Tricyclic triazole compounds as DGK inhibitors

Abstract

This application provides a tricyclic triazol compound I that regulates the activity of diacylglycerol kinase (DGK), which is useful for the treatment of various diseases including cancer. JPEG2025519493000441.jpg59165

Description

Technical Field

[0001] The present invention provides a tricyclic triazole compound that regulates the activity of diacylglycerol kinase (DGK) and is useful for the treatment of diseases related to diacylglycerol kinase, including cancer.

Background Art

[0002] Diacylglycerol kinases (DGKs) are a family of enzymes that control many biological processes, including the etiology of diseases such as cell proliferation, migration, immunity, and cancer. In the mammalian system, there are 10 DGK family members classified into 5 subtypes based on a common domain (Sakane F. et al., Int. J. Mol. Sci., 2020. 21: p6794-6829). The diverse and specific cellular functions of individual DGK isoforms are controlled through their tissue-specific expression, intracellular localization, and interaction with regulatory proteins (Joshi, R.P. and Koretzky, G.A., Int. J. Mol. Sci., 2013. 14: p6649-6673).

[0003] In T lymphocytes, DGKα and ζ are the predominantly expressed DGK isoforms (Krishna, S. and Zhong, X.-P., Front Immunol., 2013. 4:178). Specifically, in response to T cell receptor (TCR) activation, phospholipase Cγ1 (PLCγ1) hydrolyzes the membrane phospholipid PIP2 to generate diacylglycerol (DAG) (Krishna, S. and Zhong, X.-P., Front Immunol., 2013. 4:178, Riese, M. J. et al., Front Cell Dev Biol., 2016. 4:108). Next, DAG functions as a second messenger to recruit RasGRP1 and PKCθ to the cell membrane, thereby initiating multiple downstream signaling events that lead to T cell activation. To prevent hyperactivation of T cells, DGKα and ζ potently control intracellular DAG levels by phosphorylating DAG to produce phosphatidic acid (PA). Genetic studies in both mouse and human cell lines support the important regulatory role of DGKα and ζ in T cell activation. Knockout or depletion of DGKα and ζ has been reported to enhance T cell activation, cytokine production, and proliferation. Furthermore, knockout of both DGKα and ζ shows more potent T cell activation than individual knockouts, indicating that the roles of these two isoforms do not overlap (Riese, M. J. et al., Cancer Res., 2013. 73:p3566-3577, Jung, I.-Y. et al., Cancer Res., 2018. 78:p4692-4703). Thus, DGKα and ζ function as important regulators of T cell activation by linking lipid metabolism and intracellular signaling cascades through controlling cellular DAG levels.

[0004] Cytotoxic T lymphocytes (CTLs) are a major component of the adaptive immune system that recognize and kill cells presenting abnormal proteins such as bacterial or viral infected cells, or tumor antigens. However, cancer cells can evolve to utilize multiple mechanisms that mimic peripheral immune tolerance to avoid immune surveillance and killing by CTLs. Such mechanisms include downregulation of antigen presentation, suppression of T cell function by increased expression of inhibitory molecules, and increased production of immunosuppressive proteins in the tumor microenvironment (Speiser, D.E. et al., Nat. Rev. Immunol., 2016.16: p.599-611, Gonzalez H. et al., Genes & Dev., 2018.32: p1267-1284). Immune checkpoint therapy (ICT) by blocking inhibitory molecules such as PD(L)-1 and CTLA4 can restore T cell activity and is clinically useful for the treatment of many different cancer types. However, due to primary or acquired resistance, only a subset of patients respond to ICT (Sharma, P. et al., Cell. 2017.168: p707-723). Therefore, despite the important clinical successes of immunotherapy in treating cancer in recent years, resistance remains an issue (Sharma, P., et al., Cancer Discov., 2021.11: p838-857).

[0005] Overexpression of DGKα and ζ has been observed in tumor-infiltrating lymphocytes (TILs) derived from human tumors and has been proposed to suppress T cell function. Importantly, significant immune-mediated antitumor activity has been shown in DGKα- and DGKζ-deficient mouse models (Merida, I. et al., Adv. Biol. Regul., 2017. 63: p22-31, Prinz, P. U. et al., J. Immunol., 2012. 188: p5990-6000). Furthermore, DGKα- and DGKζ-deficient T cells are resistant to several immunosuppressive factors within the tumor microenvironment, such as TGFβ, PGE2, and adenosine, as well as to other T cell inhibitory pathways, such as PD(L)-1-mediated immunosuppression (Riese, M. J. et al., Cancer Res., 2013. 73: p3566-77, Jung, I.-Y. et al. (2018) Cancer Res., 2018. 78: p4692-4703, Arranz-Nicolas, J. et al., Cancer Immunol. Immunother., 2018. 67: p965-980, Riese, M. J. et al., Front. Cell Dev. Biol., 2016. 4: 108). Therefore, DGKα and DGKζ are attractive targets as immunotherapies alone or in combination with current ICT therapies such as PD(L)-1 and CTLA4. By targeting T cell lipid metabolism, inhibition of DGKα and DGKζ may restore antitumor immunity in a subset of patients with primary or acquired immune resistance and as a result are refractory to current ICTs. In addition to their function in T lymphocytes, DGKα and DGKζ have also been reported to directly contribute to cancer growth, migration, invasion, and survival by controlling DAG levels within cancer cells. Therefore, DGK inhibition may have a direct antitumor effect by interfering with tumor-intrinsic oncogenic survival pathways (Cooke, M. and Kaznietz, M. G., Sci. Signal., 2022. 15: eabo0264).

[0006] The compounds in this application may have selective activity against one or both of DGKα and DGKζ. These DGK inhibitors can be used for the treatment of cancer alone or in combination with other therapeutic agent(s).

SUMMARY OF THE INVENTION

[0007] The present invention relates, inter alia, to a compound of formula I,

CHEM.

[0008] The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] The present invention further provides a method for inhibiting the activity of a kinase, comprising contacting a diacylglycerol kinase (DGK) with a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0010] The present invention further provides a method for treating a disease or disorder associated with the expression or activity of diacylglycerol kinase (DGK) in a patient by administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0012] The present invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0013] This application relates to a compound of formula I,

CHEM.

Chemical formula

Chemical formula

[0014] In some embodiments, U is CR 3 .

[0015] In some embodiments, R 3 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0016] In some embodiments, R 3 is selected from H and C 1-6 alkyl.

[0017] In some embodiments, U is CH or N.

[0018] In some embodiments, U is CH.

[0019] In some embodiments, U is N.

[0020] In some embodiments, X is CR 4 or NR 4 .

[0021] In some embodiments, X is CR 4 .

[0022] In some embodiments, X is NR 4 .

[0023] In some embodiments, R 4 is selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0024] In some embodiments, R 4 is H or C 1-6 alkyl.

[0025] In some embodiments, R 4 is H or C 1-3 alkyl.

[0026] In some embodiments, R 4 is H, methyl, or ethyl.

[0027] In some embodiments, X is CH, CCH3, N, or -NCH2CH3.

[0028] In some embodiments, X is N.

[0029] In some embodiments, X is S.

[0030] In some embodiments, X is O.

[0031] In some embodiments, X is CH, CCH3, N, -NCH2CH3, S, or O.

[0032] In some embodiments, Y is CR 5 or N.

[0033] In some embodiments, Y is N.

[0034] In some embodiments, Y is CR 5 is.

[0035] In some embodiments, R 5 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, OR a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)NR c5 (OR a5 ), C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 NR c5 R d5 , NR c5 , C(O)R b5 , NR c5 , C(O)OR a5 , NR c5 , C(O)NR c5 R d5 , C(=NR e5 )R b5 , C(=NR e5 )NR c5 R d5 , NR c5 , C(=NR e5 )NR c5 R d5 , NR c5 , C(=NR e5 )R b5 , NR c5 , S(O)R b5 , NR c5 , S(O)NR c5 R d5 , NR c5 , S(O)2R b5 , NR c5 , S(O)(=NR e5 )R b5 , NR c5 , S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , S(O)2NR c5R d5 、 OS(O)(=NR e5 )R b5 、 and OS(O)2R b5 selected from, R 5 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 5A substituents.

[0036] In some embodiments, R 5 is H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- selected from, R 5 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0037] In some embodiments, R 5 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is selected from, R 5 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0038] In some embodiments, R 5 is H, D, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; R 5 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl each have 1, 2, 3, or 4 independently selected R 5A It is optionally substituted with a substituent.

[0039] In some embodiments, R 5 , H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; R 5 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl each have 1, 2, 3, or 4 independently selected R 5A It is optionally substituted with a substituent.

[0040] In some embodiments, R 5 H, D, C 1-6 Alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl; R 5 C 1-6 The alkyl and 5- to 6-membered heteroaryl each have 1, 2, 3, or 4 independently selected R 5A It is optionally substituted with a substituent.

[0041] In some embodiments, R5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and R 5 's C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0042] In some embodiments, R 5 is selected from H, D, methyl, ethyl, difluoromethyl, and pyrazolyl, and R 5 's methyl, ethyl, and pyrazolyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0043] In some embodiments, R 5 is selected from H, methyl, ethyl, difluoromethyl, and pyrazolyl, and R 5 's methyl, ethyl, and pyrazolyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0044] In some embodiments, R 5 is selected from H, D, ethyl, difluoromethyl, and pyrazolyl, and R 5 's ethyl and pyrazolyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0045] In some embodiments, R 5 is selected from H, ethyl, difluoromethyl, and pyrazolyl, and R 5 's ethyl and pyrazolyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0046] In some embodiments, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5- to 6-membered heteroaryl)-C 1-6 Alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 Alkyl-, and independently selected from CN, R 5A of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5- to 6-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R M substituents.

[0047] In some embodiments, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, and independently selected from CN.

[0048] In some embodiments, each R 5A is halo, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and CN are independently selected.

[0049] In some embodiments, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN are independently selected.

[0050] In some embodiments, each R 5A is CN.

[0051] In some embodiments, R 5 is H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5 substituents, 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C1-6 alkyl-, (5- or 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 is independently selected from alkyl-, and CN.

[0052] In some embodiments, R 5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the C 5 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- or 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, and CN, independently selected.

[0053] In some embodiments, R 5 is H, D, C 1-6 alkyl, C 1-6 haloalkyl, and 5- or 6-membered heteroaryl, and the C 5 of R 1-6Alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN.

[0054] In some embodiments, R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and the C 5 of R 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN.

[0055] In some embodiments, R 5 is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and the C 5 of R 1-6 alkyl is optionally substituted with cyano.

[0056] In some embodiments, R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and the C 5 of R 1-6 alkyl is optionally substituted with cyano.

[0057] In some embodiments, R 5is selected from H, D, methyl, cyanoethyl, difluoromethyl, and pyrazolyl.

[0058] In some embodiments, R 5 is selected from H, methyl, cyanoethyl, difluoromethyl, and pyrazolyl.

[0059] In some embodiments, R 5 is selected from H, cyanoethyl, difluoromethyl, and pyrazolyl.

[0060] In some embodiments, Z is CR 6 , NR 6 , or S.

[0061] In some embodiments, Z is CR 6 .

[0062] In some embodiments, Z is NR 6 .

[0063] In some embodiments, Z is S.

[0064] In some embodiments, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl-C 1-6 alkyl-, or (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, where C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0065] In some embodiments, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, and C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl-C 1-6 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0066] In some embodiments, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, and C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl-C 1-6 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1 or 2 independently selected R 6A substituents.

[0067] In some embodiments, R 6 is H, C 1-6 alkyl, C 3-7Cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- and C 1-6 alkyl, C 3-7 Cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- is each independently selected from 1, 2, 3, or 4 R 6A substituents and is optionally substituted therewith.

[0068] In some embodiments, R 6 is H, C 1-6 alkyl, C 3-7 Cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- and C 1-6 alkyl, C 3-7 Cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- is each independently selected from 1 or 2 R 6A substituents and is optionally substituted therewith.

[0069] In some embodiments, each R 6A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and NR c61 R d61 and is independently selected therefrom.

[0070] In some embodiments, each R 6A is independently selected from NR c61 R d61 and is independently selected therefrom.

[0071] In some embodiments, each R a61 , R b61 , R c61 and R d61 is H, C 1-6 alkyl, and C1-6 is selected independently of haloalkyl.

[0072] In some embodiments, each R a61 , R b61 , R c61 , and R d61 are selected independently of H and C 1-6 alkyl.

[0073] In some embodiments, each R c61 and R d61 are selected independently of H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0074] In some embodiments, each R c61 and R d61 are selected independently of H and C 1-6 alkyl.

[0075] In some embodiments, each R 6A is selected independently of NR c61 R d61 , and each R c61 and R d61 are selected independently of H and C 1-6 alkyl.

[0076] In some embodiments, each R 6A is selected independently of NR c61 R d61 , and each R c61 and R d61 are independently selected C 1-6 alkyl.

[0077] In some embodiments, R 6 is H, C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, and C 1-6 alkyl is NR c61 R d61is optionally replaced by, R c61 and R d61 are each independently selected from H and C 1-6 alkyl.

[0078] In some embodiments, R 6 is H, C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, where C 1-6 alkyl is optionally replaced by NR c61 R d61 and R c61 and R d61 are each independently selected C 1-6 alkyl.

[0079] In some embodiments, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0080] In some embodiments, R 6 is H or C 1-6 alkyl.

[0081] In some embodiments, R 6 is H or C 1-3 alkyl.

[0082] In some embodiments, R 6 is H, methyl, cyclopropylmethyl, tetrahydrofuranylmethyl, and dimethylaminoethyl.

[0083] In some embodiments, R 6 is H or methyl.

[0084] In some embodiments, R 6 is H.

[0085] In some embodiments, R 6 is methyl.

[0086] In some embodiments, R 6 is cyclopropylmethyl.

[0087] In some embodiments, R 6 is tetrahydrofuranylmethyl.

[0088] In some embodiments, R 6 is dimethylaminoethyl.

[0089] In some embodiments, Z is CH, NCH3, NCH2CH2N(CH3)2, NCH2-cyclopropyl, NCH2-tetrahydrofuranyl, or S.

