and one or two independently selected R G Arbitrarily replaced with Independently selected from the group consisting of 3-6 member cycloalkyls;

[0582] Here, R 4 Is For the N atom of the element moiety blue It is coupled to the position of ring A1;

[0583] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently It is hydrogen, a 4-6-membered heterocyclile, a C1-C6 haloalkyl, a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or a C1-C6 alkyl optionally substituted with one or two substituents independently selected from hydroxyl, a 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0584] RC and R D Is, They form 4-6 member heterocyclies together with the attached nitrogen atoms;

[0585] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0586] In some embodiments, ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A1 is pyrimidinyl. In some embodiments, ring A1 is pyridyl. In some embodiments, ring A1 is pyrazolyl.

[0587] In some embodiments, ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A1 is 5-pyrimidinyl. In some embodiments, ring A1 is 3-pyridyl. In some embodiments, ring A1 is 4-pyrazolyl.

[0588] In some embodiments of the chemical formula (IA), Is and, here: R 4B is -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 silver It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0589] In some embodiments of the chemical formula (IA), R A and R B Each is hydrogen.

[0590] In some embodiments of the chemical formula (IA), R A and R B are each 4-6-membered heterocycliles. In some embodiments of the chemical 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 heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R B Another one is a quaternary heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a pentoecious heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is 1,1-dioxidotetrahydrothiophene-3-yl. In some embodiments of the chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R B Another one is a 6-membered heterocyclile.

[0591] In some embodiments of the chemical formula (IA), R A and R B are each a C1-C6 haloalkyl. In some embodiments of the formula (IA), R A and R B One of them is It is hydrogen and R A and R B The other one among them is It is a C1-C6 haloalkyl. In some embodiments of the chemical formula (IA), RA and R B One of them is It is hydrogen and R A and R B The other one among them is It is a C1-C3 haloalkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl.

[0592] In some embodiments of the chemical formula (IA), R A and R B is each a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one among them is It is a 3-6-membered cycloalkyl substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen. R A and R B The other one is unsubstituted It is a 3-6-membered cycloalkyl. In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a ternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments of chemical formula (IA), R A and RB middle One is hydrogen and R A and R B The other one among them is It is a quaternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments of chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is cis- or trans-3-hydroxycyclobutyl. In some embodiments of chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one is a 5-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hexavalent cycloalkyl optionally substituted with a hydroxyl. In some embodiments of chemical formula (IA), R A and R B middle One is a C1-C6 alkyl and R A and R B The other one among them is It is a 3-6 member cycloalkyl substituted with hydroxyl.

[0593] In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2). In some embodiments of formula (IA), R A and R B middle One is hydrogen and R A and R B The other one is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C6 alkyl. In some embodiments of chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a propyl substituted with a hydroxyl group (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl. In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is methyl.

[0594] In some embodiments of the chemical formula (IA), R A and R B is each a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B is each a hydroxyl-substituted C1-C6 alkyl. In some embodiments of the formula (IA), R A and R B middle One is a C1-C3 alkyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B middle One is methyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B middle One is methyl and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments of the formula (IA), R A and R B are each C1-C6 alkyls. In some embodiments of chemical formula (IA), R A and R B are each C1-C3 alkyls. In some embodiments of the formula (IA), R A and R B are methyl respectively.

[0595] In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one is substituted with a 3-4 cycloalkyl group It is a C1-C3 alkyl. In some embodiments of the chemical formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with a 3-quadruple cycloalkyl and a hydroxyl. In some embodiments of the formula (IA), R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of the formula (IA), R A and R B middle One It is hydrogen. R A and R B The other one is substituted with cyclopropyl and hydroxyl. Ethyl, for example, 1-cyclopropyl-2-hydroxyethyl. In some embodiments of chemical formula (IA), R A and R B middle One is a C1-C6 alkyl and R A and R B The other one is substituted with a 3-6 member cycloalkyl. It is a C1-C6 alkyl. In some embodiments of the chemical formula (IA), R A and R B Is Both are C1-C6 alkyls substituted with 3-6 member cycloalkyls.

[0596] In some embodiments of the chemical formula (IA), R A and R B middle One It is hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B middle One It is hydrogen and R A and R BThe other one is a C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of chemical formula (IA), R A and R B middle One It is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propane-2-yl. In some embodiments of formula (IA), R A and R B middle One It is a C1-C6 alkyl R A and R B The other one is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B Is Both are C1-C6 alkyls substituted with -SO2(C1-C6 alkyl).

[0597] In some embodiments of the chemical formula (IA), R A and R B middle One It is hydrogen. R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of chemical formula (IA), R A and R B middle One It is hydrogen and R A and R BThe other one is a C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropane-2-yl. In some embodiments of chemical formula (IA), R A and R B middle One It is a C1-C6 alkyl hydrogen R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of chemical formula (IA), R A and R B Is Both are C1-C6 alkyls substituted with -SO2(NH2).

[0598] In some embodiments of the chemical formula (IA), R 4B Is It includes 1 nitrogen ring member and 1-2 independently selected R G It is a 4-6 binary heterocyclile arbitrarily substituted with; where R G Is It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0599] In some embodiments of the chemical formula (IA), R 4B Is and; where ring B is each 1-2 R groups independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G It is optionally substituted with azetidinyl, pyrrolidinyl, or piperidinyl. In some embodiments of the chemical formula (IA), ring B is azetidinyl.

[0600] In some embodiments of the chemical formula (IA), ring B is unsubstituted.

[0601] In some embodiments of the chemical formula (IA), ring B has one R G It is substituted with. In some embodiments of the chemical formula (IA), R Gis a fluoro. In some embodiments of the chemical formula (IA), R G is cyano. In some embodiments of the chemical formula (IA), R G is a hydroxyl. In some embodiments of the chemical formula (IA), R G is a C1-C3 alkyl. In some embodiments of the formula (IA), R G is methyl. In some embodiments of the chemical formula (IA), R G Is It is -CO2CH3.

[0602] In some embodiments of the chemical formula (IA), ring B consists of two independently selected Rs G It is substituted with. In some embodiments of the chemical formula (IA), each R G is a fluoro. In some embodiments of the chemical formula (IA), each R G is a C1-C3 alkyl. In some embodiments of the formula (IA), each R G is methyl. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other R G is a C1-C3 alkyl. In some embodiments of the formula (IA), one R G is a hydroxyl and the other R G is methyl. In some embodiments of the chemical formula (IA), one R G Is It is fluoro and other R G is a C1-C3 alkyl. In some embodiments of the formula (IA), one R G Is It is fluoro and other R G is methyl. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other R G is a fluoro. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other RG is trifluoromethyl.

[0603] In some embodiments of the chemical formula (IA), Is and, where one or two independently selected R G is located at the 3-position of azetidine. In some embodiments of the chemical formula (IA), Is , , , , , , , , and It is selected from the group consisting of. In some embodiments of the chemical formula (IA), Is , , , and It is selected from a group consisting of.

[0604] In some embodiments, the compound of formula (I) is formula (IB):

[0605] (IB)

[0606] or a pharmaceutically acceptable salt thereof, wherein:

[0607] R 1A Is It is a halogen;

[0608] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0609] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0610] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0611] R4 Is -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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 member heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G A 3-6 binary heterocyclile arbitrarily substituted with , and one or two independently selected R G Independently selected from the group consisting of 3-6 member cycloalkyls arbitrarily substituted with;

[0612] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently a 3-6 cycloalkyl optionally substituted with hydrogen, a 4-6 cyclic, a C1-C6 haloalkyl, or a hydroxyl, or a C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, a 3-6 cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0613] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0614] Each R G-NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0615] In some embodiments, R 1A and R 1B Is Each is fluoro;

[0616] In some embodiments, R 2 is a C1-C6 alkyl. In some embodiments, R 2 is a C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0617] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C3 haloalkyl. In some embodiments, R 2 is trifluoromethyl.

[0618] In some embodiments, R 3 silver It is a C1-C6 alkyl. In some embodiments, R 3 silver It is a C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 silver It is methyl. In some embodiments, R 3 silver It is ethyl. In some embodiments, R 3 silver It is isopropyl.

[0619] In some embodiments, R 3 silver It is a C1-C6 haloalkyl. In some embodiments, R 3silver It is a C1-C3 haloalkyl. In some embodiments, R 3 silver It is trifluoromethyl.

[0620] In some embodiments, R 3 silver It is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl optionally substituted with one or two fluoro groups. In some embodiments, R 3 silver It is a C3-C6 cycloalkyl substituted with one or two fluoro groups. In some embodiments, R 3 silver It is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 is cyclopropyl.

[0621] In some embodiments, R 4 Is -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R 4 Is -NR A R B It is a C1-C3 alkyl optionally substituted with . In some embodiments, R 4 Is -NR A R B It is a methyl arbitrarily substituted with . In some embodiments, R 4 is a C1-C4 alkyl. In some embodiments, R 4 Is It is methyl.

[0622] In some embodiments, R 4 Is It is a C1-C6 alkoxy. In some embodiments, R 4 is a C1-C3 alkoxy. In some embodiments, R 4 Is It is methoxy.

[0623] In some embodiments, R 4 Is It is a C1-C6 haloalkyl. In some embodiments, R 4 is a C1-C3 haloalkyl. In some embodiments, R 4 Is It is trifluoromethyl.

[0624] In some embodiments, R 4 Is It is a hydroxyl. In some embodiments, R 4 Is It is cyano. In some embodiments, R 4 Is It is -CO2H. In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one is a C1-C3 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted propyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is methyl. In some embodiments, R A and R B Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B Is Each is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B middle One C1-C3 alkyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is It is methyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B middle One is methyl and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Is Each is a C1-C6 alkyl. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B Is Each is methyl.

[0625] In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 haloalkyl. In some embodiments, R A and R B Is Each is a C1-C6 haloalkyl. In some embodiments, R A and R B middle One is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 haloalkyl. In some embodiments, R A and R B middle One is a C1-C6 alkyl and R A and R B The other one among them is It is a C1-C6 haloalkyl.

[0626] In some embodiments, R A and R B Is Each is a 4-6-membered heterocyclile. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a 4-6-membered heterocyclile. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a quaternary heterocyclile. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is 5 won It is a heterocyclile. In some embodiments of the chemical formula (IA), R A and R B middle One It is hydrogen. R A and R B The other one among them is It is 1,1-dioxidotetrahydrothiophene-3-yl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is 6 won It is a heterocyclile.

[0627] In some embodiments, R A and R B is each a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a 3-6-membered cycloalkyl substituted with a hydroxyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one is unsubstituted It is a 3-6 member cycloalkyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a ternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a quaternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is cis- or trans-3-hydroxycyclobutyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a 5-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a hexavalent cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B middle One C1-C6 alkyl and R A and R B The other one among them is It is a 3-6 member cycloalkyl substituted with hydroxyl.

[0628] In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2).

[0629] In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with a 3-6-membered cycloalkyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with a 3-4 cycloalkyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with a 3-quadruple cycloalkyl and a hydroxyl. In some embodiments, R A and R B middle One It is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is an ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments, R A and R B middle One C1-C6 alkyl and R A and R B The other one among them is It is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments, R A and R B Is Both are C1-C6 alkyls substituted with 3-6 member cycloalkyls.

[0630] In some embodiments, R A and R B middle One is hydrogen and R A and R B Another one is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propane-2-yl. In some embodiments, R A and R B middle One C1-C6 alkyl and R A and RB The other one among them is It is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B Is Both of them It is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, R A and R B middle One is hydrogen and R A and R B The other one among them is C1-C3 alkyl substituted with -SO2(NH2), For example, it is 1-sulfamoylpropane-2-yl. In some embodiments, R A and R B middle One is a C1-C6 alkyl hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, R A and R B Is Both are C1-C6 alkyls substituted with -SO2(NH2).

[0631] In some embodiments, one R 4 is -C(=O)NR C R D is. In some embodiments, R C and R D Is Each is hydrogen. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C6 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C3 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D Is Each is a C1-C6 alkyl. In some embodiments, R C and R D Is Each is a C1-C3 alkyl. In some embodiments, R C and R D Is Each is methyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D Another one is a C1-C6 haloalkyl. In some embodiments, R C and R D Is Each is a C1-C6 haloalkyl. In some embodiments, R C and R D One of them is C1-C6 alkyl and R C and R D Another one is a C1-C6 haloalkyl. In some embodiments, R C and R D Is, They form a 4-6 member heterocyclile together with the attached nitrogen atom. In some embodiments, RC and R D Is, They form azetidine or piperazine together with the attached nitrogen atoms.

[0632] In some embodiments, one R 4 is -SO2(NR E R F ) is. In some embodiments, R E and R F Is Each is hydrogen. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C6 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is methyl. In some embodiments, R E and R F Is Each is a C1-C6 alkyl. In some embodiments, R E and R F Is Each is a C1-C3 alkyl. In some embodiments, R E and R F Is Each is methyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C6 haloalkyl. In some embodiments, R E and R F Is Each is a C1-C6 haloalkyl. In some embodiments, R E and R F One of them is C1-C6 It is alkyl and R E and R F The other one among them is C1-C6 It is a haloalkyl.

[0633] In some embodiments, R 4 is -SO2(C1-C6 alkyl). In some embodiments, R 4 is -SO2(C1-C3 alkyl). In some embodiments, R 4 is -SO2Me. In some implementations, R 4 is -SO2Et.

[0634] In some embodiments, R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 is -S(=O)(=NH)Me.

[0635] In some embodiments, R 4 is -C(=O)(C1-C6 alkyl). In some embodiments, R 4 is -C(=O)(C1-C3 alkyl). In some embodiments, R 4 is -C(=O)Me.

[0636] In some embodiments, R 4 is -CO2(C1-C6 alkyl). In some embodiments, R 4 is -CO2(C1-C3 alkyl). In some embodiments, R 4 is -CO2Me.

[0637] In some embodiments, one R 4 is a 5-6-membered heteroaryl optionally substituted with a C1-C6 alkyl group. In some embodiments, one R 4 is a 5-6-membered heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 4 is a 5-6-membered heteroaryl. In some embodiments, R 4is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isooxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R 4 is pyrazolil. In some embodiments, one R 4 is a methyl-substituted tetrazolyl. In some embodiments, one R 4 is pyrazolil. In some embodiments, one R 4 is an unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolil.

[0638] In some embodiments, R 4 is one or two independently selected Rs G It is a 3-6 binary heterocyclile arbitrarily substituted with . In some embodiments, R 4 is one or two independently selected Rs G It is a 3-6-membered heterocyclile substituted with . In some embodiments, R 4 is 1 R G It is a 3-6-membered heterocyclile substituted with . In some embodiments, R 4 is 2 independently selected R G It is a 3-6 member heterocyclile substituted with .

[0639] In some embodiments, R G is a fluoro. In some embodiments, R G is cyano. In some embodiments, R G is a hydroxyl. In some embodiments, R G is a C1-C6 alkyl. In some embodiments, R G is a C1-C3 alkyl. In some embodiments, R G is methyl.

[0640] In some embodiments, R G is a C1-C6 alkoxy. In some embodiments, R G is a C1-C3 alkoxy. In some embodiments, R G is methoxy.

[0641] In some embodiments, one R G is -NR A1 R B1 is. In some embodiments, R A1 and R B1 Each is hydrogen. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one among them is It is a C1-C6 alkyl. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one among them is C1-C3 It is an alkyl. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one among them is It is methyl. In some embodiments, R A1 and R B1 are each C1-C6 alkyls. In some embodiments, R A1 and R B1 are each C1-C3 alkyls. In some embodiments, R A1 and R B1 Each is methyl.

[0642] In some embodiments, R A1 and RB1 One of them is hydrogen and R A1 and R B1 The other one among them is C1-C6 It is a haloalkyl. In some embodiments, R A1 and R B1 are each a C1-C6 haloalkyl. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl and R A1 and R B1 The other one is C1-C6 It is a haloalkyl.

[0643] In some embodiments, one R G is -C(=O)NR C1 R D1 is. In some embodiments, R C1 and R D1 Each is hydrogen. 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-C6 alkyl. 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. In some embodiments, R C1 and R D1 One of them is It is hydrogen and R C1 and R D1 The other one is methyl. In some embodiments, R C1 and R D1 are each C1-C6 alkyls. In some embodiments, R C1 and R D1 Each is methyl. In some embodiments, R C1 and R D1 One of them is hydrogen and R C1 and RD1 Another one is a C1-C6 haloalkyl. In some embodiments, R C1 and R D1 are each a C1-C6 haloalkyl. In some embodiments, R C1 and R D1 One of them is a C1-C6 alkyl and R C1 and R D1 Another one is a C1-C6 haloalkyl.

[0644] In some embodiments, one R G is -CO2(C1-C6 alkyl). In some embodiments, one R G is -CO2CH3.

[0645] In some embodiments, one R G is a C1-C6 haloalkyl. In some embodiments, one R G Is It is trifluoromethyl.

[0646] In some embodiments, one R G is a C3-C6 cycloalkyl. In some embodiments, one R G is cyclopropyl.

[0647] In some embodiments, R G Is It is CO2H.

[0648] In some embodiments, R 4 The 3-6-membered heterocyclile is a 5-6-membered heterocyclile. In some embodiments, R 4 The 3-6-membered heterocyclile is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, R 4 The 3-6 heterocyclils are 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranil.

[0649] In some embodiments, R 4is an unsubstituted 3-6-membered heterocyclile. In some embodiments, R 4 is a 5-6-membered heterocyclile. In some embodiments, R 4 It is azetidinyl, morpholinil, or tetrahydropyranil.

[0650] In some embodiments, R 4 Is , , and It is selected from a group consisting of.

[0651] In some embodiments, R 4 is -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 silver It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0652] In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and RA and R B The other one is a C1-C3 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (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 one among them is It is a hydroxyl-substituted propyl (e.g., 2-hydroxy1-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 among them is It is a C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is methyl. In some embodiments, R A and R B Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B is each a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is a C1-C3 alkyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one is substituted with a hydroxyl It is a C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B are each C1-C6 alkyls. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B are methyl respectively.

[0653] In some embodiments, R 4 It contains one nitrogen ring member and one or two independently selected Rs G It is a 4-6 binary heterocyclile arbitrarily substituted with; where R G Is It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0654] In some embodiments, the compound of formula (I) is formula (IC):

[0655] (IC)

[0656] or a pharmaceutically acceptable salt thereof, wherein:

[0657] R 1A Is It is a halogen;

[0658] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0659] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0660] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0661] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0662] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently a C1-C6 alkyl optionally substituted with hydrogen or a hydroxyl, C1-C6 haloalkyl; or

[0663] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0664] Each R G -NR is a fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1R D1 , It is independently selected from the group consisting of and -CO2H.

[0665] In some embodiments, the compound of formula (I) is formula (ID):

[0666] (ID)

[0667] or a pharmaceutically acceptable salt thereof, wherein:

[0668] R 1A Is It is a halogen;

[0669] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0670] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0671] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0672] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0673] Each R A , R A1 , R B , R B1, R C , R C1 , R D , R D1 , R E , and R F is independently hydrogen or a C1-C6 alkyl, C1-C6 haloalkyl; or

[0674] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0675] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0676] In some embodiments, the compound of formula (I) is formula (IE):

[0677] (IE)

[0678] or a pharmaceutically acceptable salt thereof, wherein:

[0679] R 1A Is It is a halogen;

[0680] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0681] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0682] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0683] R 4-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0684] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0685] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0686] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0687] In some embodiments, the compound of formula (I) is formula (IF):

[0688] (IF)

[0689] or a pharmaceutically acceptable salt thereof, wherein:

[0690] R 1A Is It is a halogen;

[0691] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0692] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0693] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0694] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0695] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0696] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0697] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H; and wherein the compound is not the following.

[0698] .

[0699] Some embodiments provide a compound of the formula (IF), wherein the compound is not a compound selected from the group consisting of:

[0700] and .

[0701] In some embodiments, the compound of formula (I) is formula (IG):

[0702] (IG)

[0703] or a pharmaceutically acceptable salt thereof, wherein:

[0704] R 1A Is It is a halogen;

[0705] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0706] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0707] R 3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0708] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0709] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0710] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0711] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H are independently selected.

[0712] In some embodiments, the compound of formula (I) is formula (IH):

[0713] (IH)

[0714] or a pharmaceutically acceptable salt thereof, wherein:

[0715] R 1A Is It is a halogen;

[0716] R 1B is a halogen, cyano, or cyclopropyl, or is absent (the phenyl ring is R 1A Single-substituted as);

[0717] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0718] R 3 is a C1-C6 alkyl or C1-C6 haloalkyl;

[0719] R 4 -NR is a C1-C6 alkoxy, C1-C6 haloalkyl, -NR optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C3-C6 cycloalkyl. A R B , and one or two independently selected R G Independently selected from the group consisting of 3-9 member heterocyclils arbitrarily substituted with;

[0720] Each R A , R B , R C1 , and R D1 silver Independently hydrogen, 4-6-membered heterocycliles, hydroxyl, or -C(=O)NR B2 R C2 It is a C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl alkyl arbitrarily substituted with;

[0721] Each R A2 , R B2 , and RC2 Is Independently hydrogen or C1-C6 alkyl;

[0722] Each R G Is Fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted with hydroxyl, =NR A2 , -C(=O)NR C1 R D1 It is independently selected from the group consisting of -SO2(C1-C6 alkyl), -CO2H, and -C1-C6 haloalkoxy.

[0723] In some embodiments, the compound of formula (I) is formula (IJ):

[0724] (IJ)

[0725] or a pharmaceutically acceptable salt thereof, wherein:

[0726] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0727] R 1A Is It is a halogen;

[0728] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0729] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0730] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0731] Ring A1 is a 6-membered heteroaryl;

[0732] R 4 Is -NR A R BC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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 member heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G A 3-6 binary heterocyclile arbitrarily substituted with , and one or two independently selected R G Independently selected from the group consisting of 3-6 cycloalkyl groups arbitrarily substituted with;

[0733] Here, R 4 Is For the N atom of the element moiety blue It is coupled to the position of ring A1;

[0734] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently It is hydrogen, a 4-6-membered heterocyclile, a C1-C6 haloalkyl, a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or a C1-C6 alkyl optionally substituted with one or two substituents independently selected from hydroxyl, a 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0735] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0736] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0737] In some embodiments, ring A1 is pyrimidinyl, pyridyl, or pyrazolyl. In some embodiments, ring A1 is pyrimidinyl. In some embodiments, ring A1 is pyridyl. In some embodiments, ring A1 is pyrazolyl.

[0738] In some embodiments, ring A1 is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl. In some embodiments, ring A1 is 5-pyrimidinyl. In some embodiments, ring A1 is 3-pyridyl. In some embodiments, ring A1 is 4-pyrazolyl.

[0739] In some embodiments of the chemical formula (IA), Is and, here: R 4B is -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 silver It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0740] In some embodiments of the chemical formula (IA), R A and R B Each is hydrogen.

[0741] In some embodiments of the chemical formula (IA), R A and R Bare each 4-6-membered heterocycliles. In some embodiments of the chemical 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 heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a quaternary heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R B Another one is a pentoecious heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen. R A and R B The other one is 1,1-dioxidotetrahydrothiophene-3-yl. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is a 6-membered heterocyclile.

[0742] In some embodiments of the chemical formula (IA), R A and R B are each a C1-C6 haloalkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 haloalkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R BThe other one is a C1-C3 haloalkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl.

[0743] In some embodiments of the chemical formula (IA), R A and R B is each a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted 3-6-membered cycloalkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is unsubstituted It is a 3-6-membered cycloalkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a ternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a quaternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments of chemical formula (IA), R A and R B One of them is It is hydrogen. R A and R B The other one is cis- or trans-3-hydroxycyclobutyl. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a 5-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a hexavalent cycloalkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a hydroxyl-substituted 3-6 member cycloalkyl.

[0744] In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2). In some embodiments of formula (IA), R A and R B One of them is hydrogen. R A and R B The other one is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen. R A and R BThe other one is a hydroxyl-substituted C1-C6 alkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C6 alkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen. R A and R B The other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted propyl (e.g., 2-hydroxy1-propyl or 1-hydroxy-2-propyl). In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is methyl.

[0745] In some embodiments of the chemical formula (IA), RA and R B is each a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments of the formula (IA), R A and R B is each a hydroxyl-substituted C1-C6 alkyl. In some embodiments of the formula (IA), R A and R B One of them is a C1-C3 alkyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B One of them is It is methyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments of the formula (IA), R A and R B One of them is methyl and R A and R B The other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments of the formula (IA), R A and R B are each C1-C6 alkyls. In some embodiments of chemical formula (IA), R A and R B are each C1-C3 alkyls. In some embodiments of the formula (IA), R A and R B are methyl respectively.

[0746] In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and RA and R B The other one is a C1-C3 alkyl substituted with a 3-6-membered cycloalkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with a 3-4 cycloalkyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with a 3-quadruple cycloalkyl and a hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with cyclopropyl and hydroxyl. In some embodiments of the formula (IA), R A and R B One of them is hydrogen. R A and R B The other one is an ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments of formula (IA), R A and R B One of them is a C1-C6 alkyl and R A and R B The other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments of the formula (IA), R A and R B Both are C1-C6 alkyls substituted with 3-6 member cycloalkyls.

[0747] In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and RB The other one among them is It is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments of chemical formula (IA), R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propane-2-yl. In some embodiments of formula (IA), R A and R B One of them is It is a C1-C6 alkyl R A and R B The other one is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments of chemical formula (IA), R A and R B Both are C1-C6 alkyls substituted with -SO2(C1-C6 alkyl).

[0748] In some embodiments of the chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of chemical formula (IA), R A and R B One of them is It is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropane-2-yl. In some embodiments of chemical formula (IA), R A and R B One of them is It is a C1-C6 alkyl hydrogen R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments of chemical formula (IA), R A and R B Both are C1-C6 alkyls substituted with -SO2(NH2).

[0749] In some embodiments of the chemical formula (IA), R 4B It contains one nitrogen ring member and one or two independently selected Rs G It is a 4-6 binary heterocyclile arbitrarily substituted with; where R G is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0750] In some embodiments of the chemical formula (IA), R 4B Is and; where ring B is each 1-2 R groups independently selected from fluoro, hydroxyl, and C1-C6 alkyl. G It is optionally substituted with azetidinyl, pyrrolidinyl, or piperidinyl. In some embodiments of the chemical formula (IA), ring B is azetidinyl.

[0751] In some embodiments of the chemical formula (IA), ring B is unsubstituted.