[0090] In some embodiments, Z is CH, NCH3, or S.

[0091] In some embodiments, Z is CH.

[0092] In some embodiments, Z is NCH3.

[0093] In some embodiments, Z is NCH2CH2N(CH3)2.

[0094] In some embodiments, Z is NCH2-cyclopropyl.

[0095] In some embodiments, Z is NCH2-tetrahydrofuranyl.

[0096] In some embodiments, Z is S.

[0097] In some embodiments, R 1 is Cy 1 is.

[0098] In some embodiments, R 1 is L-Cy 1 .

[0099] In some embodiments, Cy 1 is C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, and C 3-10 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents.

[0100] In some embodiments, Cy 1 is C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, and C 3-10 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0101] In some embodiments, Cy 1 is C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, and C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0102] In some embodiments, Cy 1 is 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0103] In some embodiments, Cy 1 is 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 1Ais substituted with a substituent.

[0104] In some embodiments, Cy 1 is a 4- to 7-membered heterocycloalkyl, which is substituted with 2 or 3 independently selected R 1A substituents.

[0105] In some embodiments, Cy 1 is piperazinyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0106] In some embodiments, Cy 1 is piperazinyl, which is optionally substituted with 2 or 3 independently selected R 1A substituents.

[0107] In some embodiments, Cy 1 is piperazinyl, which is substituted with 1, 2, 3, or 4 independently selected R 1A substituents.

[0108] In some embodiments, Cy 1 is piperazinyl, which is substituted with 2 or 3 independently selected R 1A substituents.

[0109] In some embodiments, Cy 1 is

Chemical formula

[0110] In some embodiments, Cy 1 is

Chemical formula

[0111] In some embodiments, Cy 1 is [Chem.] is.

[0112] In some embodiments, Cy 1 is [Chem.] is.

[0113] In some embodiments, each R 1A is halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is independently selected from, and the C 1A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0114] In some embodiments, each R1A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C of R 1A 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0115] In some embodiments, each R 1A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and the C of R 1A 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0116] In some embodiments, each R 1A is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, and the C of R 1A 1-6 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0117] In some embodiments, each R 1A is C 1-6 ​​​Independently selected from alkyl, each of which is independently selected from 1, 2, 3, or 4 R 1B Optionally substituted with substituents.

[0118] In some embodiments, Cy 1 is

Chemical formula

[0119] In some embodiments, Cy 1 is

Chemical formula

[0120] In some embodiments, Cy 1 is

Chemical formula

[0121] In some embodiments, Cy 1 is

Chemical formula

[0122] In some embodiments, Cy 1 is

Chemical formula

[0123] In some embodiments, Cy 1 is

Chemical formula

[0124] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0125] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0126] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0127] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0128] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0129] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0130] In some embodiments, Cy 1 is [Chemical formula] is as follows.

[0131] In some embodiments, Cy 1 is [Chemical formula] is.

[0132] In some embodiments, Cy 1 is [Chemical formula] is.

[0133] In some embodiments, Cy 1 is [Chemical formula] is.

[0134] In some embodiments, each R 1B is halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO2, and OR a12 is independently selected from, R 1B 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6Alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-6 Each alkyl- is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0135] In some embodiments, each R 1B is C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl-, CN, and OR a12 independently selected from, and R 1B of C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Each alkyl- is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0136] In some embodiments, each R 1B is C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl-, CN, and OR a12 independently selected from, R 1B 's C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- each has 1, 2, 3, or 4 independently selected R 1C substituents and is optionally substituted.

[0137] In some embodiments, each R 1B is C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl-, CN, and OR a12 independently selected from, R 1B 's C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- each has 1, 2, 3, or 4 independently selected R1C It is optionally substituted with a substituent.

[0138] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, CN, and OR a12 is independently selected from 1B and the C of R 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with one, two, three, or four independently selected R 1C substituents.

[0139] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, CN, and OR a12 is independently selected from 1B and the phenyl, C of R 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C1-6 Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5- to 6-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 Each alkyl- is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0140] In some embodiments, each R 1B is phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl-, CN, and OR a12 and is independently selected from R 1B wherein the phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5- to 6-membered heteroaryl)-C 1-6 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 Each alkyl- is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0141] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 and is independently selected from R 1B wherein the C 1-6 alkyl, phenyl, C 3-7Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0142] In some embodiments, each R 1B is independently selected from C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 , and the phenyl, C 1B cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0143] In some embodiments, each R 1B is independently selected from phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 , and the phenyl, C 1B cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0144] In some embodiments, each R 1B is independently selected from C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, CN, and OR a12 , and the C 1B alkyl, phenyl, C 1-6 cycloalkyl, and 5- to 6-membered heteroaryl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0145] In some embodiments, each R1B is selected independently from C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, CN, and OR a12 and the phenyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0146] In some embodiments, each R1B is selected independently from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents.

[0147] In some embodiments, each R 1C is selected independently from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 and the C 1C alkyl, C 1-6 haloalkyl, C 1-6 alkenyl, and C 2-6 alkynyl of R 2-6 is optionally substituted with 1, 2, 3, or 4 independently selected R 1D substituents.

[0148] In some embodiments, each R 1C is selected independently from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 and is selected independently therefrom.

[0149] In some embodiments, each R 1C is selected independently from halo, C 1-6 alkyl, C 1-6Haloalkyl, CN, and OR a13 are independently selected from

[0150] In some embodiments, each R 1C is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 and is independently selected from each R a13 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl and is independently selected from

[0151] In some embodiments, each R 1C is halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a13 and is independently selected from each R a13 is H, C 1-6 alkyl, and C 1-6 haloalkyl and is independently selected from

[0152] In some embodiments, each R 1C is independently selected from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy, and hydroxy

[0153] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, pyridinyl, CN, and OR a12 and is independently selected, and the C 1B of R 1-6 alkyl, phenyl, C 3-7 cycloalkyl, and pyridinyl are each halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and ORa13 1, 2, 3, or 4 Rs independently selected from 1C are optionally substituted with substituents.

[0154] In some embodiments, each R 1B is independently selected from C 1-6 alkyl, phenyl, pyridinyl, CN, and OR a12 , and the phenyl and pyridinyl of R 1B are each optionally substituted with 1, 2, 3, or 4 independently selected halo or OR a13 groups.

[0155] In some embodiments, each R1B is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R 1B is each optionally substituted with 1, 2, 3, or 4 independently selected R 1-6 substituents independently selected from alkyl, C 1-6 haloalkyl, CN, and OR a13 . 1C are optionally substituted with substituents.

[0156] In some embodiments, each R a12 , R b12 , R c12 , and R d12 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0157] In some embodiments, each R a12 , R b12 , R c12 , and R d12 are independently selected from H and C 1-6 alkyl.

[0158] In some embodiments, each R a13, R b13 , R c13 , and R d13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0159] In some embodiments, each R a13 , R b13 , R c13 , and R d13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0160] In some embodiments, each R a13 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0161] In some embodiments, each R a13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0162] In some embodiments, each R a13 is independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.

[0163] In some embodiments, each R a13 is C 1-6 haloalkyl.

[0164] In some embodiments, each R a13 is C 1-3 haloalkyl.

[0165] In some embodiments, each R a13 is trifluoromethyl.

[0166] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, pyridinyl, CN, and OR a12 independently selected from, and the C 1B of R 1-6 alkyl, phenyl, C 3-7 cycloalkyl, and pyridinyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R 1C is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 independently selected from, each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl independently selected from, each R a13 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl independently selected from.

[0167] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, CN, and OR a12 independently selected from, and the phenyl of R 1B is each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl independently selected from.

[0168] In some embodiments, each R1B is C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, pyridinyl, CN, and OR a12 independently selected from, R 1B of C 1-6 alkyl, C 3-7 cycloalkyl, phenyl and pyridinyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R 1C is halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and OR a13 independently selected from, each R a12 is H and C 1-6 alkyl independently selected from, each Ra13 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0169] In some embodiments, each R 1B is C 1-6 alkyl, phenyl, pyridinyl, CN, and OR a12 independently selected from, R 1B of phenyl and pyridinyl are each optionally substituted with 1, 2, 3, or 4 independently selected halo or OR a13 groups, each R a12 is H and C 1-6 alkyl independently selected from, each Ra13 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl.

[0170] In some embodiments, each R 1B is phenyl, CN, and OR a12 independently selected from, R 1B of phenyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, Each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0171] In some embodiments, R 1B is independently selected from phenyl, CN, and OR a12 , and each phenyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents. Each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0172] In some embodiments, each R 1B is independently selected from phenyl, CN, and OR a12 , and each phenyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected halo groups. Each R a12 is independently selected from H and C 1-6 alkyl.

[0173] In some embodiments, each R1B is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, hydroxy, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1-6 substituents independently selected from halo, C 1-6 alkyl, C a13 haloalkyl, CN, and OR 1C . Each R a13 is H, C 1-6 alkyl, and C1-6 is selected independently from haloalkyl.

[0174] In some embodiments, each R1B is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1-6 substituents independently selected from halo, C 1-6 alkyl, C a13 haloalkyl, CN, and OR 1C and each R is independently selected from H, C a13 alkyl, and C 1-6 haloalkyl. 1-6 is selected independently from haloalkyl.

[0175] In some embodiments, each R1B is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, hydroxy, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R 1B is optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents independently selected from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy, and hydroxy.

[0176] In some embodiments, each R1B is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, and methoxy, and R 1BEach methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl is independently selected from 1, 2, 3, or 4 independently selected Rs from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy, and hydroxy 1C Optionally substituted with substituents.

[0177] In some embodiments, each R 1B is independently selected from isopropyl, hydroxymethyl, difluorocyclobutyl, trifluoromethylcyclobutyl, difluorocyclohexyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, bromofluorophenyl, chlorofluorophenyl, (fluoro)(difluoromethyl)phenyl, (fluoro)(trifluoromethyl)phenyl, (chloro)(methyl)phenyl, difluoromethylphenyl, trifluoromethylphenyl, (trifluoromethyl)(methyl)phenyl, (trifluoromethyl)(difluoro)phenyl, (chloro)(trifluoromethyl)phenyl, (chloro)(difluoro)phenyl, (trifluoromethoxy)(fluoro)phenyl, trifluoromethoxyphenyl, methoxyphenyl, cyanophenyl, trifluoromethylpyridinyl, (trifluoromethyl)(fluoro)pyridinyl, trifluoromethoxypyridinyl, CN, hydroxy, and methoxy.

[0178] In some embodiments, each R 1Bis independently selected from isopropyl, hydroxymethyl, difluorocyclobutyl, trifluoromethylcyclobutyl, difluorocyclohexyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, bromofluorophenyl, chlorofluorophenyl, (fluoro)(difluoromethyl)phenyl, (fluoro)(trifluoromethyl)phenyl, (chloro)(methyl)phenyl, difluoromethylphenyl, trifluoromethylphenyl, (trifluoromethyl)(methyl)phenyl, (trifluoromethyl)(difluoro)phenyl, (chloro)(trifluoromethyl)phenyl, (chloro)(difluoro)phenyl, (trifluoromethoxy)(fluoro)phenyl, trifluoromethoxyphenyl, methoxyphenyl, cyanophenyl, trifluoromethylpyridinyl, (trifluoromethyl)(fluoro)pyridinyl, trifluoromethoxypyridinyl, CN, and methoxy.

[0179] In some embodiments, each R 1B is independently selected from isopropyl, CN, methoxy, hydroxy, hydroxymethyl,

Chemical formula

[0180] In some embodiments, each R 1B is independently selected from CN, methoxy, hydroxy,

Chemical formula

[0181] In some embodiments, each R1B is independently selected from isopropyl, fluorophenyl, trifluoromethoxypyridinyl, CN, and methoxy.

[0182] In some embodiments, each R 1B is independently selected from fluorophenyl, CN, and methoxy.

[0183] In some embodiments, R 2 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- selected from, R 2 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

[0184] In some embodiments, R 2 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl selected from, R 2 of C 1-6 alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents.

[0185] In some embodiments, R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the C 2 alkyl, phenyl, C 1-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 3-7 substituents. 2A In some embodiments, R

[0186] is selected from H, C 2 alkyl, and C 1-6 cycloalkyl. 3-7 In some embodiments, R

[0187] is selected from H, methyl, and cyclopropyl. 2 In some embodiments, R

[0188] is H. 2 In some embodiments, R

[0189] is methyl. 2 In some embodiments, R

[0190] is cyclopropyl. 2 In some embodiments,

[0191] each

Chemical Formula

Chemical formula

[0192] In some embodiments of the preceding embodiments, R 5 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- 5 and the C of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each independently selected from 1, 2, 3, or 4 R 5A substituents and is optionally substituted.

[0193] In some embodiments, each

Chemical formula

Chemical formula

[0194] In some embodiments of the preceding embodiments, R 5 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- and is selected, and R 5 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each 1, 2, 3, or 4 independently selected R5A Optionally substituted with a substituent.

[0195] In some embodiments, U is CH or N, X is CR 4 , N, NR 4 , S, or O, Y is CR 5 or N, Z is CR 6 , NR 6 , or S, R 1 is Cy 1 where Cy 1 is C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, and C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and the C 1A alkyl, C 1-6 alkenyl, and C 2-6 alkynyl of R 2-6 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents, each R 1B is C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-6 Alkyl, CN, and OR a12 independently selected from 1B C of 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R 1C is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 independently selected from each R a12 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl independently selected from each R a13 is H, C 1-6 alkyl, and C 1-6 haloalkyl independently selected from R 2 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and R 2 C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents, R 4 is H or C 1-6 alkyl, R 5 is H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl selected from R 5 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN independently selected from, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl-C 1-6 alkyl-, or (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- and C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl-, and (4- to 7-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted by NR c61 R d61 and, each Rc61 and R d61 is independently selected from H and C 1-6 alkyl.

[0196] In some embodiments of the preceding embodiments, R 5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and R 5 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0197] In some embodiments each

Chemical formula

Chemical formula

[0198] In some embodiments of the preceding embodiments, R 5 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- selected from, and R 5 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5- to 10-membered heteroaryl)-C 1-6 Alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents.