[0752] In some embodiments of the chemical formula (IA), ring B has one R G It is substituted with. In some embodiments of the chemical formula (IA), R G is a fluoro. In some embodiments of the chemical formula (IA), R Gis cyano. In some embodiments of the chemical formula (IA), R G is a hydroxyl. In some embodiments of the chemical formula (IA), R G is a C1-C3 alkyl. In some embodiments of the formula (IA), R G is methyl. In some embodiments of the chemical formula (IA), R G Is It is -CO2CH3.

[0753] In some embodiments of the chemical formula (IA), ring B consists of two independently selected Rs G It is substituted with. In some embodiments of the chemical formula (IA), each R G is a fluoro. In some embodiments of the chemical formula (IA), each R G is a C1-C3 alkyl. In some embodiments of the formula (IA), each R G is methyl. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other R G is a C1-C3 alkyl. In some embodiments of the formula (IA), one R G is a hydroxyl and the other R G is methyl. In some embodiments of the chemical formula (IA), one R G is fluoro and other R G is a C1-C3 alkyl. In some embodiments of the formula (IA), one R G is fluoro and other R G is methyl. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other R G is a fluoro. In some embodiments of the chemical formula (IA), one R G is a hydroxyl and the other R G is trifluoromethyl.

[0754] In some embodiments of the chemical formula (IA), Is and, where one or two independently selected R G is located at the 3-position of azetidine. In some embodiments of the chemical formula (IA), Is , , , , , , , , and It is selected from the group consisting of. In some embodiments of the chemical formula (IA), Is , , , and It is selected from a group consisting of.

[0755] In some embodiments, the compound of formula (I) is formula (IK):

[0756] (IK)

[0757] or a pharmaceutically acceptable salt thereof, wherein:

[0758] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0759] R 1A Is It is a halogen;

[0760] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0761] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0762] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[0763] R 4 Is -NR A R B C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR optionally substituted with 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 member heteroaryl optionally substituted with C1-C6 alkyl, one or two independently selected R G A 3-6 binary heterocyclile arbitrarily substituted with , and one or two independently selected R G Independently selected from the group consisting of 3-6 cycloalkyl groups arbitrarily substituted with;

[0764] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently hydrogen , 4-6 member heterocyclil, C1-C6 haloalkyl, 3-6 member cycloalkyl optionally substituted with hydroxyl, or C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl, 3-6 member cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2); or

[0765] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0766] Each R G-NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0767] In some embodiments, R 1A and R 1B Is Each is fluoro;

[0768] In some embodiments, R 2 is a C1-C6 alkyl. In some embodiments, R 2 is a C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0769] In some embodiments, R 2 is a C1-C6 haloalkyl. In some embodiments, R 2 is a C1-C3 haloalkyl. In some embodiments, R 2 is trifluoromethyl.

[0770] In some embodiments, R 3 is a C1-C6 alkyl. In some embodiments, R 3 is a C1-C3 alkyl. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 It is isopropyl.

[0771] In some embodiments, R 3 is a C1-C6 haloalkyl. In some embodiments, R 3 silver It is a C1-C3 haloalkyl. In some embodiments, R 3 It is trifluoromethyl.

[0772] In some embodiments, R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl. In some embodiments, R 3 is a C3-C6 cycloalkyl optionally substituted with one or two fluoro groups. In some embodiments, R 3 is a C3-C6 cycloalkyl substituted with one or two fluoro groups. In some embodiments, R 3 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, R 3 The C3-C6 cycloalkyl group is cyclopropyl. In some embodiments, R 3 is cyclopropyl.

[0773] In some embodiments, R 4 is -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R 4 is -NR A R B It is a C1-C3 alkyl optionally substituted with . In some embodiments, R 4 Is -NR A R B It is a methyl arbitrarily substituted with . In some embodiments, R 4 is a C1-C4 alkyl. In some embodiments, R 4 Is It is methyl.

[0774] In some embodiments, R 4 is a C1-C6 alkoxy. In some embodiments, R 4 is a C1-C3 alkoxy. In some embodiments, R 4 is methoxy.

[0775] In some embodiments, R 4 is a C1-C6 haloalkyl. In some embodiments, R 4is a C1-C3 haloalkyl. In some embodiments, R 4 is trifluoromethyl.

[0776] In some embodiments, R 4 is a hydroxyl. In some embodiments, R 4 is cyano. In some embodiments, R 4 is -CO2H. In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. 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 optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R BThe other one is a hydroxyl-substituted ethyl (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 Another one is a hydroxyl-substituted propyl (e.g., 2-hydroxy1-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. 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 Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B Is Each is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is a C1-C3 alkyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is It is methyl and R A and R B The other one is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Is Each is a C1-C6 alkyl. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B Is Each is methyl.

[0777] In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is a C1-C6 haloalkyl. In some embodiments, R A and R B Is Each is a C1-C6 haloalkyl. In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl. 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. In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 haloalkyl.

[0778] In some embodiments, R A and R B Is Each is a 4-6-membered heterocyclile. In some embodiments, R A and R B One of them is hydrogen and R A and R B Another one is a 4-6-membered heterocyclile. In some embodiments, R A and R B One of them is hydrogen and R A and RB Another one is a quaternary heterocyclile. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is 5 won It is a heterocyclile. In some embodiments of the chemical formula (IA), R A and R B One of them is hydrogen and R A and R B Another one is 1,1-dioxidotetrahydrothiophene-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 6 won It is a heterocyclile.

[0779] In some embodiments, R A and R B Is Each is a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a 3-6-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is a hydroxyl-substituted 3-6-membered cycloalkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is unsubstituted It is a 3-6 member cycloalkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R BThe other one is a ternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a quaternary cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one 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 one is a 5-membered cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is It is hydrogen and R A and R B The other one is a hexavalent cycloalkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a hydroxyl-substituted 3-6 member cycloalkyl.

[0780] 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-C6 alkyl optionally substituted with one or two substituents independently selected from hydroxyl, 3-6 cycloalkyl, -SO2(C1-C6 alkyl), and -SO2(NH2).

[0781] In some embodiments, R A and R B One of them is hydrogen and R A and R BThe other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. 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 substituted with a 3-6-membered cycloalkyl. 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 substituted with a 3-4 cycloalkyl. 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 substituted with a 3-quadruple cycloalkyl and a hydroxyl. 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 substituted with cyclopropyl and hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is an ethyl substituted with cyclopropyl and hydroxyl, e.g., 1-cyclopropyl-2-hydroxyethyl. In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B The other one is a C1-C6 alkyl substituted with a 3-6 member cycloalkyl. In some embodiments, R A and R B Is Both are C1-C6 alkyls substituted with 3-6 member cycloalkyls.

[0782] In some embodiments, R A and R B One of them is hydrogen and R A and RB Another one is a C1-C6 alkyl 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 one is a C1-C3 alkyl 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 one is a C1-C3 alkyl substituted with -SO2(C1-C3 alkyl). In some embodiments, R A and R B One of them is hydrogen. R A and R B The other one is a C1-C3 alkyl substituted with -SO2CH3, e.g., 1-(methylsulfonyl)propane-2-yl. In some embodiments, R A and R B One of them is a C1-C6 alkyl and R A and R B Another one is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R A and R B Is Both are C1-C6 alkyls 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 one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, R A and R B One of them is It is hydrogen and R A and R B The other one is a C1-C3 alkyl substituted with -SO2(NH2), e.g., 1-sulfamoylpropane-2-yl. In some embodiments, R A and R BOne of them is a C1-C6 alkyl hydrogen and R A and R B The other one is a C1-C6 alkyl substituted with -SO2(NH2). In some embodiments, R A and R B Is Both of them It is a C1-C6 alkyl substituted with -SO2(NH2).

[0783] In some embodiments, one R 4 is -C(=O)NR C R D is. In some embodiments, R C and R D are each hydrogen. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C6 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is a C1-C3 alkyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D The other one is methyl. In some embodiments, R C and R D are each C1-C6 alkyls. In some embodiments, R C and R D are each C1-C3 alkyls. In some embodiments, R C and R D are each methyl. In some embodiments, R C and R D One of them is It is hydrogen and R C and R D Another one is a C1-C6 haloalkyl. In some embodiments, RC and R D are each a C1-C6 haloalkyl. In some embodiments, R C and R D One of them is a C1-C6 alkyl and R C and R D Another one is a C1-C6 haloalkyl. In some embodiments, R C and R D They form a 4-6 member heterocyclile together with the nitrogen atoms to which they are attached. In some embodiments, R C and R D They form azetidine or piperazine together with the nitrogen atoms to which they are attached.

[0784] In some embodiments, one R 4 is -SO2(NR E R F ) is. In some embodiments, R E and R F Is Each is hydrogen. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is a C1-C6 alkyl. In some embodiments, R E and R F One of them is hydrogen and R E and R F The other one among them is It is methyl. In some embodiments, R E and R F Is Each is a C1-C6 alkyl. In some embodiments, R E and R F are each C1-C3 alkyls. In some embodiments, R E and R F Is Each is methyl. In some embodiments, R E and R F One of them is hydrogen and R E and R FThe other one among them is It is a C1-C6 haloalkyl. In some embodiments, R E and R F Is Each is a C1-C6 haloalkyl. In some embodiments, R E and R F One of them is C1-C6 It is alkyl and R E and R F The other one among them is C1-C6 It is a haloalkyl.

[0785] In some embodiments, R 4 is -SO2(C1-C6 alkyl). In some embodiments, R 4 is -SO2(C1-C3 alkyl). In some embodiments, R 4 is -SO2Me. In some implementations, R 4 is -SO2Et.

[0786] In some embodiments, R 4 is -S(=O)(=NH)(C1-C6 alkyl). In some embodiments, R 4 is -S(=O)(=NH)(C1-C4 alkyl). In some embodiments, R 4 is -S(=O)(=NH)Me.

[0787] In some embodiments, R 4 is -C(=O)(C1-C6 alkyl). In some embodiments, R 4 is -C(=O)(C1-C3 alkyl). In some embodiments, R 4 is -C(=O)Me.

[0788] In some embodiments, R 4 is -CO2(C1-C6 alkyl). In some embodiments, R 4 is -CO2(C1-C3 alkyl). In some embodiments, R 4 is -CO2Me.

[0789] In some embodiments, one R4 is a 5-6-membered heteroaryl optionally substituted with a C1-C6 alkyl group. In some embodiments, one R 4 is a 5-6-membered heteroaryl substituted with a C1-C6 alkyl group. In some embodiments, R 4 is a 5-6-membered heteroaryl. In some embodiments, R 4 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isooxazolyl, isothiazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, R 4 is pyrazolil. In some embodiments, one R 4 is a methyl-substituted tetrazolyl. In some embodiments, one R 4 is pyrazolil. In some embodiments, one R 4 is an unsubstituted pyrazolyl. In some embodiments, one R 4 is 1-pyrazolil.

[0790] In some embodiments, R 4 is one or two independently selected Rs G It is a 3-6 binary heterocyclile arbitrarily substituted with . In some embodiments, R 4 is one or two independently selected Rs G It is a 3-6-membered heterocyclile substituted with . In some embodiments, R 4 is 1 R G It is a 3-6-membered heterocyclile substituted with . In some embodiments, R 4 is 2 independently selected R G It is a 3-6 member heterocyclile substituted with .

[0791] In some embodiments, R G is a fluoro. In some embodiments, R Gis cyano. In some embodiments, R G Is It is a hydroxyl. In some embodiments, R G is a C1-C6 alkyl. In some embodiments, R G is a C1-C3 alkyl. In some embodiments, R G is methyl.

[0792] In some embodiments, R G is a C1-C6 alkoxy. In some embodiments, R G is a C1-C3 alkoxy. In some embodiments, R G is methoxy.

[0793] In some embodiments, one R G is -NR A1 R B1 is. In some embodiments, R A1 and R B1 Each is hydrogen. 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-C6 alkyl. In some embodiments, R A1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is C1-C3 It is an alkyl. 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 are each C1-C6 alkyls. In some embodiments, R A1 and R B1 are each C1-C3 alkyls. In some embodiments, R A1 and R B1 Each is methyl.

[0794] In some embodiments, RA1 and R B1 One of them is hydrogen and R A1 and R B1 The other one is C1-C6 It is a haloalkyl. In some embodiments, R A1 and R B1 are each a C1-C6 haloalkyl. In some embodiments, R A1 and R B1 One of them is a C1-C6 alkyl and R A1 and R B1 The other one is C1-C6 It is a haloalkyl.

[0795] In some embodiments, one R G is -C(=O)NR C1 R D1 is. In some embodiments, R C1 and R D1 Each is hydrogen. 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-C6 alkyl. 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. 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 are each C1-C6 alkyls. In some embodiments, R C1 and R D1 Each is methyl. 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. In some embodiments, R C1 and RD1 are each a C1-C6 haloalkyl. In some embodiments, R C1 and R D1 One of them is a C1-C6 alkyl and R C1 and R D1 Another one is a C1-C6 haloalkyl.

[0796] In some embodiments, one R G is -CO2(C1-C6 alkyl). In some embodiments, one R G is -CO2CH3.

[0797] In some embodiments, one R G is a C1-C6 haloalkyl. In some embodiments, one R G is trifluoromethyl.

[0798] In some embodiments, one R G is a C3-C6 cycloalkyl. In some embodiments, one R G is cyclopropyl.

[0799] In some embodiments, R G Is It is CO2H.