[0199] In some embodiments, U is CH or N, X is CH, CCH3, N, -NCH2CH3, S, or O, Y is CR 5 or N, Z is CH, NCH3, NCH2CH2N(CH3)2, NCH2-cyclopropyl, NCH2-tetrahydrofuranyl, or S, R 1 is Cy 1 and Cy 1 is a 4- to 7-membered heterocycloalkyl which is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently selected from C 1-6 alkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents, each R 1B is independently selected from C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 and the C 1B alkyl, phenyl, C 1-6 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R 1C is halo, C 1-6 alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, and OR a13 are independently selected from each R a12 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl are independently selected from each Ra13 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, R 5 is H, D, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl selected from, R 5 's C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN are independently selected.

[0200] In some embodiments, U is CH or N, X is CH, CCH3, N, -NCH2CH3, S, or O, Y is CR 5 or N, Z is CH, NCH3, NCH2CH2N(CH3)2, NCH2-cyclopropyl, NCH2-tetrahydrofuranyl, or S, R 1 is Cy 1 and, Cy 1 is 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, Each R 1A is independently selected from C 1-6 alkyl, and each is optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents, Each R 1B is independently selected from C 1-6 alkyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 , and the phenyl, C 1B cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, Each R 1C is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, and OR a13 , Each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, Each Ra13 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl, R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heteroaryl, and the C 5 alkyl and 5- to 6-membered heteroaryl of R 1-6 are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, Each R 5A is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 It is independently selected from alkynyl and CN.

[0201] In some embodiments, U is CH or N, X is CR 4 , N, NR 4 , S, or O, Y is CR 5 or N, Z is CR 6 , NR 6 , or S, R 1 is Cy 1 and Cy 1 is C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, and C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is independently selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, and the C 1A alkyl, C 1-6 alkenyl, and C 2-6 alkynyl of R 2-6 are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents, each R 1B is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-6Alkyl, CN, and OR a12 independently selected from, R 1B of C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5- to 10-membered heteroaryl)-C 1-6 alkyl-, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R 1C substituents, each R 1C is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN, each R a12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, R 2 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and R 2 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents, R 4is H or C 1-6 is alkyl, R 5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and R 5 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 5A substituents, each R 5A is halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and CN, independently selected, R 6 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

[0202] In some embodiments, U is CH or N, X is CH, CCH3, N, -NCH2CH3, S, or O, Y is CR 5 or N, Z is CH, NCH3, or S, R 1 is Cy 1 where, Cy 1 is 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents, each R 1A is C1-6 Independently selected from alkyl, each of which is one, two, three, or four independently selected Rs 1B Optionally substituted with substituents Each R 1B Is phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR a12 Independently selected from, and R 1B Phenyl, C 3-7 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one, two, three, or four independently selected Rs 1C Substituents Each R 1C Is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and CN, independently selected from Each R a12 Is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl, independently selected from R 5 Is H, C 1-6 Alkyl, C 1-6 Haloalkyl, and 5- to 6-membered heteroaryl, selected from, and R 5 Of C 1-6 Alkyl and 5- to 6-membered heteroaryl are each optionally substituted with one, two, three, or four independently selected Rs 5A Substituents Each R 5A Is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, and CN, independently selected from

[0203] In some embodiments, the compound of formula I is a compound of formula II,

Chemical formula

[0204] In some embodiments, the compound of formula I is a compound of formula IIa,

Chemical formula

[0205] In some embodiments, the compound of formula I is a compound of formula IIb,

Chemical formula

[0206] In some embodiments, the compound of formula I is a compound of formula III,

Chemical formula

[0207] In some embodiments, the compound of formula I is a compound of formula IIIa,

Chemical formula

[0208] In some embodiments, the compound of formula I is a compound of formula IIIb,

Chemical formula

[0209] In some embodiments, the compound of formula I is a compound of formula IV,

Chemical formula

[0210] In some embodiments, the compound of formula I is a compound of formula IVa,

Chemical formula

[0211] In some embodiments, the compound of formula I is a compound of formula IVb,

Chemical formula

[0212] In some embodiments, the compound of formula I is a compound of formula V,

Chemical formula

[0213] In some embodiments, the compound of formula I is a compound of formula Va,

Chemical formula

[0214] In some embodiments, the compound of formula I is a compound of formula Vb,

Chemical formula

[0215] In some embodiments, the compound of formula I is a compound of formula VI,

Chemical formula

[0216] In some embodiments, the compound of formula I is a compound of formula VIa,

Chemical formula

[0217] In some embodiments, the compound of Formula I is a compound of Formula VIb, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the compound of Formula I is a compound of Formula VII, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the compound of Formula I is a compound of Formula VIIa, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the compound of Formula I is a compound of Formula VIIb, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the compound of Formula I is a compound of Formula VIII, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the compound of Formula I is a compound of Formula VIIIa, [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the compound of formula I is a compound of formula VIIIb,

Chemical formula

[0224] In some embodiments, the compound of formula I is a compound of formula IX,

Chemical formula

[0225] In some embodiments, the compound of formula I is a compound of formula IXa,

Chemical formula

[0226] In some embodiments, the compound of formula I is a compound of formula IXb,

Chemical formula

[0227] In some embodiments, the compound of formula I is a compound of formula X,

Chemical formula

[0228] In some embodiments, the compound of formula I is a compound of formula Xa,

Chemical formula

[0229] In some embodiments, the compound of formula I is a compound of formula Xb,

Chemical formula

[0230] In some embodiments, the compound of formula I is a compound of formula Xc,

Chemical formula

[0231] In some embodiments, the compound of formula I is a compound of formula Xd,

Chemical formula

[0232] In some embodiments, the compound of formula I is a compound of formula Xe,

Chemical formula

[0233] In some embodiments, the compound of formula I is a compound of formula XI,

Chemical formula

[0234] In some embodiments of Formulas X, Xa, Xb, Xc, Xd, Xe, and XI, each R 1A is independently selected from C 1-6 alkyl and C 1-6 haloalkyl, and each C 1A alkyl of R 1-6 is optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0235] In some embodiments of Formulas X, Xa, Xb, Xc, Xd, Xe, and XI, each R 1A is independently selected from C 1-6 alkyl, and each C 1A alkyl of R 1-6 is optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents.

[0236] In some embodiments, the compounds provided herein are selected from: 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-8-methylthiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-(difluoromethyl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 3-(4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-2-yl)propanenitrile, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-(1H-pyrazol-4-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)furo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-1H-[1,2,4]triazolo[3,4-b]purine, 5-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-6-ethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1,3-dimethyl-1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyridine, 4-((2S,5S)-4-(Bis(4-fluorophenyl)methyl)-5-(methoxymethyl)-2-methylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-((2R,5S)-1-(Bis(4-fluorophenyl)methyl)-5-methyl-4-(thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)piperazin-2-yl)acetonitrile, 2-((2R,5S)-1-(Bis(4-fluorophenyl)methyl)-4-(8-cyclopropylthiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)-5-methylpiperazin-2-yl)acetonitrile, 2-((2R,5S)-1-(Bis(4-fluorophenyl)methyl)-5-methyl-4-(1-methyl-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)acetonitrile, (R)-3-(1-(Bis(4-fluorophenyl)methyl)-4-(thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)piperazin-2-yl)propanenitrile, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]purine, 1-(Cyclopropylmethyl)-4-((2S,5R)-4-((S)-1-(4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purine, 1-(Cyclopropylmethyl)-4-((2S,5R)-4-((R)-1-(4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purine, 1-(Cyclopropylmethyl)-4-((2S,5R)-4-((S)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purine, 1-(Cyclopropylmethyl)-4-((2S,5R)-4-((R)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purine-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-(3,3-difluorocyclobutyl)(3,4-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-(3,3-difluorocyclobutyl)(3,4-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-(3,4-dichlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-(3,4-dichlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-chloro-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-chloro-3-methylphenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(3,4,5-trifluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(2,5-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(3-(difluoromethyl)-4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(3-methyl-4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((2,5-Difluoro-4-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3-Chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3-Chloro-4-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-Chloro-3-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-Chlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-Bromophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3-Bromo-4-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-Bromo-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((4-Chlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((4-Bromophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((4-Chlorophenyl)(3,3-difluorocyclobutyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-Dimethyl-4-((S)-2-methyl-1-(3-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-Dimethyl-4-((R)-2-methyl-1-(3-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(2-Fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(2-Fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-(Difluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-(Difluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-(Difluoromethoxy)-2-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-(Difluoromethoxy)-2-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-Methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-Methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-(Difluoromethoxy)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-(Difluoromethoxy)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(4-(Difluoromethyl)-3-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-(difluoromethyl)-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(3-chloro-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(3-chloro-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((S)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((R)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((4-(difluoromethyl)phenyl)(4-methoxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(3-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(3-Fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(3-Chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(3-Chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(3-Methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(3-Methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-(bis(4-(difluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-2,5-dimethyl-4-((S)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-2,5-dimethyl-4-((R)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((S)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(bis(5-(trifluoromethyl)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((3-chloro-4-fluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-2,5-dimethyl-4-(((trans)-3-(trifluoromethyl)cyclobutyl)(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-2,5-dimethyl-4-(((trans)-3-(trifluoromethyl)cyclobutyl)(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((4,4-difluorocyclohexyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-((4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, ((2S,5S)-1-((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)methanol, (R)-1-((2S,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)ethan-1-ol, (S)-1-((2S,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)ethan-1-ol, 2-((2R,5S)-2-ethyl-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-1-yl)-2,2-bis(4-fluorophenyl)ethan-1-ol, 4-((2S,5R)-4-((S)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((S)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((R)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2R,5S)-2-Ethyl-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-1-yl)(4-fluorophenyl)methyl)benzonitrile, 4-(((2R,5S)-2-Ethyl-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-1-yl)(4-fluorophenyl)methyl)benzonitrile, 4-((2S,5R)-4-(Bis(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-Difluorocyclobutyl)(4-(difluoromethyl)-3-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((4-chloro-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, ((2S,5S)-1-(bis(4-chlorophenyl)methyl)-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)methanol, 4-((2S,5R)-4-((S)-1-(4-bromophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-bromophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, and 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the compounds provided herein are selected from the following: 2-(4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(Bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(Bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-Difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-chloro-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((4-bromo-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(2-Fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 2-(4-((2S,5R)-2,5-Dimethyl-4-((S)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine 2-(4-((2S,5R)-2,5-Dimethyl-4-((R)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine 4-((2S,5R)-4-(Bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 4-((2S,5R)-4-(Bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine 2-(4-((2S,5R)-4-(Bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine 2-(4-((2S,5R)-4-(Bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine 4-((2S,5R)-4-(Bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, and 4-((2S,5R)-4-((3,3-Difluorocyclobutyl)(4-(difluoromethyl)-3-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compounds provided herein are 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compounds provided herein are 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine.

[0240] In some embodiments, the compounds provided herein are 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the compounds provided herein are 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine.

[0242] In some embodiments, the compounds provided herein are 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the compounds provided herein are 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine.

[0244] It is further understood that, for clarity, certain features of the invention described in connection with separate embodiments may also be provided in combination in a single embodiment. Conversely, the various features of the invention described in connection with a single embodiment may also be provided separately or in any suitable subcombination.

[0245] At various places herein, divalent linking substituents are described. Each divalent linking substituent is specifically intended to include both the forward and the backward forms of the linking substituent. For example, -NR(CR’R’’) n - is -NR(CR’R’’) n - and -(CR’R’’) n both include NR-. When the structure clearly requires a linking group, the Markush variables listed for that group are understood to be the linking group.

[0246] The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0247] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected and the substitution can be at any chemically available position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence.

[0248] As used herein, the phrase "each 'variable' is independently selected from ~" means substantially the same as "in each occurrence, the 'variable' is selected from ~".

[0249] Throughout the definitions, the terms "C n-m " and "C m-n " denote a range including the endpoints, where n and m are integers and denote the number of carbons. Examples include C 1-3 , C 1-4 , C 1-6 and the like.

[0250] As used herein, the term "C n-mThe term "alkyl" refers to a saturated hydrocarbon group that can be straight-chain or branched and has n to m carbon atoms. Examples of alkyl moieties include chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc., but are not limited thereto. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0251] As used herein, "C" n-m "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbon atoms. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0252] As used herein, "C" n~m "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0253] As used herein, "C" used alone or in combination with other terms n-mThe term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has from n to m carbon atoms. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0254] As used herein, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). "C n-m aryl" refers to an aryl group having from n to m ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, aryl is phenyl.

[0255] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0256] As used herein, "C n-m haloalkoxy" refers to a group of the formula -O-haloalkyl having from n to m carbon atoms. Exemplary haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0257] As used herein, the term "Cn~m The term "haloalkyl" refers to an alkyl group having from one halogen atom to 2s + 1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0258] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cycloalkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two fused rings) groups, spiro rings, and bridged rings (e.g., bridged bicycloalkyl groups). The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted by oxo or sulfide (e.g., C(O) or C(S)). The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having shared bonds), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom that includes a ring-forming atom of the fused aromatic ring. The cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C 3-10 ). In some embodiments, the cycloalkyl is C 3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 4-10It is a spiro ring or a bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0259] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocyclic ring having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, or 15-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5- to 10-membered or 5- to 15-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, heteroaryl is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom.When the heteroaryl group contains a heteroatomic ring member with more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinyl, furo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidinyl, thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidinyl, 1H-[1,2,4]triazolo[3,4-b]purinyl, 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidinyl, thieno[2,3-e][1,2,4]triazolo[4,3-a]pyridinyl, 1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyridinyl, etc., but are not limited thereto.