[0800] In some embodiments, R 4 The 3-6-membered heterocyclile is a 5-6-membered heterocyclile. In some embodiments, R 4 The 3-6-membered heterocyclile is azetidinyl, azetidin-2-onyl, morpholinyl, piperazinyl, or tetrahydropyranyl. In some embodiments, R 4 The 3-6 heterocyclils are 1-azetidinyl, 1-azetidin-2-onyl, 1-piperazinyl, 1-morpholinyl, or 4-tetrahydropyranil.

[0801] In some embodiments, R 4 is an unsubstituted 3-6-membered heterocyclile. In some embodiments, R 4 Is It is a 5-6-membered heterocyclile. In some embodiments, R4 It is azetidinyl, morpholinil, or tetrahydropyranil.

[0802] In some embodiments, R 4 Is , , and It is selected from a group consisting of.

[0803] In some embodiments, R 4 is -NR A R B and includes 1 nitrogen ring member and 1-2 independently selected R G1 Selected from 4-6 binary heterocyclines arbitrarily substituted with; where R G1 silver It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0804] In some embodiments, R A and R B Is Each is hydrogen. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a C1-C6 alkyl. In some embodiments, R A and R BOne of them is hydrogen and R A and R B The other one among them is It is a C1-C3 alkyl optionally substituted with a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one is substituted with a hydroxyl It is a C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (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 one among them is It is a hydroxyl-substituted propyl (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 among them is It is a C1-C3 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The other one among them is It is methyl. In some embodiments, R A and R B Is Each is a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, RA and R B Is Each is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is C1-C3 alkyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one among them is It is a hydroxyl-substituted C1-C3 alkyl. In some embodiments, R A and R B One of them is methyl and R A and R B The other one among them is It is a hydroxyl-substituted ethyl (e.g., 2-hydroxy-1-propyl). In some embodiments, R A and R B Is Each is a C1-C6 alkyl. In some embodiments, R A and R B Is Each is a C1-C3 alkyl. In some embodiments, R A and R B Is Each is methyl.

[0805] In some embodiments, R 4 It contains one nitrogen ring member and one or two independently selected Rs G It is a 4-6 binary heterocyclile arbitrarily substituted with; where R G Is It is selected from fluoro, hydroxyl, and C1-C6 alkyl.

[0806] In some embodiments, the compound of formula (I) is formula (IL):

[0807] (IL)

[0808] or a pharmaceutically acceptable salt thereof, wherein:

[0809] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0810] R 1A Is It is a halogen;

[0811] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0812] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0813] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0814] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0815] Each RA , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0816] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0817] Each R G -NR is a fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -NR A1 R B1 , -C(=O)NR C1 R D1 , It is independently selected from the group consisting of and -CO2H.

[0818] In some embodiments, the compound of formula (I) is formula (IM):

[0819] (IM)

[0820] or a pharmaceutically acceptable salt thereof, wherein:

[0821] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0822] R 1A is a halogen;

[0823] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0824] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0825] R 3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0826] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0827] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently hydrogen or a C1-C6 alkyl, C1-C6 haloalkyl; or

[0828] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0829] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0830] In some embodiments, the compound of formula (I) is formula (IN):

[0831] (IN)

[0832] or a pharmaceutically acceptable salt thereof, wherein:

[0833] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0834] R 1A Is It is a halogen;

[0835] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0836] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0837] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0838] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0839] Each R A , R A1 , R B , RB1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0840] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0841] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0842] In some embodiments, the compound of formula (I) is formula (IO):

[0843] (IO)

[0844] or a pharmaceutically acceptable salt thereof, wherein:

[0845] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0846] R 1A Is It is a halogen;

[0847] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0848] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0849] R 3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0850] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R G Independently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0851] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0852] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0853] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1, independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0854] In some embodiments, the compound of formula (I) is formula (IP):

[0855] (IP)

[0856] or a pharmaceutically acceptable salt thereof, wherein:

[0857] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0858] R 1A Is It is a halogen;

[0859] R 1B is a halogen or is absent (the phenyl ring is R 1A Single-substituted as);

[0860] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0861] R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[0862] R 4 -C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, cyano, -CO2H, -NR A R B , -C(=O)NR C R D , -SO2(NR E R F ), -SO2(C1-C6 alkyl), -S(=O)(=NH)(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -CO2(C1-C6 alkyl), 5-6-membered heteroaryl, and one or two independently selected R GIndependently selected from the group consisting of 3-6 member heterocyclils arbitrarily substituted with;

[0863] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is independently optionally substituted with hydrogen or hydroxyl, a C1-C6 alkyl or C1-C6 haloalkyl; or

[0864] R C and R D ..., together with the nitrogen atoms to which they are attached, form a 4-6 member heterocyclile;

[0865] Each R G -NR A1 R B1 , -C(=O)NR C1 R D1 , independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, and -CO2H.

[0866] In some embodiments, the compound of formula (I) is formula (IQ):

[0867] (IQ)

[0868] or a pharmaceutically acceptable salt thereof, wherein:

[0869] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0870] R 1A Is It is a halogen;

[0871] R 1Bis a halogen, cyano, or cyclopropyl, or is absent (the phenyl ring is R 1A Single-substituted as);

[0872] R 2 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0873] R 3 is a C1-C6 alkyl or C1-C6 haloalkyl;

[0874] R 4 -NR is a C1-C6 alkoxy, C1-C6 haloalkyl, -NR optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, hydroxyl, and C3-C6 cycloalkyl. A R B , and one or two independently selected R G Independently selected from the group consisting of 3-9 member heterocyclils arbitrarily substituted with;

[0875] Each R A , R B , R C1 , and R D1 silver Independently hydrogen, 4-6-membered heterocycliles, hydroxyl, or -C(=O)NR B2 R C2 It is a C1-C6 alkyl, -C(=O)O(C1-C6 alkyl), or C1-C6 haloalkyl alkyl arbitrarily substituted with;

[0876] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[0877] Each R G Is Fluoro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted with hydroxyl, =NR A2 , -C(=O)NR C1 R D1It is independently selected from the group consisting of -SO2(C1-C6 alkyl), -CO2H, and -C1-C6 haloalkoxy.

[0878] In some embodiments, the compound of formula (I) is

[0879]

[0880] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0881]

[0882] In some embodiments, the compound of formula (I) is

[0883]

[0884] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0885]

[0886] In some embodiments, the compound of formula (I) is

[0887]

[0888] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein; and wherein the compound is not a compound selected from the group consisting of:

[0889]

[0890] In some embodiments, the compound of formula (I) is

[0891]

[0892] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein.

[0893] In some embodiments, the compound of formula (I) is

[0894]

[0895] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein.

[0896] In some embodiments, the compound of formula (I) is

[0897]

[0898] or a pharmaceutically acceptable salt thereof, where R 3 , R 4 , and ring A is as described herein.

[0899] Non-limiting exemplary compounds

[0900] In some embodiments, the compound is selected from the group consisting of the compounds of Example 1-195 (e.g., compound 1-276) or is a pharmaceutically acceptable salt thereof.

[0901] In some embodiments, the compound is selected from the group consisting of the compounds described in Table A, or is a pharmaceutically acceptable salt thereof.

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921] In some embodiments, the compound is selected from the group consisting of the compounds described in Table B, or is a pharmaceutically acceptable salt thereof.

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941] In some embodiments, the compound is selected from the group consisting of the compounds described in Table C, or is a pharmaceutically acceptable salt thereof.

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960] In some embodiments, the compound is selected from the group consisting of the compounds described in Table D, or is a pharmaceutically acceptable salt thereof.

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967] Pharmaceutical composition and administration

[0968] common

[0969] In some embodiments, a chemical entity (e.g., a compound that inhibits PI3Kα, or a pharmaceutically acceptable salt thereof) is administered into a pharmaceutical composition comprising the chemical entity, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0970] In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., Tween, poloxamer, or other similar polymeric delivery matrices, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, Polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, and wool fats are included, but not limited thereto. Cyclodextrins, e.g., α-, β, and γ-cyclodextrins, or chemically modified derivatives, e.g., 2- and 3-hydroxypropyl-β-cyclodextrins, hydroxyalkylcyclodextrins, or other dissolved derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions may be prepared containing the chemical entities as described herein in a range of 0.005% to 100% and the remainder consisting of pharmaceutically acceptable excipients. The compositions under consideration may contain the chemical entities provided herein in an amount of 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in further embodiments.The actual method of manufacturing such a dosage form will be known to or obvious to a person skilled in the art; for example,. Remington: The Science and Practice of Pharmacy , 22 nd Refer to Edition (Pharmaceutical Press, London, UK. 2012).

[0971] Route of administration and composition components

[0972] In some embodiments, the chemical entity or pharmaceutical composition thereof described herein may be administered to a subject in need by any acceptable route of administration. Acceptable routes of administration include, but are not limited to: buccal, cutaneous, intracervix, sinus, trachea, intestinal, epidural, interstitial, abdominal, intra-arterial, intrabronchial, bursal, intracerebral, cistern, coronary artery, intradermal, glandular, duodenal, intradural, intraepidermal, esophageal, gastric, gingival, ileal, lymphatic, bone marrow, meningeal, muscular, ovarian, abdominal cavity, prostate, lung, intrasinus, spinal cord, synovial membrane, testicular, spinal canal, tubular, tumor, uterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosa, trans-trachea, ureter, urethra, and vagina. In a specific embodiment, the preferred route of administration is parenteral (e.g., intratumoral).

[0973] The composition may be formulated for parenteral administration and may be formulated for injection via, for example, intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such composition may be prepared for injection, such as a liquid solution or suspension; may also be prepared in a solid form suitable for use in preparing a solution or suspension by adding a liquid prior to injection; and the preparation may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of the present disclosure.

[0974] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations comprising sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the forms must be sterile and fluid enough to be easily injected. They must also be stable under production and storage conditions and preserved against the action of microorganisms, such as bacteria and fungi.

[0975] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oil. Suitable fluidity may be maintained by the use of a coating, for example, lecithin, for maintaining the required particle size in the case of dispersion, and the use of a surfactant. Prevention of microbial action may be achieved by various antimicrobial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it will be desirable to include an isotonic agent, for example, sugars or sodium chloride. Long-term absorption of the injectable composition may be achieved by using an absorption retardant, for example, aluminum monostearate and gelatin in the composition.

[0976] Sterile injectable solutions are prepared by incorporating the required amount of an active compound, as needed, into a suitable solvent along with various other components listed above, and then filtering and sterilizing. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a base dispersion medium and other necessary components among those listed above. For sterile powders for the preparation of sterile injectable solutions, the preferred manufacturing method is vacuum-drying and freeze-drying techniques, which produce a powder of any additional desirable component in addition to the active ingredient from a previously sterile-filtered solution.

[0977] Intratumoral injection, for example, Lammers et al., “ Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia . 2006, 10 It is discussed in 788-795.

[0978] Pharmaceutically acceptable excipients usable in rectal compositions such as gels, creams, enemas, or rectal suppositories are, without limitation, cocoa butter glycerides, synthetic polymers, e.g., polyvinylpyrrolidone, PEG (such as in PEG ointments), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols, petroleum jelly, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidized SBN, vanilla essential oil, parabens in aerosols and phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, and isopropyl It includes any one or more of alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, e.g., vitamins A and E and potassium acetate.

[0979] In a specific embodiment, a suppository may be prepared by mixing the chemical entity described herein with a suitable non-irritating, pharmaceutically acceptable excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts rectum to release the active compound. In another embodiment, the composition for rectal administration is in the form of an enema.

[0980] In other embodiments, the compound or pharmaceutical composition thereof described herein is suitable for local delivery to the digestive tract or GI tract via oral administration (e.g., in the form of a solid or liquid dose).

[0981] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the chemical entity comprises one or more pharmaceutically acceptable excipients, e.g., sodium citrate or dicalcium phosphate and / or: a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants, e.g., paraffin; f) absorption promoters, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and Bentonite clay, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof are mixed. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using such pharmaceutically acceptable excipients as high molecular weight polyethylene glycol, as well as lactose or lactose.

[0982] In one embodiment, the composition will take the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with the chemical entity provided herein, a diluent, e.g., lactose, sucrose, dicalcium phosphate, etc.; a lubricant, e.g., magnesium stearate, etc.; and a binder, e.g., starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, marume, solution, or suspension (e.g., among propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more of the chemical entities or additional active agents provided herein are physically separated; e.g., a capsule (or tablet within a capsule) containing granules of each drug; a two-layer tablet; a two-compartment gel cap, etc. are also considered. Enteric coatings or delayed-release oral administration forms are also considered.

[0983] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are known, including, for example, phenol and ascorbic acid.

[0984] In specific embodiments, pharmaceutically acceptable excipients are sterilized and do not contain generally undesirable substances. These compositions may be sterilized by conventional known sterilization techniques. Sterility is not required for various oral dosage forms and pharmaceutically acceptable excipients, e.g., tablets and capsules. USP / NF standards are generally sufficient.

[0985] In specific embodiments, the solid oral administration form may further comprise one or more components such that the composition is chemically and / or structurally inclined to deliver chemical entities to the upper or lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small intestine. Exemplary formulation techniques are, e.g., Filipski, KJ et al. Current Topics in Medicinal Chemistry , 2013 , 13 , 776 - It is described in 802, the full text of which is incorporated herein by reference.

[0986] Examples include upper-GI targeting technologies, such as Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to the mucosal wall.