[0260] As used herein, "heterocycloalkyl" is a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, S, and B, and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted by one or more oxo or sulfide (e.g., C(O), S(O), C(S), or S(O)2, etc.). When the ring-forming carbon atom or heteroatom of the heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of the group is added to the number of ring-forming atoms specified herein (e.g., 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, the ring-forming carbon atom is substituted by an oxo group, and the 6-membered heterocycloalkyl group is further substituted by a methyl group). Examples of heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl includes monocyclic and polycyclic 3- to 15-membered, 3- to 10-membered, 4- to 10-membered, 4- to 15-membered, 5- to 10-membered, 4- to 7-membered, 5- to 7-membered, or 5- to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro and bridged rings (e.g., 5- to 10-membered or 4- to 15-membered bridged biheterocycloalkyl rings having one or more ring-forming carbon atoms replaced by heteroatoms independently selected from N, O, S, and B). The heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0261] The definition of heterocycloalkyl includes moieties having one or more aromatic rings fused (i.e., having a common bond) to a non-aromatic heterocycle, such as, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom including the ring-forming atoms of the fused aromatic ring.

[0262] In some embodiments, the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 15 ring-forming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5- to 10-membered, or 5- to 15-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5- to 10-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5- to 6-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.

[0263] Examples of heterocycloalkyl groups include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, benzazepane, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azadamantanyl, diazadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, diazaspiro[5.5]undecanyl, diazaspiro[5.6]dodecanyl, diazaspiro[6.6]tridecanyl, and the like.

[0264] As used herein, "C o-p Cycloalkyl-C n-m alkyl-" refers to a group of the formula cycloalkyl-alkylene-, wherein cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0265] As used herein, "C o~p Aryl-C n~m alkyl-" refers to a group of the formula aryl-alkylene-, wherein aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0266] As used herein, "heteroaryl-C n~m alkyl-" refers to a group of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0267] As used herein, "heterocycloalkyl-C n-m alkyl-" refers to a group of the formula heterocycloalkyl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0268] As used herein, "alkyl linking group" or "alkylene linking group" is a divalent straight-chain or branched-chain alkyl linking group ("alkylene group"). For example, "C o-p Cycloalkyl-C n-m alkyl-", "C o-p Aryl-C n-m alkyl-", "phenyl-C n-m alkyl-", "heteroaryl-C n-m alkyl-", and "heterocycloalkyl-C n-m alkyl-" contain an alkyl linking group. Examples of "alkyl linking group" or "alkylene group" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0269] At a specified location, the definition or embodiment refers to a specific ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be attached to any ring member as long as the valence of the atom is not exceeded. For example, the azetidine ring can be attached at any position of the ring, while the pyridin-3-yl ring is attached at the 3-position.

[0270] As used herein, the term "oxo" refers to an oxygen atom as a divalent substituent (i.e., =O), which forms a carbonyl group (e.g., C=O or C(O)) when bonded to carbon, or forms a nitroso, sulfinyl, or sulfonyl group when bonded to a nitrogen or sulfur heteroatom.

[0271] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent (e.g., each R M ) is independently selected from the applicable list at each occurrence.

[0272] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers such as enantiomers and diastereomers are intended unless otherwise specified. Compounds of the present disclosure containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers such as olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or in separated isomeric forms. In some embodiments, the compound has the (R) configuration. In some embodiments, the compound has the (S) configuration. The formulas provided herein (e.g., Formula I, Formula II, etc.) include stereoisomers of the compounds.

[0273] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolution acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional recrystallization method are, for example, optically active acids such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0274] The resolution of a racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0275] The compounds described herein also include tautomeric forms. Tautomeric forms are obtained by the exchange of adjacent double and single bonds and the simultaneous migration of a proton. Tautomeric forms include prototropic tautomers, which are protonation states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imido acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in an equilibrium state or can be stereochemically fixed in one form by appropriate substitution.

[0276] All compounds and their pharmaceutically acceptable salts can be identified together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.

[0277] In some embodiments, the preparation of the compounds can include, for example, the addition of an acid or a base that affects the catalysis of the desired reaction or the formation of a salt form such as an acid addition salt.

[0278] In some embodiments, the compounds or salts thereof described herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition in which the compounds described herein are concentrated. Substantial separation can include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds or salts thereof described herein.

[0279] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structures. Compounds herein identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms as well, unless otherwise specified.

[0280] The phrase "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0281] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of the two, and generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0282] Synthesis As will be appreciated by those skilled in the art, the compounds provided herein can be prepared using known organic synthetic techniques, including their salts and stereoisomers, and can be synthesized according to any of a number of possible synthetic routes.

[0283] The compounds of formula I can be synthesized using the process shown in Scheme 1. As shown in Scheme 1, a number of methods (e.g., nucleophilic aromatic substitution or suitable cross-coupling reactions) can be used to reach the compounds of general formula 1-2. For example, the compound of formula 1-1 (i.e., each Hal can independently be F, Cl, Br, or I) can react with a suitable amine nucleophile in a suitable solvent (e.g., 1-butanol) at a suitable temperature (e.g., in the range of room temperature to 200 °C) for a suitable time (e.g., in the range of several minutes to several days) to produce the compound of formula 1-2. Alternatively, the compound of formula 1-2 can be obtained by a transition metal (e.g., Pd, Cu, Ni) catalyzed reaction (including but not limited to Buchwald, Ullman, Suzuki, Stille, Negishi couplings) of the compound of formula 1-1 with a suitable coupling partner (e.g., a primary or secondary amine, a nitrogen heterocycle, or a heteroarylboronic acid / ester, a trialkyltin, or a zinc reagent). The compound of formula 1-1 is commercially available or can be easily synthesized according to methods known to those skilled in the art. The compound of formula 1-3 is produced by a C-N bond formation reaction (e.g., a transition metal catalyzed or nucleophilic aromatic substitution) between the compound of formula 1-2 and hydrazine under suitable conditions (e.g., in the presence of a palladium catalyst such as methanesulfonato(2-(di-t-butylphosphino)-3,6-dimethoxy-2’,4’,6’-tri-i-propyl-1,1’-biphenyl)(2’-amino-1,1’-biphenyl-2-yl)palladium(II) (“tBuBrettPhos Pd G3”) in a suitable solvent such as THF or 1,4-dioxane and in the presence of a base such as Cs2CO3 or NaOt-Bu). The compound of formula I is obtained by the reaction of the compound of formula 1-3 with the compound of formula 1-4 (e.g., trimethyl orthoformate or triethyl orthoacetate) under suitable conditions (e.g., in the presence of AcOH).

Chemical formula

[0284] The compounds of formula I can also be prepared using the process shown in Scheme 2. As shown in Scheme 2, the compound of formula 2-1 can be converted to the compound of formula 2-2 by a number of methods. For example, halogenation of the compound of formula 2-1 (e.g., deprotonation with a suitable base such as lithium chloride of 2,2,6,6-tetramethylpiperidinylmagnesium chloride (“TMPMgCl·LiCl”), followed by addition of a suitable electrophile such as 1-chloro-2-iodoethane, etc.), followed by suitable cross-coupling, gives the compound of formula 2-2. Examples of suitable cross-coupling reactions include, but are not limited to, Suzuki (see, e.g., Tetrahedron 2002, 58, 9633-9695), Negishi (see, e.g., ACS Catalysis 2016, 6, 1540-1552), Stille (see, e.g., ACS Catalysis 2015, 5, 3040-3053), Sonogashira (see, e.g., Chem.Soc.Rev.2011, 40, 5084-5121), Buchwald-Hartwig amination (see, e.g., Chem.Sci.2011, 2, 27-50), Cu-catalyzed amination (see, e.g., Org.React.2014, 85, 1-688). Alternatively, the compound of formula 2-2 can be reached by conversion of the compound of formula 2-1 to a carbonyl intermediate (e.g., deprotonation with a suitable base such as TMPMgCl·LiCl, followed by addition of a suitable electrophile such as DMF, etc.), followed by reaction with a suitable fluorination reagent (e.g., diethylaminosulfur trifluoride). The compound of formula 2-2 is produced by a C-N bond formation reaction (e.g., transition metal catalysis or nucleophilic aromatic substitution) between the compound of formula 2-2 and hydrazine under suitable conditions (e.g., in the presence of a para-cycle precatalyst such as tBuBrettPhos Pd G3 and a base such as Cs2CO3). The compound of formula I is obtained by reaction of the compound of formula 2-2 with the compound of formula 2-3 (e.g., triethyl orthoformate) under suitable conditions (e.g., in the presence of AcOH).

Chemical formula

[0285] The compound of Formula 3-8 can be synthesized, for example, according to the process shown in Scheme 3. As shown in Scheme 3, the compound of Formula 3-2 is produced by protecting the amino compound of Formula 3-1 under suitable conditions (including, but not limited to, a reductive amination reaction with a suitable aldehyde such as benzaldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride). The compound of Formula 3-1 is commercially available or can be easily synthesized according to methods known to those skilled in the art. The compound of Formula 3-4 is obtained by an amide coupling reaction between the compound of Formula 3-2 and the compound of Formula 3-3 under suitable conditions (such as in the presence of a coupling reagent such as HATU and a base such as N-ethyl-N-isopropylpropan-2-amine in a suitable solvent such as N,N-dimethylformamide). Deprotection of the tert-butyloxycarbonyl group in the compound of Formula 3-4 under suitable conditions (such as using an acid such as trifluoroacetic acid), followed by intramolecular cyclization under suitable conditions (such as using a suitable solvent such as MeOH), gives the compound of Formula 3-5. Reduction of the compound of Formula 3-5 under suitable conditions (such as using a reducing agent such as borane in a suitable solvent such as THF) produces the compound of Formula 3-6. Protection of the compound of Formula 3-6 under suitable conditions (such as by reaction with di-tert-butyl dicarbonate in the presence of a base such as N-ethyl-N-isopropylpropan-2-amine) gives the compound of Formula 3-7. Selective deprotection of PG (for example, when PG is a protecting group such as benzyl) in the compound of Formula 3-7 under suitable conditions (such as in the presence of hydrogen gas using a suitable catalyst such as palladium on carbon) gives the compound of Formula 3-8.

Chemical Structure

[0286] The compound of Formula 4-4 can be prepared, for example, using the process shown in Scheme 4. In the process shown in Scheme 4, the compound of Formula 4-3 is formed by a nucleophilic substitution reaction between the compound of Formula 4-1 and the compound of Formula 4-2 under appropriate conditions (e.g., in the presence of a base such as N-ethyl-N-isopropylpropan-2-amine in a suitable solvent such as CH3CN). The compound of Formula 4-4 is obtained by removal of an appropriate protecting group (e.g., when PG is a group such as tert-butoxycarbonyl) from the compound of Formula 4-3 under appropriate conditions (e.g., in a suitable solvent such as tetrahydrofuran, 1,4-dioxane, or CH2Cl2 in the presence of an acid such as HCl or trifluoroacetic acid).

Chemical formula

[0287] Alternatively, the compound of Formula 4-4 can be prepared, for example, using the process shown in Scheme 5. In the process shown in Scheme 5, the compound of Formula 5-3 is obtained by an amide coupling reaction between the compound of Formula 5-1 and the compound of Formula 5-2. The compound of Formula 5-4 is obtained by subjecting the compound of Formula 5-3 to reductive alkylation conditions (e.g., using a suitable transition metal catalyst such as IrCl(CO)(PPh3)2 in the presence of a silane such as 1,1,3,3-tetramethyldisiloxane, followed by addition of a suitable organometallic reagent such as a Grignard reagent). The compound of Formula 4-4 is obtained by removal of an appropriate protecting group (e.g., when PG is a group such as tert-butoxycarbonyl) from the compound of Formula 5-4 under appropriate conditions (e.g., in a suitable solvent such as tetrahydrofuran, 1,4-dioxane, or CH2Cl2 in the presence of an acid such as HCl or trifluoroacetic acid).

Chemical formula

[0288] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a solvent suitable for the particular reaction step can be selected by one of ordinary skill in the art.

[0289] As used herein, the expressions “ambient temperature” or “room temperature” or “rt” are understood in the art and generally refer to a reaction temperature close to a temperature, e.g., the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20 °C to about 30 °C.

[0290] The preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. For the chemical nature of protecting groups, see, e.g., T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999).

[0291] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), etc., by mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). The compounds can be purified by one of ordinary skill in the art by various methods including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0292] Usage The compounds described herein can inhibit the activity of DGK. Compounds that inhibit DGK are useful for providing a means to prevent the growth of cancer cells or to induce their apoptosis. Such compounds are also useful for the treatment of cancer cells that exhibit changes in diacylglycerol regulatory enzymes and effectors. Therefore, the compounds of the present disclosure are expected to be useful for the treatment or prevention of cancers such as solid tumors.

[0293] In certain embodiments, the present disclosure provides a method for treating a patient in need of treatment for a DGK-related disorder, the method comprising administering to the patient a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0294] The compounds or salts described herein can be selective. "Selective" means that the compound binds to or inhibits DGKα or DGKζ with a greater affinity or potency, respectively, compared to at least one other DGK isoform, or kinase, etc. In some embodiments, the selectivity can be at least about 2-fold, 5-fold, 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. The compounds of the present disclosure can also be dual antagonists (i.e., inhibitors), for example, inhibiting both DGKα and DGKζ kinases. In some embodiments, the compounds of the present invention are selective inhibitors of DGKα (e.g., compared to one or more other DGK isoforms, or kinases, etc.). In some embodiments, the compounds of the present invention are selective inhibitors of DGKζ (e.g., compared to one or more other DGK isoforms, or kinases, etc.). Selectivity can be measured by routine methods in the art. In some embodiments, selectivity can be tested at the ATP concentration of each enzyme. In some embodiments, the selectivity of the compounds of the present invention can be determined by a cell assay related to a specific DGK kinase activity. m In some embodiments, the selectivity of the compounds of the present invention can be determined by a cell assay related to a specific DGK kinase activity.

[0295] Based on compelling evidence that DGKα and DGKζ negatively regulate the signaling pathways downstream of the T cell receptor, developing DGK inhibitors can enhance the effector functions of T cells and inhibit tumor progression. DGK inhibitors can be used to treat cancers, including solid tumors and hematological malignancies, such as renal cell carcinoma, mesothelioma, glioblastoma multiforme, colorectal cancer, melanoma, and pancreatic cancer, either alone or in combination with other therapies (Chen, S. S. et al., Front. Cell Dev. Biol., 2016. 4:130, Gu, J. et al., Oncoimmunol., 2021. 10, e1941566, Jung I.-Y. et al., Cancer Res., 2018. 78: p4692-4703, Sitaram, P., et al., Int. J Mol. Sci., 2019. 20: p5821-5848, Wesley, E. M., et al., Immunohorizons, 2018. 2: p107-118). Furthermore, pharmacological inhibition of DGK offers advantages for controlling viral infections and can be used in the treatment of such viral infections, including coronavirus infection, HIV infection, and hepatitis virus infection, in preclinical models (Harabuchi, S. et al., Front. Immunol., 2022. 13:1032113).