[0987] Other examples include lower-GI targeting technologies. For targeting various regions of the intestinal tract, various enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available. These materials are polymers designed to dissolve or corrode within a specific pH range, typically selected based on the GI region of the desired drug release. These materials also function to protect acid-unstable drugs from gastric juice or to limit exposure when the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylate-methyl methacrylate copolymer), and Marcoat). Other technologies include dosing forms that respond to local flora in the GI tube, pressure-controlled colon delivery capsules, and Pulsincap.

[0988] The ocular composition may include, without limitation, any one or more of viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.).

[0989] Topical compositions may include ointments and creams. Ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often in the form of oil in water or water in oil. The cream base is typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes also referred to as the "internal" phase, generally consists of petrolatum and fatty alcohols, such as cetyl or stearyl alcohols; the aqueous phase, which generally exceeds the oil phase in volume but not necessarily, and generally contains a humectant. The emulsifier in the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. Like other carriers or vehicles, the ointment base must be inert, stable, non-irritating, and non-sensitizing.

[0990] In any of the aforementioned embodiments, the pharmaceutical composition described herein may comprise one or more of the following: a lipid, a multilayer vesicle cross-linked within a bilayer, a biodegradable poly(D,L-lactic-co-glycolic acid)[PLGA]-based or polyanhydride-based nanoparticle or microparticle, and a nanoporous particle-supported lipid bilayer.

[0991] Dosage

[0992] The dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the specific compound used. The determination of the appropriate dosage for a specific situation may be made by a person skilled in the art of medicine. The total daily dosage may be divided and administered over the course of a day, either in parts or by means of providing continuous delivery.

[0993] In some embodiments, the compound described herein is 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 It is administered at doses of 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 1 mg / kg; about 0.1 mg / kg to about 0.5 mg / kg).

[0994] Regimen

[0995] The aforementioned dosage may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every 2 days, every 3 days, once a week, twice a week, once every 2 weeks, once a month).

[0996] In some embodiments, the duration of administration 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 than that. In an additional embodiment, the period during which administration is discontinued 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 than that. In one embodiment, the therapeutic compound is administered to the individual for a separate predetermined period after a predetermined period. In another embodiment, a therapeutic compound is administered during a first period, followed by a second period, during which administration is discontinued, followed by a third period, during which administration of the therapeutic compound begins, followed by a fourth period, during which administration is discontinued. In one aspect of this embodiment, the period during which administration is discontinued following the administration of the therapeutic compound is repeated for a predetermined period, which may or may not be determined. In an additional 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 for a longer period.In an additional embodiment, the period during which administration is discontinued 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 than that.

[0997] Treatment methods

[0998] Indications

[0999] PIK3CA A method for inhibiting phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (PI3Kα), encoded by a gene, is provided herein. For example, PIK3CA Diseases or disorders associated with dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these (i.e., PI3Kα-associated diseases or disorders), e.g., PIK3CA-associated overgrowth syndrome (PROS; PIK3CA-related overgrowth syndrome; see, e.g., Venot et al., Nature, 558, 540-546 (2018)), brain disorders (e.g., macrocephaly-capillary malformation (MCAP) and hemegalencephaly)), congenital lipomatous (e.g., overgrowth of vascular malformations), epidermal nevi, skeletal / spinal malformations (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-associated cancer) or Inhibitors of PI3Kα useful for prevention are provided herein.

[1000] "PI3Kα inhibitor" as used herein comprises any compound exhibiting PI3Kα inactivating activity (e.g., inhibition or reduction). In some embodiments, the PI3Kα inhibitor may be selective for PI3Kα having one or more mutations.

[1001] The ability of a test compound to act as an inhibitor of PI3Kα can be demonstrated by tests known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors is demonstrated in vitro, in vivo, Alternatively, it can be tested in cell lines. In vitro The assay includes an assay to determine the inhibition of a kinase. An alternative in vitro assay quantifies the ability of an inhibitor to bind to a protein kinase and can be measured by radiolabeling the compound before binding, isolating the compound / kinase complex and determining the amount of bound radiolabel, or performing a competitive experiment in which a novel compound is incubated with a kinase bound to a known radioligand.

[1002] The efficacy of PI3Kα inhibitors as provided herein is EC 50 It can be determined by the value. A lower EC as determined under substantially similar conditions. 50 Compounds with values ​​have a higher EC 50 It is a more potent inhibitor compared to compounds having a value. In some embodiments, substantially similar conditions include determining PI3Kα-dependent phosphorylation levels in vitro or in vivo (e.g., in tumor cells expressing wild-type PI3Kα, mutant PI3Kα, or a fragment of any of these, A594 cells, U2OS cells, A431 cells, Ba / F3 cells, or 3T3 cells).

[1003] The efficacy of PI3Kα inhibitors as provided herein is also IC 50It may also be determined by the value. A lower IC, as determined under substantially similar conditions. 50 value Compounds having a higher IC 50 It is a more potent inhibitor compared to compounds having a value. In some embodiments, substantially similar conditions are in vitro. or includes determining PI3Kα-dependent phosphorylation levels in vivo (e.g., in tumor cells expressing wild-type PI3Kα, mutant PI3Kα, or a fragment of any of these, 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).

[1004] The selectivity between wild-type PI3Kα and PI3Kα containing one or more mutations as described herein is also in vitro, such as through surface plasmon resonance and fluorescence-based binding assays. Cell assays such as pAKT levels, which are biomarkers of PI3Kα activity, or proliferation assays in which cell proliferation depends on mutant PI3Kα kinase activity may also be measured.

[1005] 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 helical phosphatidylinositol kinase homologous domain and catalytic domain of PI3Kα. In some embodiments, the compounds provided herein may exhibit nanomolar efficacy against PI3Kα kinase comprising one or more mutations, for example, the mutations of Tables 1 and 2.

[1006] 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 alloseric sites of the kinase domain. In some embodiments, the compounds provided herein may exhibit nanomolar efficacy against PI3Kα proteins containing activating mutations that have minimal activity against the associated kinase (e.g., wild-type PI3Kα). Inhibition of wild-type PI3Kα may cause undesirable side effects (e.g., hyperglycemia and skin rash) that may affect quality of life and compliance. In some cases, inhibition of wild-type PI3Kα may lead to dose-limiting toxicity. See, for example, Hanker et al., Cancer Disc. 2019, 9, 4, 482-491. Mutation-selective inhibitors may reduce the risk of such dose-limiting toxicity, including hyperglycemia, observed with inhibitors of wild-type PI3Kα.

[1007] 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 compared to another kinase or non-kinase target.

[1008] 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) compared 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 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit up to 1,000 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit up to 10,000 times greater inhibition of PI3Kα having the combination of mutations described herein compared to inhibition of wild-type PI3Kα.

[1009] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 2 to about 10 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 10 to about 100 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 100 to about 1000 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may exhibit about 1,000 to about 10,000 times greater inhibition of PI3Kα containing one or more mutations as described herein compared to inhibition of wild-type PI3Kα.

[1010] The compound of formula (I), or a pharmaceutically acceptable salt thereof, is useful for treating diseases and disorders that can be treated with PI3Kα inhibitors, such as cancer, including PI3Kα-associated diseases and disorders, e.g., PIK3CA-associated overgrowth syndrome (PROS) and proliferative disorders, e.g., blood cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[1011] In some embodiments, the object is PIK3CA Cancer (PI3Kα-associated cancer) has been identified or diagnosed as having dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these (e.g., determined using regulatory agency approval, e.g., FDA-approved test or kit). In some embodiments, the subject isPIK3CA The subject has a tumor positive for the expression or activity, or dysregulation of the level of the gene, PI3Kα protein, or any of these (e.g., determined using a regulatory agency-approved test or kit). For example, the subject has a tumor positive for mutations as described in Table 1 or Table 2. The subject PIK3CA The subject may have a tumor(s) that are positive for the expression or activity, or dysregulation of the level of the gene, PI3Kα protein, or any of these (e.g., identified as positive using regulatory agency-approved, e.g., FDA-approved tests or kits). The subject has a tumor(s) that PIK3CA The subject may be having a gene, PI3Kα protein, or dysregulation of their expression or activity, or level (e.g., when a tumor is thus identified using regulatory agency approval, e.g., an FDA-approved kit or assay). In some embodiments, the subject is suspected of having a PI3Kα-associated cancer. In some embodiments, the subject is PIK3CA The subject has a clinical record indicating a tumor having dysregulation of the expression or activity or level of the gene, PI3Kα protein, or any of these (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[1012] In some embodiments, the subject is a pediatric subject.

[1013] As used herein, the term “pediatric subject” refers to a subject under the age of 21 at the time of diagnosis or treatment. The term “pediatric” may be further classified into various subpopulations including: neonatals (from birth to the first month of life); infants (from 1 month to 2 years); children (from 2 years to 12 years); and adolescents (from 12 years to 21 years (up to the 22nd birthday, but excluding the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to the first 28 days of life, from the 29th to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (up to the 22nd birthday, but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to the first 28 days of life, from the 29th to less than 1 year of age, from 1 month to less than 4 months, from 3 months to less than 7 months, from 6 months to less than 1 year of age, from 1 year to less than 2 years of age, from 2 years to less than 3 years of age, from 2 years to less than 7 years of age, from 3 years to less than 5 years of age, from 5 years to less than 10 years of age, from 6 years to less than 13 years of age, from 10 years to less than 15 years of age, or from 15 years to less than 22 years of age.

[1014] In specific embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is useful for preventing diseases and disorders as defined herein (e.g., PIK3CA-associated overgrowth syndrome (PROS) and cancer). The term “preventive” as used herein means delaying the onset, recurrence, or spread of all or part of the disease or condition, or symptoms thereof, as described herein.

[1015] The term "PI3Kα-associated disease or disorder" as used herein is PIK3CA gene , Dysregulation of the expression, activity, or level of the PI3Kα protein, or any of these (e.g., one or more) (e.g., PIK3CA It refers to a disease or disorder associated with or having any type of dysregulation of the expression, activity, or level of a gene, or the PI3Kα protein, or any of those described herein. Non-limiting examples of PI3Kα-associated diseases or disorders include, for example, PI3Kα-associated overgrowth syndrome (PROS), brain disorders (e.g., macrocephaly-capillary malformation (MCAP) and unilateral macroencephalopathy), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal malformations (e.g., CLOVES syndrome) and fibrolipopyrrhosis (FH), or cancer (e.g., PI3Kα-associated cancer).

[1016] The term "PI3Kα-associated cancer" as used herein is PIK3CA It refers to a cancer associated with or having dysregulation of the expression or activity or level of a gene, PI3Kα protein, or any of these. Non-limiting examples of PI3Kα-associated cancers are described herein.

[1017] Phrase “ PIK3CA"Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these" refers to a genetic mutation (e.g., resulting in the expression of PI3Kα containing a deletion of at least one amino acid compared to wild-type PI3Kα) PIK3CA Gene mutations, resulting in the expression of PI3Kα with one or more point mutations compared to wild-type PI3Kα PIK3CA A mutation in the gene resulting in the expression of PI3Kα having at least one inserted amino acid compared to wild-type PI3Kα PIK3CA It refers to increased expression (e.g., increased levels) of wild-type PI3Kα in mammalian cells due to gene mutations, gene duplication resulting in increased levels of PI3Kα in cells, or mutations in regulatory sequences (e.g., promoters and / or enhancers) resulting in increased levels of PI3Kα in cells), alternative spliced ​​versions of PI3Kα mRNA resulting in PI3Kα having at least one amino acid deletion compared to wild-type PI3Kα, or dysregulation of abnormal cell signaling and / or autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, PIK3CA The expression or activity, or level dysregulation of the gene, PI3Kα protein, or any of these, does not involve a mutation PIK3CA Encoding PI3Kα that is constitutively active or has increased activity compared to the protein encoded by the gene PIK3CA It may be a mutation of the gene. Non-restrictive examples of PI3Kα point mutations / substitutions / insertions / deletions are listed in Tables 1 and 2.

[1018] In relation to PI3Kα, the term "activating mutation" refers to, for example, the expression of PI3Kα having increased kinase activity compared to wild-type PI3Kα when tested under the same conditions. PIK3CA Describe gene mutations.. For example, the activating mutation may be a mutation in the PIK3CA gene that results in the expression of PI3Kα having one or more amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) having increased kinase activity compared to wild-type PI3Kα when tested, for example, under the same conditions. In another example, the activating mutation may be a mutation in PIK3CA that results in the expression of PI3Kα having one or more amino acids deleted (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) compared to wild-type PI3Kα when tested, for example, under the same conditions. In another example, the activating mutation may be a mutation in the PIK3CA gene that results in the expression of PI3Kα with at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted when tested under the same conditions as wild-type PI3Kα, e.g., the exemplary wild-type PI3Kα described herein. Additional examples of activating mutations are known in the art.

[1019] The terms “wild type” or “wild-type” describe a sequence of nucleic acid (e.g., PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) typically found in subjects that do not have a disease or disorder associated with the reference nucleic acid or protein.

[1020] The term "wild-type PI3Kα" or "wild-type PI3Kα" refers to normal PI3Kα nucleic acids found in subjects who do not have a PI3Kα-associated disease, e.g., PI3Kα-associated cancer (and optionally also do not have an increased risk of developing a PI3Kα-associated disease or are not suspected of having a PI3Kα-associated disease), or found in the cells or tissues of subjects who do not have a PI3Kα-associated disease, e.g., PI3Kα-associated cancer (and optionally also do not have an increased risk of developing a PI3Kα-associated disease or are not suspected of having a PI3Kα-associated disease) (e.g., PIK3CA or PI3Kα mRNA) or protein is described.