[0296] In addition, DGKα has been shown to enhance the progression of esophageal squamous cell carcinoma (ESCC) and human hepatocellular carcinoma (HCC) (Chen, J. et al., Oncogene, 2019. 38: p2533-2550, Takeishi, K. et al., J. Hepatol., 2012. 57: p77-83), support the growth of colon cancer and breast cancer in three-dimensional (3D) culture (Torres-Ayuso, P. et al., Oncotarget, 2014. 5: p9710-9726), enhance the invasiveness of breast cancer (Rainero, E. et al., PLOS ONE, 2014. 9(6): e97144), and promote the metastasis of non-small cell lung cancer (NSCLC) (Fu, L. et al., Cancer letters, 2022. 532: 215585), while DGKζ is potentially involved as an oncogene in the proliferation of osteosarcoma (Yu, W. et al., Front. Oncol., 2019. 8: 655) and contributes to the enhanced invasion of human metastatic colon cancer cells (Cai, K. et al., BMC Cancer, 2014. 14: 208). Also, it has been reported that DGK inhibition may have the potential to reduce the immunopathology of patients with X-linked lymphoproliferative disease (Velnati, S. et al., Eur. J. Med. Chem., 2019. 164: p378-390, Ruffo, E. et al., Sci. Transl. Med. 2016. 8(321): 321ra7).

[0297] In some embodiments, the DGK-related disorder is a solid tumor. Exemplary solid tumors include, but are not limited to, breast cancer, colorectal cancer, gastric cancer, and glioblastoma (see, e.g., Cooke & Kazanietz, Sci. Signal, 2022, 15, eabo0264:1-26). Exemplary cancers associated with changes in DAG control enzymes and effectors include melanoma, myelodysplastic syndrome (MDS), angiosarcoma, cutaneous peripheral T-cell lymphoma, adult T-cell leukemia lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL) / Sezary syndrome, chronic lymphocytic leukemia (CLL), breast cancer, gastric cancer, colorectal cancer, oral squamous cell carcinoma (SCC), esophageal SCC, chronic myelogenous leukemia (CML), colon cancer, prostate cancer, hepatocellular carcinoma (HCC), blue nevus, NK / T-cell lymphoma, glioma, ovarian cancer, liver cancer, melanoma, heptacarcinoma, osteosarcoma, chordiod glioma, pigmented epithelial melanocytoma, papillary glioneuronal tumor, fibrous histiocytoma, pituitary tumor, thyroid cancer, head and neck SCC, lung cancer, pediatric T-cell acute lymphoblastic leukemia (T-ALL), endometrial cancer, angiolipoma, salivary gland cancer, acute myeloid leukemia (AML), Epstein-Barr virus-related (EBV)-associated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and cervical cancer, but are not limited to these (see, e.g., Cooke & Kazanietz, Sci. Signal, 2022, 15, eabo0264:1-26).

[0298] In some embodiments, the cancer is selected from lung cancer, bladder cancer, urothelial cancer, esophageal cancer, gastric cancer, mesothelioma, liver cancer, diffuse large B-cell lymphoma, kidney cancer, head and neck cancer, cholangiocarcinoma, cervical cancer, endocervical cancer, melanoma, Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), melanoma, MSI high tumors, ICI-sensitive tumors, and virus infection-related cancers, such as HPV-related anal cancer, vaginal cancer, vulvar cancer, cervical cancer, and oropharyngeal cancer, etc.

[0299] In some embodiments, the cancer is selected from lung cancer, bladder cancer, urothelial cancer, esophageal cancer, gastric cancer, mesothelioma, liver cancer, diffuse large B-cell lymphoma, kidney cancer, head and neck cancer, cholangiocarcinoma, cervical cancer, endocervical cancer, and melanoma.

[0300] In some embodiments, the cancer is selected from non-small cell lung cancer (lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD)), bladder urothelial cancer, esophageal cancer, gastric adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B-cell lymphoma (DLBCL), kidney clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, and metastatic melanoma.

[0301] In some embodiments, the cancer is myelodysplastic syndrome. As used herein, myelodysplastic syndrome is intended to include heterogeneous and clonal hematopoietic disorders characterized by ineffective hematopoiesis in one or more of the major myeloid cell lineages. Myelodysplastic syndrome is associated with bone marrow failure, peripheral cytopenia, and a tendency to progress to acute myeloid leukemia (AML). In addition, clonal cytogenetic abnormalities can be detected in about 50% of cases of MDS. In 1997, the World Health Organization (WHO), together with the Society for Hematology (SH) and the European Association for Haematology (EAHP), proposed a new classification of hematopoietic tumors (Harris, et al., J Clin Oncol 1999;17:3835-3849; Vardiman, et al., Blood 2002;100:2292-2302). In the case of MDS, the WHO not only utilized morphological criteria from the French-American-British (FAB) classification, but also incorporated genetic, biological, and clinical features available to define subsets of MDS (Bennett, et al., Br.J.Haematol.1982;51:189-199). In 2008, the WHO classification of MDS (Table 1) was further refined to allow for accurate and prognostically relevant subclassification of single-lineage dysplasia by incorporating new clinical and scientific information (Vardiman, et al., Blood 2009;114:937-951; Swerdlow, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th Edition. Lyon France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic syndromes / neoplasms” in Chapter 5, Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (ed. 4th edition): Lyon, France: IARC Press; 2008:88-103).

Table 1

[0302] In some embodiments, myelodysplastic syndrome is refractory cytopenia with unilineage dysplasia (RCUD).

[0303] In some embodiments, myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS).

[0304] In some embodiments, myelodysplastic syndrome is refractory anemia with ring sideroblasts associated with thrombocytosis (RARS-T).

[0305] In some embodiments, myelodysplastic syndrome is refractory cytopenia with multilineage dysplasia.

[0306] In some embodiments, myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1).

[0307] In some embodiments, myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2).

[0308] In some embodiments, myelodysplastic syndrome is myelodysplastic syndrome, unclassifiable (MDS-U).

[0309] In some embodiments, myelodysplastic syndrome is myelodysplastic syndrome associated with isolated del(5q).

[0310] In some embodiments, myelodysplastic syndrome is refractory to erythropoietin.

[0311] In some embodiments, the compounds of the present disclosure may be useful for the treatment of myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome).

[0312] In some embodiments, methods are provided herein for increasing a patient's survival or progression-free survival, the methods comprising administering to the patient a compound provided herein. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after treatment of a solid tumor during which a patient lives with the disease without worsening. Progression-free survival refers to the period from the first administration of the compound until the earlier of death or disease progression. Disease progression can be defined by RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors) as evaluated by an independent central review committee. In some embodiments, administration of the compound results in a progression-free survival of greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, administration of the compound results in a progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, administration of the compound results in an increase in progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0313] The disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0314] The disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0315] As used herein, the term "cell" means cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, in vitro cells can be cells in a cell culture. In some embodiments, in vivo cells are cells that live in an organism such as a mammal.

[0316] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" DGK with a compound described herein includes administering the compound described herein to an individual or patient such as a human having DGK, as well as introducing, for example, the compound described herein into a sample containing a cell preparation or purified preparation containing DGK.

[0317] As used herein, the terms "individual" or "patient," used interchangeably, refer to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans.

[0318] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as any amount of a solid form or a salt thereof disclosed herein, that elicits a biological or pharmaceutical response in a tissue, system, animal, individual, or human as desired by a researcher, veterinarian, physician, or other clinician. The appropriate "effective" amount in any individual case can be determined using techniques known to those of ordinary skill in the art.

[0319] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0320] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, neither biologically undesirable nor otherwise undesirable, and include excipients or carriers acceptable for veterinary use as well as for human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0321] As used herein, the terms "treating" or "treatment" refer to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or presenting the pathology or general symptoms of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or general symptoms), or improving a disease, e.g., improving a disease, condition, or disorder in an individual who is experiencing or presenting the pathology or general symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or general symptoms), e.g., reducing the severity of the disease.

[0322] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases referred to herein, e.g., for preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be susceptible to a disease, condition, or disorder but has not yet experienced or presented the clinical manifestations or symptoms of the disease.

[0323] It is understood that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (while these embodiments are intended to be combined as if they were described in multiple dependent forms). Conversely, various features of the disclosure that are, for brevity, described in a single embodiment may also be provided separately or in any suitable sub-combination.

[0324] Combination therapy I. Immune checkpoint therapy In some embodiments, the DGKα and DGKζ inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described herein.

[0325] The compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0326] In some embodiments, the compounds provided herein can be used in combination with an agonist of one or more of the immune checkpoint molecules such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0327] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0328] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1 monoclonal or bispecific antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, semaprimab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054.In some embodiments, the inhibitor of PD-1 or PD-L1 is disclosed in U.S. Patent Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Patent Publications 2017 / 0145025, 2017 / 0174671, 2017 / 0174679, 2017 / 0320875, 2017 / 0342060, 2017 / 0362253, 2018 / 0016260, 2018 / 0057486, 2018 / 0177784, 2018 / 0177870, 2018 / 0179179, 2018 / 0179201, 2018 / 0179202, 2018 / 0273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524, or 2019 / 0345170; or PCT Publications WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, the entireties of each of which are incorporated herein by reference. In some embodiments, the inhibitor of PD-L1 is INCB086550. In some embodiments, the inhibitor of PD-L1 is INCB099280.

[0329] In some embodiments, the antibody is an anti-PD-1 antibody, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalizumab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab, spartalizumab, camrelizumab, cetrelimab, tripalizumab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is semiprimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is tripalizumab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012 (INCMGA0012, retifanlimab). In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (MPDL3280A; also known as RG7446), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0330] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a compound selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, U.S. Patent No. 16 / 369,654 (filed on March 29, 2019), and U.S. Patent No. 62 / 688,164, or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in its entirety.

[0331] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFR beta.

[0332] In some embodiments, the inhibitor is MCLA-145.

[0333] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0334] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or efalizumab alpha (IMP321).

[0335] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0336] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0337] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0338] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0339] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0340] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0341] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is trabedersen, galusertinib, or M7824.

[0342] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0343] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0344] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0345] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cosatumumab or BMS-936561.

[0346] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0347] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is ofatumumab or rituximab.

[0348] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0349] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomilumab.

[0350] In some embodiments, the agonist of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of the immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tabalumab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0351] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0352] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0353] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is seralizumab.

[0354] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is balilumab.

[0355] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0356] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or the TGF-beta receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0357] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. An example of an arginase inhibitor is INCB1158.

[0358] As provided throughout, additional compounds, inhibitors, agents, etc. can be used in combination with the present compounds in single or continuous dosage forms, or they can be administered simultaneously or sequentially as separate dosage forms.

[0359] II. Cancer Therapy The growth and survival of cancer cells can be affected by multiple signaling pathways. Therefore, it is useful to treat such conditions by combining different enzyme / protein / receptor inhibitors that exhibit different selectivities among targets that modulate the activity of the target. Examples of agents that may be used in combination with the compounds of the present disclosure, or their solid forms or salts, include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, inhibitors of the beta-catenin pathway, inhibitors of the notch pathway, inhibitors of the hedgehog pathway, inhibitors of Pim kinase, and inhibitors of protein chaperones and cell cycle progression. Targeting two or more signaling pathways (or two or more biomolecules involved in a given signaling pathway) may reduce the likelihood of drug resistance arising in a cell population and / or reduce the toxicity of the treatment.

[0360] The compounds of the present disclosure, or their solid forms or salts, can be used in combination with one or more other enzyme / protein / receptor inhibitors for the treatment of diseases such as cancer. Examples of cancer include solid tumors and liquid tumors such as blood cancers. For example, the compounds of the present disclosure, or their solid forms or salts, can be used in combination with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of the present disclosure, or their solid forms or salts, can be used in combination with one or more of the following inhibitors for the treatment of cancer.Non-limiting examples of inhibitors that can be used in combination with the compounds of the present disclosure, or their solid forms or salts, for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio 1347, INCB54828, INCB62079 and INCB63904), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., INCB50797 and INCB50465), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extraterminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., OTX015, CPI-0610, INCB54329 and INCB57643, etc.), and adenosine receptor antagonists or combinations thereof. Inhibitors of HDAC such as panobinostat and vorinostat. Inhibitors of c-Met such as onartumzumab, tivantinib, INC-280. Inhibitors of BTK such as ibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus. Inhibitors of Raf such as vemurafenib and dabrafenib. Inhibitors of MEK such as trametinib, selumetinib, GDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), inhibitors of cyclin-dependent kinases (e.g., palbociclib), inhibitors of PARP (e.g., olaparib), and inhibitors of Pim kinase (LGH447, INCB053914 and SGI-1776) can also be used in combination with the compounds of the present disclosure.

[0361] The compounds of the present disclosure, or their solid forms or salts, can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chloromethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0362] The compounds of the present disclosure, or their solid forms or salts, may further be used in combination with other methods of treating cancer, such as chemotherapy, radiotherapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, adoptive T cell transfer, CAR (chimeric antigen receptor) T cell therapy as a booster of T cell activation, oncolytic virus therapy and immunomodulatory small molecules (including thalidomide or JAK1 / 2 inhibitors, etc.). The compounds may be administered in combination with one or more anti-cancer agents such as chemotherapeutic agents. Exemplary chemotherapeutic agents include abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxifene, drostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate,Any of histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pirarubicin, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, lefloxifene, revlimid, rituximab, luxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat and zoledronate is included.