[1021] A method for treating cancer (e.g., PI3Kα-associated cancer) in a subject requiring treatment is provided herein, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, a method for treating PI3Kα-associated cancer in a subject requiring treatment is provided herein, the method comprising a) from a sample from the subject PIK3CA The method comprises: a) detecting a dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these; and b) administering 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 these includes one or more PI3Kα protein substitutions / point mutations / insertions. Non-restrictive examples of PI3Kα protein substitutions / insertions / deletions are listed in Tables 1 and 2.

[1022] 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.

[1023] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from blood cancers and solid tumors.

[1024] In some embodiments of any of the methods or uses described herein, cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Breast cancer, ER + It is selected from breast cancer, including triple-negative breast cancer, endometrial cancer, lung cancer (including adenocarcinoma and squamous cell lung carcinoma), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (head and neck squamous cell carcinoma, e.g., oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasm (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, and pancreatic cancer.

[1025] In some embodiments of any of the methods or uses described herein, cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Breast cancer, ER +It is selected from breast cancer, including 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), renal cancer, pancreatic neuroendocrine neoplasm (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma and squamous cell lung carcinoma), and endometrial cancer.

[1026] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer, lung cancer, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal gastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[1027] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is lung cancer.

[1028] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated arm is selected from the arms listed in Table 1 and Table 2.

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050] In some embodiments, PIK3CA Dysregulation of the expression or activity or level of the gene, PI3Kα protein, or any of these includes a splice variant of PI3Kα mRNA resulting in an expressed protein that is an alternatively spliced ​​variant of PI3Kα with at least one residue deleted (compared to the wild-type PI3Kα protein) resulting in constitutive activity of the PI3Kα protein domain.

[1051] In some embodiments, PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these results in the production of a PI3Kα protein with one or more amino acids inserted or removed compared to the wild-type PI3Kα protein. PIK3CACausing the production of PI3Kα protein having one or more amino acid substitutions, insertions, or deletions in the gene PIK3CA The gene contains at least one point mutation. In some cases, the generated mutant PI3Kα protein has increased activity compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation. In some embodiments, the compound described herein selectively inhibits the generated mutant PI3Kα protein compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation.

[1052] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ No. 1)

[1053] MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK

[1054] VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA

[1055] VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP

[1056] NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY

[1057] ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD

[1058] CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD

[1059] IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA

[1060] RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH

[1061] GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV

[1062] SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF

[1063] LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME

[1064] LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV

[1065] RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK

[1066] HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG

[1067] FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII

[1068] FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV

[1069] VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS

[1070] CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE

[1071] RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN

[1072] LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG

[1073] WTTKMDWIFH TIKQHALN

[1074] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable variant thereof, is useful for treating cancer identified as having one or more PI3Kα mutations. Accordingly, a method for treating a subject diagnosed with (or identified as having) cancer is provided herein, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[1075] Additionally, a method for treating a subject identified or diagnosed with PI3Kα-associated cancer is provided herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is from the subject or a biopsy sample from the subject PIK3CA Expression or activity or level of the gene, PI3Kα protein, or any of these It has been identified or diagnosed as having PI3Kα-associated cancer through the use of regulatory agency-approved, e.g., FDA-approved tests or assays to identify dysregulation, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is PI3Kα-associated cancer.

[1076] The term "regulatory agency" refers to a national agency that approves the medical use of pharmaceutical preparations. For example, a non-restrictive example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[1077] Additionally, a method for treating cancer in a subject in need is provided, the method comprising: (a) detecting PI3Kα-associated cancer in the subject; and (b) administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. Some embodiments of these methods further comprise administering another anticancer agent (e.g., immunotherapy) to the subject. In some embodiments, the subject has previously been treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is from the subject or a biopsy sample from the subject PIK3CA It is determined that a person has PI3Kα-associated cancer by using a regulatory agency-approved, e.g., FDA-approved test or assay to identify dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is PI3Kα-associated cancer.

[1078] In addition, the object PIK3CA A step of performing an assay on a sample obtained from a subject to determine whether there is dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these, and PIK3CAA method for treating a subject is provided, comprising the step of administering (e.g., specifically or optionally) a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject determined to have dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. Some embodiments of these methods further comprise administering another anticancer agent (e.g., immunotherapy) to the subject. In some embodiments of these methods, the subject has previously been treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having PI3Kα-associated cancer, a subject exhibiting one or more symptoms of PI3Kα-associated cancer, or a subject at high risk of developing PI3Kα-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the test is a regulatory agency-approved test, e.g., an FDA-approved kit. In some embodiments, the test is a liquid biopsy. Additional non-limiting tests that may be used in this method are described herein. Additional tests are also known in the art.

[1079] In addition, the object PIK3CA A compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is provided for use in treating PI3Kα-associated cancer in a subject identified or diagnosed as having PI3Kα-associated cancer through the step of performing a test (e.g., an in vitro test) on a sample obtained from the subject to determine whether there is dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these, wherein PIK3CAThe presence of dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these identifies that the subject has PI3Kα-associated cancer. Additionally, the subject PIK3CA The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the production of a drug to treat PI3Kα-associated cancer in a subject identified or diagnosed as having PI3Kα-associated cancer through the step of performing an assay on a sample obtained from the subject to determine whether there is dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these, wherein PIK3CA The presence of a gene, PI3Kα protein, or dysregulation of the expression, activity, or level of any of these identifies that the subject has PI3Kα-associated cancer. Some embodiments of any of the methods or uses described herein involve, through the performance of an assay, that the subject PIK3CA It further includes recording in the subject's clinical record (e.g., computer-readable medium) that the subject is determined to have dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these, and that a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or brake-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[1080] Additionally, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer in a subject in need, or in a subject identified or diagnosed as having PI3Kα-associated cancer. Additionally, a use of the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for the production of a drug for treating cancer in a subject identified or diagnosed as having PI3Kα-associated cancer. In some embodiments, the subject is from a subject or a biopsy sample from a subject PIK3CA It is identified or diagnosed as having PI3Kα-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved kit, to identify dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. As provided herein, PI3Kα-associated cancer includes those described herein and known in the art.

[1081] In some embodiments of any of the methods or uses described herein, the object is PIK3CA It has been identified or diagnosed as having cancer having 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 PIK3CA A tumor having a benign tumor for 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 has a tumor. PIK3CA The subject may be having a tumor(s) that is benign 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 is a tumor(s) PIK3CAThe subject may be having 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-associated cancer. In some embodiments, a method for treating PI3Kα-associated cancer in a subject requiring treatment is provided herein, the method comprising: a) from a sample from the subject PIK3CA The method comprises: a) detecting a dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these; and b) administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, PIK3CA The gene, PI3Kα protein, or dysregulation of the expression, activity, or level of any of these comprises one or more PI3Kα protein point mutations / insertions / deletions. Non-limiting examples of PI3Kα protein point mutations / insertions / deletions are listed in Tables 1 and 2. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Kα protein point mutation / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, PIK3CA Cancers having dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these are determined using regulatory agency-approved, e.g., FDA-approved tests or kits. In some embodiments, PIK3CATumors having dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these are determined using regulatory agency-approved, e.g., FDA-approved tests or kits.

[1082] In some embodiments of any of the methods or uses described herein, the object is an object PIK3CA The subject has a clinical record indicating that they have a tumor with dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these. Additionally, the subject has a clinical record indicating that they have a tumor. PIK3CA A method for treating a subject is provided comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having a clinical record indicating dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these.

[1083] In some embodiments, the method provided herein is such that the object PIK3CA The method includes performing an assay on a sample obtained from a subject to determine whether there is dysregulation of the expression or level of the gene, the PI3Kα protein, or any of these. In some of these embodiments, the method also includes a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. PIK3CA It comprises administering to a subject determined to have dysregulation of the expression or activity, or level, of the gene, PI3Kα protein, or any of these. In some embodiments, the method through a test performed on a sample obtained from the subject The object PIK3CAIt includes determining whether there is dysregulation of the expression or level of a gene, PI3Kα protein, or any of these. In such an embodiment, the method also includes administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these PIK3CA It is one or more point mutations of a gene (e.g., any of one or more PI3Kα point mutations described herein). PIK3CA One or more point mutations in the gene may result in the translation of the PI3Kα protein having one or more of the following amino acid substitutions, deletions, and insertions, for example: 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 a gene may result in the translation of a PI3Kα protein having one or more of the following amino acids, for example: 542, 545, 1043, and 1047 and 1049. In some embodiments, PIK3CA The dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these is one or more PI3Kα amino acid substitutions (e.g., any of the PI3Kα amino acid substitutions described herein). Some embodiments of these methods further include administering another anticancer agent (e.g., immunotherapy) to the subject.

[1084] In some embodiments of any of the methods or uses described herein, using a sample from an object, the object PIK3CAThe assay used to determine whether there is dysregulation of the expression, activity, or level of the gene, or the PI3Kα protein, or any of these, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, Brake Apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As known in the art, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. The assay PIK3CA Other detection methods known in the art may be utilized to detect dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these (e.g., see references cited herein). In some embodiments, the sample is a biological sample or biopsy sample from a subject (e.g., a paraffin-embedded biopsy sample). In some embodiments, the subject is a subject suspected of having PI3Kα-associated cancer, a subject having one or more symptoms of PI3Kα-associated cancer, and / or a subject at increased risk of developing PI3Kα-associated cancer.

[1085] In some embodiments, PIK3CA Dysregulation of the expression, activity, or level of a gene, the PI3Kα protein, or any of these can be identified using liquid biopsy (variably referred to as fluid biopsy or fluid phase biopsy). For example, Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med. See , 3(3):36, 2016. . Total tumor burden and / or using liquid biopsy methods PIK3CA Gene, PI3Kα protein, Or, dysregulation of the expression, activity, or level of any of these can be detected. Liquid biopsy can be performed on biological samples obtained relatively easily from a subject (e.g., through a simple blood draw) and generally involves tumor burden and / or PIK3CA It is less invasive than traditional methods used to detect dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. In some embodiments, using a liquid biopsy PIK3CA The presence of dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these can be detected at an earlier stage than traditional methods. In some embodiments, the biological samples used in the liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, circulating tumor cells (CTCs) can be detected using the liquid biopsy. In some embodiments, cell-free DNA can be detected using the liquid biopsy. In some embodiments, the cell-free DNA detected using the liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. ctDNA analysis (e.g., using sensitive detection techniques, e.g., next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis, without limitation) PIK3CA It is possible to identify dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these.

[1086] Additionally, a method for inhibiting PI3Kα activity in cells is provided, comprising contacting cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, contact is made in vitro. In some embodiments, contact is made in vivo. In some embodiments, contact is made in vivo The method comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject having cells having abnormal 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" refers to in vitro In a system or in vivo It refers to bringing together the indicated moiety in the system. For example, “contacting” a PI3Kα protein with a compound provided herein includes administering the compound provided herein to an individual or subject having a PI3Kα protein, e.g., a human, as well as introducing the compound provided herein into a sample containing a cell or purified preparation containing a PI3Kα protein, e.g.

[1087] Additionally, the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting cells with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[1088] A method for increasing apoptosis in vitro or in vivo is further provided herein, comprising contacting cells with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Additionally, a method for increasing tumor cell apoptosis in a subject is provided herein. The method comprises administering to a subject an effective compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for increasing tumor cell apoptosis.

[1089] The term “therapeutic effective dose” means an amount of compound sufficient to (i) treat a PI3Kα protein-associated disease or disorder, (ii) alleviate, improve, or eliminate one or more symptoms of a specific disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof corresponding to such an amount may vary depending on factors such as the specific compound, the condition and severity thereof, and the characteristics of the subject requiring treatment (e.g., body weight), but can nevertheless be routinely determined by a person skilled in the art.

[1090] When used as a pharmaceutical agent, a compound of formula (I) containing a pharmaceutically acceptable salt It may be administered in the form of a pharmaceutical composition as described herein.

[1091] mixture

[1092] In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each individual subject with cancer. In medical oncology, other component(s) of such co-treatment or therapy in addition to the composition provided herein may be, for example, surgery, radiotherapy, and chemotherapy agents, such as other kinase inhibitors, signaling inhibitors, and / or monoclonal antibodies. For example, surgery may be open surgery or minimally invasive surgery. The compound of formula (I), or a pharmaceutically acceptable salt thereof, may therefore also be useful as an adjuvant for cancer treatment; that is, they may be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapy agents acting with the same or different mechanisms of action. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be used prior to the administration of additional therapeutic agents or additional therapies. For example, at least partial resection of the tumor may be performed after one or more doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, have been administered to the subject in need over a specified period. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject in need for a specified period, and one or more radiation therapy sessions may be performed. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor burden) prior to one or more radiation therapy sessions.

[1093] In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is refractory or tolerant to standard therapy (e.g., chemotherapy agents, e.g., administration of multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is refractory or tolerant to prior therapy (e.g., chemotherapy agents, e.g., administration of multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that has not received standard therapy. In some embodiments, the subject has no experience with PI3Kα inhibitors. For example, the subject has no experience with treatment using a selective PI3Kα inhibitor. In some embodiments, the subject is not without experience with PI3Kα inhibitors. In some embodiments, the subject has no experience with kinase inhibitors. In some embodiments, the subject is not without experience with kinase inhibitors. In some embodiments, the subject has received previous treatment.For example, multi-kinase inhibitors (MKIs) or other PI3K inhibitors, e.g., bupalisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), Pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), Treatment with VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2 023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, or GSK2636771.