[0363] Other anti-cancer agent(s) include antibody therapeutic agents such as trastuzumab (Herceptin), antibodies against co-stimulatory molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), antibodies against 4-1BB, PD-1 and PD-L1, or antibodies against cytokines (such as IL-10, TGF-β, etc.). Examples of antibodies against PD-1 and / or PD-L1 that can be combined with the compounds of the present disclosure for the treatment of cancer or infectious diseases such as viral, bacterial, fungal, and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210.

[0364] Other anti-cancer agents include inhibitors of kinase-related cell proliferative disorders. These kinases include, but are not limited to, aurora A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinase, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

[0365] Other anti-cancer agents also include those that block immune cell migration, such as antagonists against chemokine receptors, including CCR2 and CCR4.

[0366] The compounds of the present disclosure, or their solid forms or salts, can be further used in combination with one or more anti-inflammatory agents, steroids, immunosuppressive agents, or therapeutic antibodies. Steroids include, but are not limited to, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0367] The compounds of the present disclosure, or their solid forms or salts, may also be used in combination with lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS214662, tiazofurin (MDL101731), Sml1, triapine, zidovudine, trimidox, and amidox.

[0368] The compounds of the present disclosure, or their salts or solid forms, may be used in combination with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0369] The compounds of the present disclosure, or their solid forms or salts, may be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). In some embodiments, the compounds of the present disclosure, or their solid forms or salts, may be used in combination with tumor-specific antigens, such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of the present disclosure, or their solid forms or salts, may be used in combination with dendritic cell immunity to activate a strong anti-tumor response.

[0370] The compounds of the present disclosure, or their solid forms or salts, can be used in combination with a bispecific macrocyclic peptide that targets tumor cells to effector cells expressing the Fe alpha or Fe gamma receptor. The compounds of the present disclosure, or their solid forms or salts, can also be used in combination with a macrocyclic peptide that activates the host's immune responsiveness.

[0371] The compounds of the present disclosure, or their solid forms or salts, can be used in combination with bone marrow transplantation to treat various tumors of hematopoietic origin.

[0372] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, as well as other antiviral drugs.

[0373] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2’,3’-dideoxy-5-fluoro-cytidine); DAPD, ((-)-beta-D-2,6,-diaminopurine dioxolane); and rodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587), delavirdine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (nelfnavir)(AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0374] When two or more pharmaceuticals are administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., in the case of three or more agents).

[0375] In some embodiments, the compounds of the disclosure, or solid forms or salts thereof, can be used in combination with INCB086550.

[0376] Pharmaceutical Formulations and Dosage Forms When used as a medicament, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local treatment is desired or systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and delivery to mucous membranes including nasal, vaginal, and rectal delivery), via the lungs (e.g., by inhalation or insufflation of powders or aerosols including those by nebulizer; intratracheal or nasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickening agents, etc. may be essential or desirable.

[0377] The present disclosure also includes pharmaceutical compositions comprising, as an active ingredient, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for local administration. In preparing the compositions of the present disclosure, typically the active ingredient is admixed with an excipient and diluted by the excipient or enclosed within such a carrier in the form of, for example, capsules, sachets, paper or other containers. An excipient can be a solid, semi-solid, or liquid material that functions as a diluent and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0378] When preparing the formulation, the active compound can be milled to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0379] The compounds of the present disclosure can be milled using known milling procedures such as wet milling to obtain a particle size suitable for tablet formation and other formulation types. A finely divided (nanoparticle) preparation of the compounds of the present disclosure can be prepared by processes known in the art. See, for example, the disclosure of International Application No. WO2002 / 000196.

[0380] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying agents and suspending agents, preservatives such as methyl benzoate and propyl hydroxybenzoate, sweetening agents, and flavoring agents. The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0381] The composition can be formulated in unit dosage form, with each dosage containing from about 5 to about 1000 mg (1 g), more usually from about 100 to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0382] In some embodiments, the compositions of the present disclosure contain from about 5 to about 50 mg of an active ingredient. Those skilled in the art will understand that this is a specific embodiment of a composition containing from about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45 or about 45 to about 50 mg of an active ingredient.

[0383] In some embodiments, the compositions of the present disclosure contain from about 50 to about 500 mg of an active ingredient. Those skilled in the art will understand that this is a specific embodiment of a composition containing from about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400 or about 450 to about 500 mg of an active ingredient.

[0384] In some embodiments, the compositions of the present disclosure contain from about 500 to about 1000 mg of an active ingredient. Those skilled in the art will understand that this is a specific embodiment of a composition containing from about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950 or about 950 to about 1000 mg of an active ingredient.

[0385] In the methods and uses of the present disclosure, similar dosages of the compounds described herein may be used.

[0386] Since the active compounds can be effective over a wide range of dosages, they are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by the physician according to relevant circumstances including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, and the severity of the patient's condition.

[0387] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these pre-formulation compositions are referred to as homogeneous substances, the active ingredient is usually uniformly dispersed throughout the composition, whereby the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the above-mentioned type containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0388] The tablets or pills of the present disclosure can be coated or otherwise formulated to provide a dosage form that offers the advantage of long-term action. For example, a tablet or pill can contain components for internal and external use, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that functions to prevent degradation in the stomach and allows its internal component to reach the duodenum intact or with delayed release. A variety of substances, including numerous polymeric acids and mixtures of polymeric acids with substances such as shellac, cetyl alcohol, and cellulose acetate, can be utilized as such enteric layers or coatings.

[0389] Liquid forms in which the compounds and compositions of the present disclosure can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0390] Compositions for inhalation or insufflation include liquids and suspensions, as well as powders, in a pharmaceutically acceptable aqueous or organic solvent, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic effects. The composition may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing apparatus. Solutions, suspensions, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0391] Topical formulations may contain one or more conventional carriers. In some embodiments, an ointment may contain water and one or more hydrophobic carriers selected, for example, from liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, and the like. The carrier composition of a cream may be based on a combination of water and glycerol and one or more other components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. A gel may be formulated using isopropyl alcohol and water, preferably in combination with other components such as glycerol, hydroxyethyl cellulose, and the like. In some embodiments, the topical formulation contains at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 weight % of a compound of the present disclosure. The topical formulation may be suitably packaged, for example, in a 100 g tube optionally accompanied by instructions for treating selected indications such as psoriasis or other skin conditions.

[0392] The amount of the compound or composition to be administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic use, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose depends on the medical judgment of the attending physician based on the disease state being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0393] The composition to be administered to a patient can be in the form of the above pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or may be aseptically filtered. Aqueous solutions can be packaged for use as such or can be lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation will typically be between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers can result in the formation of pharmaceutical salts.

[0394] The therapeutic amount of the compounds of the present disclosure can vary, for example, according to the particular use for which the treatment is being carried out, the method of administration of the compound, the health and symptoms of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present disclosure in the pharmaceutical composition can vary depending on several factors including the dosage, chemical nature (e.g., hydrophobicity), and route of administration. For example, the compounds of the present disclosure can be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg of body weight to about 100 mg / kg of body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or disorder, the overall health of the particular patient, the relative bioefficacy of the selected compound, the formulation of the excipients, and the route of its administration. The effective dose can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

[0395] The compositions of the present disclosure can further include one or more additional pharmaceuticals such as chemotherapeutic agents, steroids, anti-inflammatory compounds or immunosuppressive agents, examples of which are provided herein.

[0396] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds (radiolabels, fluorescent labels, etc.) of the present disclosure that are useful in assays both in vitro and in vivo, as well as in imaging techniques, to identify and quantify the location of DGK in tissue samples, including human tissue samples, by binding of the labeled compound, and to identify DGK inhibitors. Substitution of one or more of the atoms of the compounds of the present disclosure may also be useful in creating differential ADME (absorption, distribution, metabolism, and excretion). Accordingly, the present disclosure includes DGK assays that include such labeled or substituted compounds.

[0397] The present disclosure further includes isotopically labeled compounds of the present disclosure. An “isotopically labeled” or “radioactively labeled” compound is a compound of the present disclosure in which one or more atoms have been replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number typically found in nature (i.e., naturally occurring), i.e., substituted. Suitable radionuclides that can be incorporated into the compounds of the present disclosure include 2 H (also denoted as D as deuterium), 3 H (also denoted as T as tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131I is included, but not limited to these. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced by deuterium atoms, enabling deuteration of the compounds (e.g., C in formula I 1-6 One or more hydrogen atoms of an alkyl group can optionally be replaced by deuterium atoms such as -CD3 which is substituted with -CH3). In some embodiments, the alkyl groups of the disclosed formula (e.g., formula I) can be per-deuterated.

[0398] One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of natural or non-natural abundance atoms. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein can be replaced or substituted with deuterium (C 1-6 One or more hydrogen atoms of an alkyl group can be replaced by deuterium atoms such as -CD3 which is substituted relative to -CH3). In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 - 2, 1 - 3, 1 - 4, 1 - 5, 1 - 6, 1 - 8, 1 - 10, 1 - 12, 1 - 14, 1 - 16, 1 - 18, or 1 - 20 deuterium atoms. In some embodiments, all hydrogen atoms in the compound can be replaced, i.e., substituted, with deuterium atoms.

[0399] In some embodiments, each hydrogen atom of the compounds provided herein, such as a hydrogen atom bonded to a carbon atom of an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent, or a -C1-4 alkyl-, alkylene, alkenylene, and alkynylene linking group, as described herein, is optionally replaced by a deuterium atom.

[0400] In some embodiments, as described herein, an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent, or a -C 1-4Each hydrogen atom of the compounds provided herein from a hydrogen atom to a carbon atom of an alkyl-, alkylene-, alkenylene-, and alkynylene-linking group is replaced by a deuterium atom (i.e., an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent, or -C 1-4 alkyl-, alkylene-, alkenylene-, and alkynylene-linking groups are perdeuterated).

[0401] In some embodiments, an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent or -C as described herein 1-4 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogen atoms bonded to the carbon atoms of the alkyl-, alkylene-, alkenylene-, and alkynylene-linking groups are optionally replaced by deuterium atoms.

[0402] In some embodiments, an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent or -C as described herein 1-4 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to the carbon atoms of the alkyl-, alkylene-, alkenylene-, and alkynylene-linking groups are optionally replaced by deuterium atoms.

[0403] In some embodiments, the compounds provided herein (e.g., any of the compounds of Formulas I-XI) or a pharmaceutically acceptable salt thereof contain at least one deuterium atom.

[0404] In some embodiments, the compounds provided herein (e.g., any of the compounds of Formulas I-XI) or a pharmaceutically acceptable salt thereof contain two or more deuterium atoms.

[0405] In some embodiments, the compounds provided herein (e.g., any of the compounds of Formulas I-XI) or pharmaceutically acceptable salts thereof contain three or more deuterium atoms.

[0406] In some embodiments, for the compounds provided herein (e.g., any of the compounds of Formulas I-XI) or pharmaceutically acceptable salts thereof, all of the hydrogen atoms are replaced by deuterium atoms (i.e., the compound is “fully deuterated”).

[0407] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971), The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various tests such as NMR spectroscopy, metabolic experiments, and / or assays.

[0408] Substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from increased metabolic stability, such as an extended in vivo half-life or a reduced dosing requirement, and can thus, in some cases, be desirable (see, e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0409] The radionuclide incorporated into the radiolabeled compound depends on the specific use of the radiolabeled compound. For example, in the case of in vitro DGK labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I or 35 S incorporated compounds may be useful. In the case of radiation imaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br may be useful.

[0410] It is understood that a "radiolabel" or "labeled compound" is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C, 125 I, 35 S, and 82 selected from the group consisting of Br.

[0411] The present disclosure can further include a synthetic method for incorporating a radioisotope into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0412] The labeled compounds of the present disclosure can be used in screening assays to identify / evaluate compounds. For example, a newly synthesized or identified compound that is labeled (i.e., a test compound) can be evaluated for its ability to bind to DGK by monitoring its concentration fluctuations upon contact with DGK through tracking the label. For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to bind to DGK. Thus, the ability of a test compound to compete with a standard compound for binding to DGK is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not. Thus, the concentration of the labeled standard compound is monitored to assess the competition between the standard compound and the test compound, and thus the relative binding affinity of the test compound is confirmed.

[0413] Kit The present disclosure also includes, for example, a pharmaceutical kit useful in the treatment or prevention of DGK-related diseases or disorders as described herein, which comprises one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. As will be readily apparent to those skilled in the art, such a kit may further comprise one or more of various conventional pharmaceutical kit components, such as, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions indicating the amount of the administered component, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit, either as an insert or as a label.

[0414] The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to yield essentially the same results.

Examples

[0415] Fractional LC-MS purification of some of the prepared compounds was carried out on a Waters mass fractionation system. The basic equipment settings, protocols, and control software for the operation of these systems are described in detail in the literature (see, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002), "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)). The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under the following conditions: Instrument: Agilent 1100 series, LC / MSD, Column: Waters Sunfire™ C 18 5 μm, 2.1×50 mm, Buffer: Mobile phase A: 0.025% TFA in water and Mobile phase B: acetonitrile, gradient of B from 2% to 80% at a flow rate of 2.0 mL / min for 3 minutes.

[0416] Some of the prepared compounds were also separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with an MS detector as shown in the examples. Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0417] pH = 2 purification: Waters Sunfire™ C 185 μm, 19 × 100 mm, eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution and mobile phase B: acetonitrile, flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see, for example, "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)). For purification using a 30 × 100 mm column, the flow rate was 60 mL / min.

[0418] pH = 10 purification: Waters XBridge (trademark) C 18 5 μm, 19 × 100 mm column, eluted with mobile phase A: 0.15% NH4OH aqueous solution and mobile phase B: acetonitrile, flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see, for example, "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)). For purification using a 30 × 100 mm column, the flow rate was 60 mL / min.

[0419] Intermediate 1. (2R,5S)-1-(bis(4-fluorophenyl)methyl

Chemical Structure

Chemical Structure

[0420] Step 2. (2R,5S)-1-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride To a mixture of tert-butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine-1-carboxylate (1.86 g, 4.5 mmol) in THF (25 mL) was added a 4 M HCl solution in 1,4-dioxane (6.25 mL, 25.0 mmol), and the reaction mixture was purged with N2 and stirred at 80 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (25 mL) and hexane (50 mL) and slurried for 30 min. The solid precipitate was collected by filtration, washed with Et2O and hexane, and dried under vacuum to give the desired product (1.34 g, 85% yield) as a white solid. C 19 H 23 F2N2(M+H) +LC-MS calculated value for: m / z = 317.2; measured value 317.2.

[0421] Intermediate 2. 7-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine

Chem.

[0422] Intermediate 3. 7-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-iodothiazolo[5,4-d]pyrimidine

Chem.

[0423] Intermediate 4. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-(difluoromethyl)thiazolo[5,4-d]pyrimidine

Chemical Structure

Chemical Structure

[0424] Step 2: 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-(difluoromethyl)thiazolo[5,4-d]pyrimidine In an oven-dried vial equipped with a stir bar, to a mixture of 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine-2-carbaldehyde (Step 1) in CH2Cl2 (2.1 mL) was added dropwise diethylaminosulfur trifluoride (163 μL, 1.2 mmol, Aldrich 235253), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched slowly by the dropwise addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated, and the crude residue was purified by flash column chromatography (12 g of SiO2, EtOAc / hexane) to afford the desired product. C 25 H 23 ClF4N5S (M+H) + Calculated LC-MS for: m / z = 536.1; found 536.1.

[0425] Intermediate 5. 3-(7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidin-2-yl)propanenitrile

Chemical formula

[0426] Intermediate 6. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine

Chemical Structure

[0427] Intermediate 7. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chlorofuro[3,2-d]pyrimidine

Chemical Structure

[0428] Intermediate 8. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chlorothieno[3,2-d]pyrimidine

Chemical Structure

[0429] Intermediate 9. 6-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-9-methyl-9H-purine

Chemical Structure

[0430] Intermediate 10. 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine

Chemical Structure

[0431] Intermediate 11.7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothieno[3,2-b]pyridine

Chemical formula

[0432] Intermediate 12. 4-((2S,5R)-4-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine

Chem.

[0433] Intermediate 13. (2S,5S)-4-(Bis(4-fluorophenyl)methyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Chem.

[0434] Intermediate 14. (2S,5S)-1-(Bis(4-fluorophenyl)methyl)-2-(methoxymethyl)-5-methylpiperazine hydrochloride

Chem.

Chem.

[0435] Step 2. (2S,5S)-1-(Bis(4-fluorophenyl)methyl)-2-(methoxymethyl)-5-methylpiperazine hydrochloride A mixture of tert-butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate (69 mg, 0.15 mmol) in THF (1.5 mL) was added with a 1,4-dioxane solution of 4 M HCl (0.4 mL, 1.6 mmol), and the reaction mixture was purged with N2 and stirred at 85 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated to 1 / 2 volume, diluted with Et2O (3 mL) and hexane (5 mL), and slurried for 30 min. The solid precipitate was allowed to stand and the supernatant solvent was decanted, and the residual solid was dried under vacuum to obtain the desired product as a white solid. C 20 H 25 F2N2O (M+H) + LC-MS calculated value for: m / z = 347.2; found 347.1.

[0436] Intermediate 15. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride

Chemical formula

Chemical formula

[0437] Step 2: tert-Butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-(cyanomethyl)-2-methylpiperazine-1-carboxylate

Chemical Structure

[0438] Step 3.2 - ((2R,5S)-1-(Bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride

Chem.

[0439] Intermediate 16.2 - ((2R,5S)-1-(Bis(4-fluorophenyl)methyl)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)-5-methylpiperazin-2-yl)acetonitrile

Chem.

[0440] Intermediate 17. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-4-(2-chloro-9-methyl-9H-purin-6-yl)-5-methylpiperazin-2-yl)acetonitrile

Chemical formula

[0441] Intermediate 18. (R)-4-(bis(4-fluorophenyl)methyl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl

Chemical formula

[0442] Intermediate 19. (R)-3-(1-(Bis(4-fluorophenyl)methyl)piperazin-2-yl)propanenitrile hydrochloride

Chemical Structure

[0443] Intermediate 20. (R)-3-(1-(Bis(4-fluorophenyl)methyl)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)piperazin-2-yl)propanenitrile

Chemical Structure

[0444] Intermediate 21. 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-9H-purine

Chemical formula

[0445] As would be understood by those skilled in the art, the compounds of the present disclosure can exist as tautomers. For example, Intermediate 21 can exist as the 7H-purine or 9H-purine form (e.g., 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-7H-purine).

[0446] Intermediate 22. (S)-(tetrahydrofuran-2-yl)methyl methanesulfonate

Chemical formula

[0447] Intermediate 23. 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-8-methyl-9H-purine

Chemical Structure

[0448] Intermediate 24. Methyl (R)-2-(benzylamino)butanoate [Chemical formula] To a stirred solution of methyl (R)-2-aminobutanoate hydrochloride (30.0 g, 195 mmol, Combi-Blocks QA-7768) in CH2Cl2 (500 mL) was added benzaldehyde (20.7 g, 195 mmol) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 0 °C in an ice bath and then sodium triacetoxyborohydride (20.7 g, 98 mmol) was added portionwise over 20 min. The ice bath was removed and the reaction mixture was stirred at ambient temperature overnight. The mixture was transferred to a separatory funnel and extracted with 1 M aqueous HCl (3 × 300 mL). The combined aqueous layers were made basic with solid KOH (pH > 12) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated aqueous NaCl and dried over MgSO4, and the filtrate was concentrated to afford the desired product (28.3 g, 70% yield) as a colorless oil. The crude material obtained was used directly without further purification. C 12 H 18 NO2(M+H) +LC-MS calculated value for it: m / z = 208.1; measured value 208.2.

[0449] Intermediate 25. (2S,5R)-5-Ethyl-2-methylpiperazine-1-carboxylic acid tert-butyl

Chem.

Chem.