[1094] In some embodiments of any of the methods described herein, the compound of formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic agents (e.g., chemotherapy agents).

[1095] Non-limiting examples of additional therapeutic agents include: other PI3Kα-targeted therapeutic agents (i.e., other PI3Kα inhibitors), EGFR inhibitors, HER2 inhibitors, RAS pathway-targeted therapeutic agents (including mTOR inhibitors as described herein), PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), farnesyl transferase inhibitors, signaling pathway inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERMs; selective estrogen receptor modulators / SERDs; selective estrogen receptor degraders), checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapy agents, angiogenesis-targeted therapeutic agents, immuno-targeted therapeutic agents including immunotherapy, and radiotherapy.

[1096] In some embodiments, the EGFR inhibitors are osimertinib (AZD9291, merelectinib, TAGRISSO™), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), Zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin, and acetylalkanin), poziotinib (NOV120101, HM781-36B),AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), felitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avicinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAB-425, modotuximab (Tab-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-armed autologous T cells, and EGFR CAR-T therapy. In some embodiments, the EGFR-targeting therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[1097] Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pirotinib, poziotinib, CP-724714, CUDC-101, and safitinib (AZD8931). Includes tanespimycin (17-AAG), IPI-504, PF299, felitinib, S-222611, and AEE-788.

[1098] "RAS pathway targeting therapeutics" as used herein comprise any compound exhibiting inactivating activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the RAS pathway. Non-limiting examples of proteins in the RAS pathway include any one of proteins in the RAS-RAF-MAPK pathway or 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 the RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway targeting therapeutic is a "KRAS pathway modulator." KRAS pathway modulators comprise any compound exhibiting inactivating activity (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of 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.

[1099] Non-limiting examples of KRAS-targeted therapeutics (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[1100] Additional non-restrictive examples of RAS-targeted therapies include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

[1101] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypotemacin, or a combination thereof.

[1102] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxogenol, 5-iodotubercidine, GDC0994, ONC201, or a combination thereof.

[1103] In some embodiments, the other PI3K inhibitor is another PI3Kα inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, other PI3K inhibitors are bupalisib (BKM120), alperisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), doctolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonorisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), filaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), ceravelisib (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, Rigosertip, XL-765, LY2023414, SAR260301, KIN-193(AZ D-6428), GS-9820, AMG319, GSK2636771, or a combination thereof is selected.

[1104] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wortmannine, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphosphocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, trisiribine (trisiribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tyrucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or combinations thereof are selected from erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, trisiribine (trisiribine phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridine-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tyrucalic acid, lactoquinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or combinations thereof.

[1105] In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

[1106] Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[1107] In some embodiments, the chemotherapeutic agent is an anthracycline, cyclophosphamide, taxane, platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVEN™), or It includes combinations of these.

[1108] Non-limiting examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[1109] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[1110] In some embodiments, the platinum-based formulation is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, trilatine tetranitrate, phenantriplatin, picoplatin, satraplatin, and combinations thereof.

[1111] Non-restrictive 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.

[1112] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[1113] Non-limiting examples of selective estrogen receptor modulators or degraders (SERM / SERD) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

[1114] 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®), cemiplimab (LIBTAYO®), or a combination thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or a combination thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. For example, Marin-Acevedo, et al. J Hematol Oncol See . 11: 39 (2018).

[1115] In some embodiments, additional therapies or treatments include fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab-paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, ribociclib, palbociclib, bupalisib, AEB071, everolimus, exemestane, cisplatin, letrozole, AMG 479, LSZ102, LEE011, cetuximab, AUY922, BGJ398, MEK162, LJM716, LGH447, imatinib, gemcitabine, It is selected from LGX818, Amsenestrant, and combinations thereof.

[1116] In some embodiments, additional therapeutic agents, such as opioids and corticosteroids, may also be administered to treat potential side effects of a specific anticancer therapy and / or as palliative therapy. In some embodiments, the additional therapy or therapeutic agent described herein is selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, metformin, and combinations thereof.

[1117] 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.

[1118] Non-restrictive 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 It includes ), and tofogliflozin.

[1119] Non-restrictive examples of DPP-4 inhibitors include sitagliptin (JANUVIA®), vildagliptin, saxagliptin (ONGLYZA®), linagliptin (TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (NESINA®), omarigliptin, evogliptin, and dutogliptin.

[1120] In some embodiments, the subject is also instructed to maintain a specific diet and / or exercise regimen to control blood glucose levels.

[1121] Accordingly, a method for treating cancer is also provided herein, comprising administering to a subject requiring a pharmaceutical combination for treating cancer comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for cancer treatment, wherein the amounts of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are effective together for treating cancer.

[1122] In some embodiments, additional therapeutic(s) include any one of the therapies listed above or a therapeutic that is a standard of cancer care, wherein the cancer PIK3CA It has dysregulation of the expression or activity or level of the gene, PI3Kα protein, or any of these.

[1123] These additional therapeutic agents may be administered as part of the same or a separate form of administration, through the same or a different route of administration, and / or in the same or a different schedule of administration according to standard pharmaceutical practices known to a person skilled in the art, with one or more doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[1124] (i) a pharmaceutical combination for treating cancer in a subject in need, comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for treating cancer, wherein the amounts of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are effective together for treating cancer; (ii) a pharmaceutical composition comprising such combination; (iii) use of such combination for the preparation of a drug for treating cancer; and (iv) a commercial package or product comprising such combination, such as a combined formulation for simultaneous, separate, or sequential use; and a method for treating cancer in a subject in need is also provided herein. In some embodiments, the cancer is PI3Kα-associated cancer.

[1125] As used herein, the term “pharmaceutical combination” refers to a pharmaceutical regimen resulting from a mixture or combination of one or more active ingredients and includes both fixed and non-fixed combinations of active ingredients. The term “fixed combination” means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapy agent) are all administered to a subject simultaneously in the form of a single composition or dosage. The term “non-fixed combination” means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapy agent) are formulated in separate compositions or dosages and administered to a subject in need simultaneously, concurrently, or sequentially with variable intervening time limits, wherein such administration provides effective levels of two or more compounds in the subject’s body. This also applies to cocktail regimens administering, for example, three or more active ingredients.

[1126] Accordingly, a method for treating cancer is also provided herein, comprising administering to a subject requiring a pharmaceutical combination for treating cancer comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, 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 are effective together for treating cancer. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously in separate doses. 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 in separate doses, in a co-therapeutic effective amount, e.g., daily or intermittent doses. In some embodiments, the compound of formula (I), Or its pharmaceutically acceptable salt and additional therapeutic agents are administered simultaneously in a combined dose.

[1127] Implementation example

[1128] Embodiment 1: Compound of chemical formula (I):

[1129] (I)

[1130] or as a pharmaceutically acceptable salt thereof, wherein:

[1131] Z is O or NR x And;

[1132] R x Is It is hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[1133] Each R 1 silver Independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl;

[1134] m is 0, 1, 2, or 3, and;

[1135] R 2 is a halogen, a hydroxyl, a C1-C6 alkyl alkyl optionally substituted with a hydroxyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with one or two fluoros;

[1136] R 3 is a C3-C6 cycloalkyl optionally substituted with one or two substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, or fluoro and C1-C6 alkyl;

[1137] Ring A is a 6-10-membered aryl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclil;

[1138] Each R 4 is independently selected from a group consisting of:

[1139] (i) Halogen,

[1140] (ii) 1 or 2 hydroxyl or -NR A R B C1-C6 alkyl alkyl arbitrarily substituted with

[1141] (iii) A C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl,

[1142] (iv) C1-C6 haloalkyl,

[1143] (v) hydroxyl,

[1144] (vi) cyano,

[1145] (vii) -CO2H,

[1146] (viii) -NR A R B ,

[1147] (ix) =NR A2 ,

[1148] (x) -C(=O)NR C R D ,

[1149] (xi) -SO2(NR E R F ),

[1150] (xii) -SO2(C1-C6 alkyl),

[1151] (xiii) -S(=O)(=NH)(C1-C6 alkyl),

[1152] (xiv) -C(=O)(C1-C6 alkyl),

[1153] (xv) -CO2(C1-C6 alkyl),

[1154] (xvi) 5-6 member heteroaryl optionally substituted with C1-C6 alkyl,

[1155] (xvii) 1 or 2 independently selected R G A 3-9 member heterocyclile arbitrarily substituted with , and

[1156] (xviii) One or two independently selected R G 3-6 member cycloalkyl arbitrarily substituted with;

[1157] n is 0, 1, or 2, and;

[1158] Each R A , R A1 , R B , R B1 , R C , R C1 , R D , R D1 , R E , and R F is doing it independently or

[1159] (i) hydrogen,

[1160] (ii) Hydroxyl,

[1161] (iii) 4-6-membered heterocyclil,

[1162] (iv) C1-C6 haloalkyl,

[1163] (v) -C(=O)(C1-C6 alkyl),

[1164] (vi) -C(=O)O(C1-C6 alkyl),

[1165] (vii) -SO2(C1-C6 alkyl),

[1166] (viii) a 3-6-membered cycloalkyl optionally substituted with a hydroxyl, or

[1167] (ix) Hydroxyl, -C(=O)NR B2 R C2 , C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from 5-6-membered heteroaryl, 3-6-membered cycloalkyl, -SO2(C1-C6 alkyl), -CO2H, and -SO2(NH2); or

[1168] R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 , -SO2(C1-C6 alkyl), -CO2H, a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl forming;

[1169] Each R A2 , R B2 , and R C2 Is Independently hydrogen or C1-C6 alkyl;

[1170] Each R G -NR is a fluoro, cyano, hydroxyl, or optionally hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, or -NR A1 R B1 , =NR A2 , -C(=O)NR C1 R D1Independently selected from the group consisting of -CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO2(C1-C6 alkyl), and -CO2H; and

[1171] Herein, the above compound is not a compound selected from the group consisting of:

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182] Embodiment 2: A compound in Embodiment 1, wherein m is 1.

[1183] Embodiment 3: A compound in Embodiment 1, wherein m is 2.

[1184] Example 4: In Example 1 or 2, silver Phosphorus, compound.

[1185] Example 5: In Example 1 or 2, silver Phosphorus, compound.

[1186] Example 6: In Example 1 or 3, silver Phosphorus, compound.

[1187] Embodiment 7: In any one of Embodiments 1 to 6, each R1 A compound that is a halogen.

[1188] Embodiment 8: In any one of Embodiments 1 to 7, each R 1 A compound selected from fluoro and chloro.

[1189] Embodiment 9: In any one of Embodiments 1 to 8, each R 1 It is a fluorophosphate, a compound.

[1190] Embodiment 10: In any one of Embodiments 1 to 6, one R 1 Cyanoside, compound.

[1191] Embodiment 11: In any one of Embodiments 1 to 6, one R 1 A compound that is a C1-C6 alkyl.

[1192] Embodiment 12: In any one of Embodiments 1 to 6, one R 1 A compound that is a C3-C6 cycloalkyl.

[1193] Embodiment 13: A compound in which m is 0, in Embodiment 1.

[1194] Embodiment 14: In any one of Embodiments 1 to 13, R 2 is a compound that is a C1-C6 alkyl.

[1195] Example 15: In Embodiment 14, R 2 is a methyl compound.

[1196] Example 16: In any one of embodiments 1 to 13, R 2 Is A compound that is a C1-C6 haloalkyl.

[1197] Implementation Example 17: In Embodiment 16, R 2 Is Difluoromethyl, a compound.

[1198] Example 18: In Embodiment 16, R 2 Is trifluoromethyl, a compound.

[1199] Example 19: In any one of embodiments 1 to 13, R 2 is a halogen, compound.

[1200] Implementation Example 20: In any one of embodiments 1 to 13, R 2 A compound that is a C3-C6 cycloalkyl optionally substituted with one or two fluoro groups.

[1201] Implementation Example 21: In any one of embodiments 1 to 13 or 20, R 2 1 or a compound that is a C3-C6 cycloalkyl substituted with two fluoro groups.

[1202] Implementation Example 22: In any one of embodiments 1 to 13 or 21, R 2 Is A compound that is an unsubstituted C3-C6 cycloalkyl.

[1203] Implementation Example 23: In any one of embodiments 1 to 22, R 3 A compound that is a C1-C6 alkyl.

[1204] Implementation Example 24: In any one of embodiments 1 to 23, R 3 silver A compound that is methyl, ethyl, or isopropyl.

[1205] Implementation Example 25: In any one of embodiments 1 to 23, R 3 It is methyl, a compound.

[1206] Implementation Example 26: In any one of embodiments 1 to 23, R 3 silver Ethyl phosphorus, compound.

[1207] Example 27: In any one of embodiments 1 to 23, R 3 silver isopropyl, compound.

[1208] Implementation Example 28: In any one of embodiments 1 to 22, R 3 A compound that is a C1-C6 haloalkyl.

[1209] Implementation Example 29: In any one of embodiments 1 to 22 and 28, R 3 silver trifluoromethyl, a compound.

[1210] Implementation Example 30: In any one of embodiments 1 to 22, R 3 A compound that is optionally substituted with one or two substituents independently selected from fluoro and C1-C6 alkyl, which is a C3-C6 cycloalkyl.

[1211] Implementation Example 31: In any one of embodiments 1 to 22 and 30, R 3 A compound that is a C3-C6 cycloalkyl substituted with one or two fluoro groups.

[1212] Implementation Example 32: In any one of embodiments 1 to 22 and 30, R 3 A compound that is an unsubstituted C3-C6 cycloalkyl.

[1213] Implementation Example 33: In any one of embodiments 1 to 22, 30, and 31, the R 3 A compound in which the C3-C6 cycloalkyl is cyclopropyl.

[1214] Implementation Example 34: A compound in any one of Embodiments 1 to 33, wherein ring A is a 6-10 aryl.

[1215] Implementation Example 35: In any one of Embodiments 1 to 34, ring A is a phenyl compound.

[1216] Implementation Example 36: A compound in any one of embodiments 1 to 33, wherein ring A is a C3-C8 cycloalkyl.

[1217] Example 37: A compound in any one of embodiments 1 to 33 and 36, wherein ring A is a C5-C6 cycloalkyl.

[1218] Implementation Example 38: A compound in any one of embodiments 1 to 33 and 36 to 37, wherein ring A is cyclohexyl.

[1219] Implementation Example 39: A compound in any one of embodiments 1 to 33, wherein ring A is a 5-10-membered heteroaryl.

[1220] Implementation Example 40: A compound in any one of embodiments 1 to 33 and 39, wherein ring A is a 5-6-membered heteroaryl.

[1221] Implementation Example 41: A compound in any one of embodiments 1 to 33 and 39 to 40, wherein ring A is pyrimidinyl, pyridyl, thiazolyl, thiophenyl, or pyrazolyl.

[1222] Implementation Example 42: A compound in any one of embodiments 1 to 33 and 39 to 41, wherein ring A is pyrimidinyl.

[1223] Implementation Example 43: In any one of embodiments 1 to 33 and 39 to 41, ring A is pyridyl, a compound.

[1224] Implementation Example 44: A compound in any one of embodiments 1 to 33 and 39 to 41, wherein ring A is thiazolyl.

[1225] Implementation Example 45: A compound in any one of embodiments 1 to 33 and 39 to 41, wherein ring A is thiophenyl.

[1226] Implementation Example 46: A compound in any one of embodiments 1 to 33 and 39 to 41, wherein ring A is pyrazolyl.

[1227] Implementation Example 47: A compound in any one of embodiments 1 to 33 and 39 to 41, wherein ring A is 5-pyrimidinyl, 3-pyridyl, or 4-pyrazolyl.

[1228] Implementation Example 48: A compound in any one of embodiments 1 to 33, 39 to 41, and 47, wherein ring A is 5-pyrimidinyl.

[1229] Implementation Example 49: A compound in any one of embodiments 1 to 33, 39 to 41, and 47, wherein ring A is 3-pyridyl.

[1230] Implementation Example 50: A compound in any one of embodiments 1 to 33, 39 to 41, and 47, wherein ring A is 4-pyrazolyl.

[1231] Example 51: A compound in any one of embodiments 1 to 33 and 39, wherein ring A is a 9-10-membered heteroaryl.

[1232] Implementation Example 52: A compound in any one of embodiments 1 to 33, 39, and 51, wherein ring A is benzimidazolyl, indazolyl, indolyl, quinazolone, isobenzofuranonyl, isoindolinyl, or imidazo[1,2-a]pyridinyl.

[1233] Implementation Example 53: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is benzimidazolyl.

[1234] Implementation Example 54: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is indazolyl.

[1235] Example 55: In any one of embodiments 1 to 33, 39, and 51 to 52, ring A is an indolyl compound.

[1236] Implementation Example 56: In any one of embodiments 1 to 33, 39, and 51 to 52, ring A is an indolyl compound.

[1237] Example 57: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is quinazolone.

[1238] Implementation Example 58: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is isobenzofuranonyl.

[1239] Example 59: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is isoindolinyl.

[1240] Implementation Example 60: A compound in any one of embodiments 1 to 33, 39, and 51 to 52, wherein ring A is imidazo[1,2-a]pyridinyl.

[1241] Example 61: In any one of embodiments 1 to 33, 39, and 51 to 52, ring A is 2-benzimidazolyl, 5-indazolyl, 2-indolyl, 7-imidazo[1,2-a]pyridinyl, , or Phosphorus, compound.

[1242] Implementation Example 62: A compound in any one of embodiments 1 to 33, 39, and 61, wherein ring A is 2-benzimidazolilic.

[1243] Example 63: A compound in any one of embodiments 1 to 33, 39, and 61, wherein ring A is 5-indazolilyl.

[1244] Implementation Example 64: In any one of embodiments 1 to 33, 39, and 61, ring A is 2-indolyl, a compound.

[1245] Example 65: A compound in any one of embodiments 1 to 33, 39, and 61, wherein ring A is 7-imidazo[1,2-a]pyridinyl.

[1246] Example 66: In any one of embodiments 1 to 33, 39, and 61, ring A is Phosphorus, compound.

[1247] Example 67: In any one of embodiments 1 to 33, 39, and 61, ring A is Phosphorus, compound.

[1248] Example 68: A compound in any one of embodiments 1 to 33, wherein ring A is a 4-10-membered heterocyclile.

[1249] Example 69: A compound in any one of embodiments 1 to 33 and 68, wherein ring A is a 6-9-membered heterocyclile.

[1250] Implementation Example 70: A compound in any one of embodiments 1 to 33 and 68 to 69, wherein ring A is piperidinyl or 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide.

[1251] Implementation Example 71: A compound in any one of embodiments 1 to 33 and 68 to 70, wherein ring A is piperidinyl.

[1252] Implementation Example 72: A compound in any one of embodiments 1 to 33 and 68 to 70, wherein ring A is 3-methyltetrahydro-2H-thiopyranyl-1,1-dioxide.

[1253] Implementation Example 73: In any one of embodiments 1 to 33 and 68 to 70, ring A is 3-piperidinyl, 4-piperidinyl, or Phosphorus, compound.

[1254] Implementation Example 73: A compound in any one of embodiments 1 to 33 and 68 to 70, wherein ring A is 3-piperidinyl.

[1255] Implementation Example 74: A compound in any one of embodiments 1 to 33 and 68 to 70, wherein ring A is 4-piperidinyl.

[1256] Example 75: In any one of embodiments 1 to 33 and 68 to 70, ring A is Phosphorus, compound.

[1257] Implementation Example 76: A compound in any one of embodiments 1 to 75, wherein n is 1.

[1258] Example 77: A compound in any one of embodiments 1 to 75, wherein n is 2.

[1259] Example 78: In any one of embodiments 1 to 77, one R 4 is a compound that is an unsubstituted C1-C6 alkyl.

[1260] Example 79: In any one of embodiments 1 to 78, one R 4is a methyl compound.

[1261] Example 80: In any one of embodiments 1 to 77, one R 4 is a compound of a C1-C6 alkoxyne optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[1262] Example 81: In any one of embodiments 1 to 77, one R 4 is a compound of a C1-C6 alkoxyne substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[1263] Implementation Example 82: In any one of embodiments 1 to 77, one R 4 is a compound of a C1-C6 alkoxyne substituted with a hydroxyl or C3-C6 cycloalkyl group.

[1264] Implementation Example 83: In any one of embodiments 1 to 77, one R 4 is a compound of a C1-C6 alkoxyne substituted with two substituents independently selected from hydroxyl and C3-C6 cycloalkyl.

[1265] Implementation Example 84: In any one of embodiments 1 to 77, one R 4 Is C1-C6 alkoxyne, compound.

[1266] Example 85: In any one of embodiments 1 to 77 and 84, one R 4 Is Methoxyin, compound.

[1267] Example 86: In any one of embodiments 1 to 77, one R 4 Is A compound that is a C1-C6 haloalkyl.

[1268] Example 87: In any one of embodiments 1 to 77 and 86, one R 4 Is trifluoromethyl, a compound.

[1269] Example 88: In any one of embodiments 1 to 77, one R 4 Is Hydroxyl, compound.

[1270] Example 89: In any one of embodiments 1 to 77, one R 4 Is Cyanoin, compound.

[1271] Implementation Example 90: In any one of embodiments 1 to 77, one R 4 Is - A compound that is CO2H.

[1272] Implementation Example 91: In any one of embodiments 1 to 77, one R 4 is a halogen, compound.

[1273] Implementation Example 92: In any one of embodiments 1 to 77, one R 4 A compound that is a C1-C6 alkyl substituted with 1-2 hydroxyl groups.

[1274] Implementation Example 93: In any one of embodiments 1 to 77 and 92, one R 4 Is A compound that is a C1-C6 alkyl substituted with a hydroxyl.

[1275] Implementation Example 94: In any one of embodiments 1 to 77 and 92, one R 4 Is A compound that is a C1-C6 alkyl substituted with two hydroxyl groups.

[1276] Implementation Example 95: In any one of embodiments 1 to 77, one R 4 Is -NR A R B A compound that is a C1-C6 alkyl substituted with

[1277] Implementation Example 96: In any one of embodiments 1 to 77, one R 4 Is -NR A R B Phosphorus, compound.

[1278] Example 97: In any one of embodiments 1 to 77 and 95 to 96, R A and R B are compounds, each containing hydrogen.

[1279] Implementation Example 98: In any one of embodiments 1 to 77 and 95 to 96, R A and R B are each C1-C6 alkyls, compound.

[1280] Implementation Example 99: In any one of embodiments 1 to 52, 95 to 96, and 98, R A and R B are methyl, a compound, respectively.

[1281] Implementation Example 100: In any one of embodiments 1 to 77 and 95 to 96, R A and R B One of them is hydrogen and R A and R B The other one is C1-C6 A compound that is a haloalkyl.

[1282] Example 101: In any one of embodiments 1 to 77, one R 4 is -C(=O)NR C R D Phosphorus, compound.

[1283] Example 102: In any one of embodiments 1 to 77 and 101, R C and R D are compounds, each containing hydrogen.

[1284] Implementation Example 103: In any one of embodiments 1 to 77 and 101, R C and R D are each C1-C6 alkyls, compound.

[1285] Example 104: In any one of embodiments 1 to 77 and 101, R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 A compound forming a 4-10-membered heterocyclile optionally substituted with 1-2 substituents independently selected from -SO2(C1-C6 alkyl), -CO2H, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with hydroxyl.

[1286] Example 105: In any one of embodiments 1 to 77 and 101, R C and R D , together with the nitrogen atoms to which they are attached, hydroxyl, halogen, -C(=O)NR B1 R C1 A compound forming a 4-10-membered heterocyclile substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy optionally substituted with -SO2(C1-C6 alkyl), -CO2H, and hydroxyl.

[1287] Example 106: In any one of embodiments 1 to 77 and 101, R C and R DA compound that forms a 4-6 member heterocyclile together with the nitrogen atoms to which they are attached.

[1288] Example 107: In any one of embodiments 1 to 77, 101, and 76, R C and R D A compound that forms azetidine or piperazine together with the nitrogen atoms to which they are attached.

[1289] Example 108: In any one of embodiments 1 to 77, one R 4 Is -SO2(NR E R F ) Phosphorus, compound.

[1290] Example 109: In any one of embodiments 1 to 77 and 108, R E and R F Is Hydrogen, compound, respectively.

[1291] Implementation Example 110: In any one of embodiments 1 to 77 and 208, R E and R F Is Compounds, each being a C1-C6 alkyl.

[1292] Implementation Example 111: In any one of embodiments 1 to 77, one R 4 Is -SO2(C1-C6 alkyl) compound.

[1293] Implementation Example 112: In any one of embodiments 1 to 77 and 111, one R 4 Is -SO2Me, a compound.

[1294] Implementation Example 113: In any one of embodiments 1 to 77 and 111, one R 4 Is - A compound that is SO2Et.

[1295] Implementation Example 114: In any one of embodiments 1 to 77, one R 4 Is -S(=O)(=NH)(C1-C6 alkyl) compound.

[1296] Example 115: In any one of embodiments 1 to 77 and 84, one R 4 Is -S(=O)(=NH)Me, a compound.

[1297] Implementation Example 116: In any one of embodiments 1 to 77, one R 4 is a compound that is -C(=O)(C1-C6 alkyl).

[1298] Example 117: In any one of embodiments 1 to 77 and 106, one R 4 Is - A compound of C(=O)Me.

[1299] Example 118: In any one of embodiments 1 to 77, one R 4 Is -CO2(C1-C6 alkyl) compound.

[1300] Example 119: In any one of embodiments 1 to 77 and 118, one R 4 Is -CO2Me, a compound.

[1301] Implementation Example 120: In any one of embodiments 1 to 77, one R 4 Is A compound that is a 5-6 member heteroaryl optionally substituted with a C1-C6 alkyl group.

[1302] Example 121: In any one of embodiments 1 to 77 and 120, one R4 Is A compound that is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group.

[1303] Implementation Example 122: In any one of embodiments 1 to 77 and 120 to 121, one R 4 Is A compound that is a methyl-substituted tetrazolyl.

[1304] Implementation Example 123: In any one of embodiments 1 to 77 and 90, one R 4 Is A compound that is an unsubstituted 5-6 member heteroaryl.

[1305] Implementation Examp...

Claims

Claim 1 Uses of the compound of chemical formula (IA).

Images