Claims

1. A compound of formula I, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein, each 【Chemical 2】 is a single bond or a double bond, and at least one [Chemical Formula 3] is a double bond, U is CR ３ or N, and X is CR ４ , N, NR ４ , S, or O, and Y is CR ５ , N, or NR ５ and Z is CR ６ , N, NR ６ , S, or O, and R １ is Cy １ or L-Cy １ and L is NR ｃ７ , O, C １－３ alkyl, C ２－３ alkenyl, or C ２－３ is alkynyl, Cy １ is C ３－１０ cycloalkyl, 5- to 15-membered heteroaryl, or 4- to 15-membered heterocycloalkyl, wherein said C ３－１０ cycloalkyl, 5- to 15-membered heteroaryl or 4- to 15-membered heterocycloalkyl is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ａ substituents, Each R １Ａ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ１１ , SR ａ１１ , NHOR ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)NR ｃ１１ (OR ａ１１ ), C(O)OR ａ１１ , OC(O)R ｂ１１ , OC(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ R ｄ１１ , NR ｃ１１ NR ｃ１１ R ｄ１１ , NR ｃ１１ , C(O)R ｂ１１ , NR ｃ１１ , C(O)OR ａ１１ , NR ｃ１１ , C(O)NR ｃ１１ R ｄ１１ , C(=NR ｅ１１ )R ｂ１１ , C(=NR ｅ１１ )NR ｃ１１ R ｄ１１ , C(=NOR ａ１１ )R ｂ１１ , C(=NOR ａ１１ )OR ａ１１ , NR ｃ１１ , C(=NR ｅ１１ )NR ｃ１１ R ｄ１１ , NR ｃ１１ , C(=NR ｅ１１ ), R ｂ１１ , NR ｃ１１ S(O)R ｂ１１ , NR ｃ１１ S(O)NR ｃ１１ R ｄ１１ , NR ｃ１１ S(O) ２ R ｂ１１ , NR ｃ１１ S(O)(=NR ｅ１１ )R ｂ１１ , NR ｃ１１ S(O) ２ NR ｃ１１ R ｄ１１ , S(O)R ｂ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , S(O) ２ NR ｃ１１ R ｄ１１ , OS(O)(=NR ｅ１１ )R ｂ１１ , and OS(O) ２ R ｂ１１ independently selected from, said R １Ａ C of １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｂ substituents, Each R ａ１１ 、R ｃ１１ 、and R ｄ１１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and said R ａ１１ 、R ｃ１１ and R ｄ１１ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｂ substituents, or or any R attached to the same N atom ｃ１１ and R ｄ１１ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｂ substituents Each R ｂ１１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ１１ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｂ substituents, Each R ｅ１１ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from Each R １Ｂ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ１２ , SR ａ１２ , NHOR ａ１２ , C(O)R ｂ１２ , C(O)NR ｃ１２ R ｄ１２ , C(O)NR ｃ１２ (OR ａ１２ ), C(O)OR ａ１２ , OC(O)R ｂ１２ , OC(O)NR ｃ１２ R ｄ１２ , NR ｃ１２ R ｄ１２ , NR ｃ１２ NR ｃ１２ R ｄ１２ , NR ｃ１２ , C(O)R ｂ１２ , NR ｃ１２ , C(O)OR ａ１２ , NR ｃ１２ , C(O)NR ｃ１２ R ｄ１２ , C(=NR ｅ１２ )R ｂ１２ , C(=NR ｅ１２ )NR ｃ１２ R ｄ１２ , C(=NOR ａ１２ )R ｂ１２ , C(=NOR ａ１２ )OR ａ１２ , NR ｃ１２ , C(=NR ｅ１２ )NR ｃ１２ R ｄ１２ , NR ｃ１２ , C(=NR ｅ１２ ), R ｂ１２ , NR ｃ１２ S(O)R ｂ１２ , NR ｃ１２ S(O)NR ｃ１２ R ｄ１２ , NR ｃ１２ S(O) ２ R ｂ１２ , NR ｃ１２ S(O)(=NR ｅ１２ ), R ｂ１２ , NR ｃ１２ S(O) ２ NR ｃ１２ R ｄ１２ , S(O)R ｂ１２ , S(O)NR ｃ１２ R ｄ１２ , S(O) ２ R ｂ１２ , S(O) ２ NR ｃ１２ R ｄ１２ , OS(O)(=NR ｅ１２ ), R ｂ１２ , and OS(O) ２ R ｂ１２ is independently selected from, said R １Ｂ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｃ substituents, Each R ａ１２ 、R ｃ１２ 、and R ｄ１２ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ１２ of said R ｃ１２ 、R ｄ１２ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｃ substituents, or or any R attached to the same N atom ｃ１２ and R ｄ１２ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １Ｃ substituents Each R ｂ１２ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl, C ｂ１２ alkenyl, C １－６ alkynyl, C ２－６ aryl, C ２－６ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C ３－１０ alkyl-, C ６－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C ３－１０ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, １－６ １Ｃ ​​ Each R ｅ１２ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from Each R １Ｃ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ１３ , SR ａ１３ , NHOR ａ１３ , C(O)R ｂ１３ , C(O)NR ｃ１３ R ｄ１３ , C(O)NR ｃ１３ (OR ａ１３ ), C(O)OR ａ１３ , OC(O)R ｂ１３ , OC(O)NR ｃ１３ R ｄ１３ , NR ｃ１３ R ｄ１３ , NR ｃ１３ NR ｃ１３ R ｄ１３ , NR ｃ１３ C(O)R ｂ１３ , NR ｃ１３ C(O)OR ａ１３ , NR ｃ１３ C(O)NR ｃ１３ R ｄ１３ , C(=NR ｅ１３ )R ｂ１３ , C(=NR ｅ１３ )NR ｃ１３ R ｄ１３ , C(=NOR ａ１２ )R ｂ１２ , C(=NOR ａ１２ )OR ａ１２ , NR ｃ１３ C(=NR ｅ１３ )NR ｃ１３ R ｄ１３ , NR ｃ１３ C(=NR ｅ１３ )R ｂ１３ , NR ｃ１３ S(O)R ｂ１３ , NR ｃ１３ S(O)NR ｃ１３ R ｄ１３ , NR ｃ１３ S(O) ２ R ｂ１３ , NR ｃ１３ S(O)(=NR ｅ１３ )R ｂ１３ , NR ｃ１３ S(O) ２ NR ｃ１３ R ｄ１３ , S(O)R ｂ１３ , S(O)NR ｃ１３ R ｄ１３ , S(O) ２ R ｂ１３ , S(O) ２ NR ｃ１３ R ｄ１３ , OS(O)(=NR ｅ１３ )R ｂ１３ , and OS(O) ２ R ｂ１３ is independently selected from, said R １Ｃ C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｄ substituents, Each R ａ１３ 、R ｃ１３ 、and R ｄ１３ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and said R ａ１３ 、R ｃ１３ and R ｄ１３ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｄ substituents, or or any R attached to the same N atom ｃ１３ and R ｄ１３ together with the N atom to which they are attached form a 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R １Ｄ substituents, Each R ｂ１３ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from alkyl, C ｂ１３ alkyl, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｄ substituents, Each R ｅ１３ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from Each R １Ｄ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ１４ , SR ａ１４ , NHOR ａ１４ , C(O)R ｂ１４ , C(O)NR ｃ１４ R ｄ１４ , C(O)NR ｃ１４ (OR ａ１４ ), C(O)OR ａ１４ , OC(O)R ｂ１４ , OC(O)NR ｃ１４ R ｄ１４ , NR ｃ１４ R ｄ１４ , NR ｃ１４ NR ｃ１４ R ｄ１４ , NR ｃ１４ C(O)R ｂ１４ , NR ｃ１４ C(O)OR ａ１４ , NR ｃ１４ C(O)NR ｃ１４ R ｄ１４ , C(=NR ｅ１４ )R ｂ１４ , C(=NR ｅ１４ )NR ｃ１４ R ｄ１４ , NR ｃ１４ C(=NR ｅ１４ )NR ｃ１４ R ｄ１４ , NR ｃ１４ C(=NR ｅ１４ )R ｂ１４ , NR ｃ１４ S(O)R ｂ１４ , NR ｃ１４ S(O)NR ｃ１４ R ｄ１４ , NR ｃ１４ S(O) ２ R ｂ１４ , NR ｃ１４ S(O)(=NR ｅ１４ )R ｂ１４ , NR ｃ１４ S(O) ２ NR ｃ１４ R ｄ１４ , S(O)R ｂ１４ , S(O)NR ｃ１４ R ｄ１４ , S(O) ２ R ｂ１４ , S(O) ２ NR ｃ１４ R ｄ１４ , OS(O)(=NR ｅ１４ )R ｂ１４ , and OS(O) ２ R ｂ１４ independently selected from, said R １Ｄ C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ１４ 、R ｃ１４ 、and R ｄ１４ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ１４ of said R ｃ１４ 、R ｄ１４ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or or any R attached to the same N atom ｃ１４ and R ｄ１４ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents; Each R ｂ１４ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the said R ｂ１４ 's C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｅ１４ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from R ２ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ２ , NHOR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)NR ｃ２ (OR ａ２ ), C(O)OR ａ２ , OC(O)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , NR ｃ２ R ｄ２ , NR ｃ２ NR ｃ２ R ｄ２ , NR ｃ２ , C(O)R ｂ２ , NR ｃ２ , C(O)OR ａ２ , NR ｃ２ , C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ), R ｂ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), NR ｃ２ R ｄ２ , NR ｃ２ , C(=NR ｅ２ ), R ｂ２ , NR ｃ２ , NR ｂ２ , NR ｃ２ , NR ｃ２ R ｄ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S(O)(=NR ｅ２ ) R ｂ２ , N.R. ｃ２ S (O) ２ N.R. ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , S(O) ２ N.R. ｃ２ R ｄ２ , OS(O)(=NR ｅ２ ) R ｂ２ , and OS(O) ２ R ｂ２ wherein R ２ C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－６ Alkyl-, C ３－１０ Cycloalkyl-C １－６ Alkyl-, (5- to 10-membered heteroaryl)-C １－６ Alkyl- and (4- to 10-membered heterocycloalkyl)-C １－６ Each alkyl- is selected from 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ２Ａ is optionally substituted with a substituent; Each R ａ２ , R ｃ２ , and R ｄ２ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ２ of said R ｃ２ , R ｄ２ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ２Ａ substituents, or or any R attached to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ２Ａ substituents Each R ｂ２ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl, C ｂ２ alkenyl, C １－６ alkynyl, C ２－６ aryl, C ２－６ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C ３－１０ alkyl-, C ６－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C ３－１０ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, １－６ and ２Ａ is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R Each R ｅ２ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from R ２Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ２１ , SR ａ２１ , NHOR ａ２１ , C(O)R ｂ２１ , C(O)NR ｃ２１ R ｄ２１ , C(O)NR ｃ２１ (OR ａ２１ ), C(O)OR ａ２１ , OC(O)R ｂ２１ , OC(O)NR ｃ２１ R ｄ２１ , NR ｃ２１ R ｄ２１ , NR ｃ２１ NR ｃ２１ R ｄ２１ , NR ｃ２１ , C(O)R ｂ２１ , NR ｃ２１ , C(O)OR ａ２１ , NR ｃ２１ , C(O)NR ｃ２１ R ｄ２１ , C(=NR ｅ２１ )R ｂ２１ , C(=NR ｅ２１ )NR ｃ２１ R ｄ２１ , NR ｃ２１ , C(=NR ｅ２１ )NR ｃ２１ R ｄ２１ , NR ｃ２１ , C(=NR ｅ２１ )R ｂ２１ , NR ｃ２１ , S(O)R ｂ２１ , NR ｃ２１ , S(O)NR ｃ２１ R ｄ２１ , NR ｃ２１ S(O) ２ R ｂ２１ , NR ｃ２１ S(O)(=NR ｅ２１ )R ｂ２１ , NR ｃ２１ S(O) ２ NR ｃ２１ R ｄ２１ , S(O)R ｂ２１ , S(O)NR ｃ２１ R ｄ２１ , S(O) ２ R ｂ２１ , S(O) ２ NR ｃ２１ R ｄ２１ , OS(O)(=NR ｅ２１ )R ｂ２１ , and OS(O) ２ R ｂ２１ selected from, wherein said R ２Ａ C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ２１ 、R ｃ２１ 、and R ｄ２１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ２１ of said R ｃ２１ 、R ｄ２１ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or or any R attached to the same N atom ｃ２１ and R ｄ２１ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｂ２１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ２１ alkyl, C １－６ alkenyl, C ２－６ alkynyl, phenyl, C ２－６ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C ３－７ alkyl-, C １－６ cycloalkyl-C ３－７ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R １－６ substituents, Ｍ ​ Each R ｅ２１ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from R ３ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ３ , SR ａ３ , NHOR ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)NR ｃ３ (OR ａ３ ), C(O)OR ａ３ , OC(O)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , NR ｃ３ R ｄ３ , NR ｃ３ NR ｃ３ R ｄ３ , NR ｃ３ C(O)R ｂ３ , NR ｃ３ C(O)OR ａ３ , NR ｃ３ C(O)NR ｃ３ R ｄ３ , C(=NR ｅ３ )R ｂ３ , C(=NR ｅ３ )NR ｃ３ R ｄ３ , NR ｃ３ C(=NR ｅ３ )NR ｃ３ R ｄ３ , NR ｃ３ C(=NR ｅ３ )R ｂ３ , NR ｃ３ S(O)R ｂ３ , NR ｃ３ SONR ｃ３ R ｄ３ , NR ｃ３ S(O) ２ R ｂ３ , NR ｃ３ S(O)(=NR ｅ３ )R ｂ３ , NR ｃ３ S(O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , S(O) ２ NR ｃ３ R ｄ３ , OS(O)(=NR ｅ３ )R ｂ３ , and OS(O) ２ R ｂ３ selected from, said R ３ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ３Ａ substituents, Each R ａ３ , R ｃ３ , and R ｄ３ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and said R ａ３ , R ｃ３ and R ｄ３ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ３Ａ substituents, or or any R attached to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ３Ａ substituents Each R ｂ３ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the said R ｂ３ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ３Ａ substituents, Each R ｅ３ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from R ３Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5 - 6 membered heteroaryl, 4 - 7 membered heterocycloalkyl, phenyl - C １－６ alkyl -, C ３－７ cycloalkyl - C １－６ alkyl -, (5 - 6 membered heteroaryl) - C １－６ alkyl -, (4 - 7 membered heterocycloalkyl) - C １－６ alkyl -, CN, NO ２ , OR ａ３１ , SR ａ３１ , NHOR ａ３１ , C(O)R ｂ３１ , C(O)NR ｃ３１ R ｄ３１ , C(O)NR ｃ３１ (OR ａ３１ ), C(O)OR ａ３１ , OC(O)R ｂ３１ , OC(O)NR ｃ３１ R ｄ３１ , NR ｃ３１ R ｄ３１ , NR ｃ３１ NR ｃ３１ R ｄ３１ , NR ｃ３１ , C(O)R ｂ３１ , NR ｃ３１ , C(O)OR ａ３１ , NR ｃ３１ , C(O)NR ｃ３１ R ｄ３１ , C(=NR ｅ３１ )R ｂ３１ , C(=NR ｅ３１ )NR ｃ３１ R ｄ３１ , NR ｃ３１ , C(=NR ｅ３１ )NR ｃ３１ R ｄ３１ , NR ｃ３１ , C(=NR ｅ３１ )R ｂ３１ , NR ｃ３１ , S(O)R ｂ３１ , NR ｃ３１ , S(O)NR ｃ３１ R ｄ３１ , NR ｃ３１ S(O) ２ R ｂ３１ , NR ｃ３１ S(O)(=NR ｅ３１ )R ｂ３１ , NR ｃ３１ S(O) ２ NR ｃ３１ R ｄ３１ , S(O)R ｂ３１ , S(O)NR ｃ３１ R ｄ３１ , S(O) ２ R ｂ３１ , S(O) ２ NR ｃ３１ R ｄ３１ , OS(O)(=NR ｅ３１ )R ｂ３１ , and OS(O) ２ R ｂ３１ selected from, said R ３Ａ C of １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ３１ 、R ｃ３１ 、and R ｄ３１ are each independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ３１ of R ｃ３１ 、R ｄ３１ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or any R attached to the same N atom ｃ３１ and R ｄ３１ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents Each R ｂ３１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the said R ｂ３１ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｅ３１ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from R ４ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ４ , SR ａ４ , NHOR ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)NR ｃ４ (OR ａ４ ), C(O)OR ａ４ , OC(O)R ｂ４ , OC(O)NR ｃ４ R ｄ４ , NR ｃ４ R ｄ４ , NR ｃ４ NR ｃ４ R ｄ４ , NR ｃ４ C(O)R ｂ４ , NR ｃ４ C(O)OR ａ４ , NR ｃ４ C(O)NR ｃ４ R ｄ４ , C(=NR ｅ４ )R ｂ４ , C(=NR ｅ４ )NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ )NR ｃ４ R ｄ４ , NR ｃ４ C(=NR ｅ４ )R ｂ４ , NR ｃ４ S(O)R ｂ４ , NR ｃ４ SONR ｃ４ R ｄ４ , NR ｃ４ S(O) ２ R ｂ４ , NR ｃ４ S(O)(=NR ｅ４ )R ｂ４ , NR ｃ４ S(O) ２ NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , S(O) ２ NR ｃ４ R ｄ４ , OS(O)(=NR ｅ４ )R ｂ４ , and OS(O) ２ R ｂ４ selected from, said R ４ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ４Ａ substituents, Each R ａ４ , R ｃ４ , and R ｄ４ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected, and said R ａ４ , R ｃ４ and R ｄ４ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ４Ａ substituents, or or any R attached to the same N atom ｃ４ and R ｄ４ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ４Ａ substituents Each R ｂ４ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ４ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ３－１０ aryl-C ６－１０ alkyl-, C １－６ cycloalkyl-C ３－１０ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, ４Ａ ​ Each R ｅ４ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from R ４Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ４１ , SR ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)NR ｃ４１ (OR ａ４１ ), C(O)OR ａ４１ , OC(O)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ R ｄ４１ , NR ｃ４１ NR ｃ４１ R ｄ４１ , NR ｃ４１ , C(O)R ｂ４１ , NR ｃ４１ , C(O)OR ａ４１ , NR ｃ４１ , C(O)NR ｃ４１ R ｄ４１ , C(=NR ｅ４１ )R ｂ４１ , C(=NR ｅ４１ )NR ｃ４１ R ｄ４１ , NR ｃ４１ , C(=NR ｅ４１ )NR ｃ４１ R ｄ４１ , NR ｃ４１ , C(=NR ｅ４１ )R ｂ４１ , NR ｃ４１ , S(O)R ｂ４１ , NR ｃ４１ , S(O)NR ｃ４１ R ｄ４１ , NR ｃ４１ S(O) ２ R ｂ４１ , NR ｃ４１ S(O)(=NR ｅ４１ )R ｂ４１ , NR ｃ４１ S(O) ２ NR ｃ４１ R ｄ４１ , S(O)R ｂ４１ , S(O)NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , S(O) ２ NR ｃ４１ R ｄ４１ , OS(O)(=NR ｅ４１ )R ｂ４１ , and OS(O) ２ R ｂ４１ selected from, said R ４Ａ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ４１ of R ｃ４１ , R ｄ４１ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or or any R attached to the same N atom ｃ４１ and R ｄ４１ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｂ４１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from alkyl, C ｂ４１ alkyl, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｅ４１ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from R ５ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ５ , SR ａ５ , NHOR ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)NR ｃ５ (OR ａ５ ), C(O)OR ａ５ , OC(O)R ｂ５ , OC(O)NR ｃ５ R ｄ５ , NR ｃ５ R ｄ５ , NR ｃ５ NR ｃ５ R ｄ５ , NR ｃ５ C(O)R ｂ５ , NR ｃ５ C(O)OR ａ５ , NR ｃ５ C(O)NR ｃ５ R ｄ５ , C(=NR ｅ５ )R ｂ５ , C(=NR ｅ５ )NR ｃ５ R ｄ５ , NR ｃ５ C(=NR ｅ５ )NR ｃ５ R ｄ５ , NR ｃ５ C(=NR ｅ５ )R ｂ５ , NR ｃ５ S(O)R ｂ５ , NR ｃ５ SONR ｃ５ R ｄ５ , NR ｃ５ S(O) ２ R ｂ５ , NR ｃ５ S(O)(=NR ｅ５ )R ｂ５ , NR ｃ５ S(O) ２ NR ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , S(O) ２ NR ｃ５ R ｄ５ , OS(O)(=NR ｅ５ )R ｂ５ , and OS(O) ２ R ｂ５ selected from, said R ５ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ５Ａ substituents, Each R ａ５ 、R ｃ５ 、and R ｄ５ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- and is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ａ５ 、R ｃ５ and R ｄ５ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ３－１０ aryl-C ６－１０ alkyl-, C １－６ cycloalkyl-C ３－１０ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, or ５Ａ ​ or any R attached to the same N atom ｃ５ and R ｄ５ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ５Ａ substituents Each R ｂ５ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ５ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ３－１０ aryl-C ６－１０ alkyl-, C １－６ cycloalkyl-C ３－１０ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, ５Ａ ​ Each R ｅ５ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, R ５Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ５１ , SR ａ５１ , NHOR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)NR ｃ５１ (OR ａ５１ ), C(O)OR ａ５１ , OC(O)R ｂ５１ , OC(O)NR ｃ５１ R ｄ５１ , NR ｃ５１ R ｄ５１ , NR ｃ５１ NR ｃ５１ R ｄ５１ , NR ｃ５１ , C(O)R ｂ５１ , NR ｃ５１ , C(O)OR ａ５１ , NR ｃ５１ , C(O)NR ｃ５１ R ｄ５１ , C(=NR ｅ５１ )R ｂ５１ , C(=NR ｅ５１ )NR ｃ５１ R ｄ５１ , NR ｃ５１ , C(=NR ｅ５１ )NR ｃ５１ R ｄ５１ , NR ｃ５１ , C(=NR ｅ５１ )R ｂ５１ , NR ｃ５１ , S(O)R ｂ５１ , NR ｃ５１ , S(O)NR ｃ５１ R ｄ５１ , NR ｃ５１ S(O) ２ R ｂ５１ , NR ｃ５１ S(O)(=NR ｅ５１ )R ｂ５１ , NR ｃ５１ S(O) ２ NR ｃ５１ R ｄ５１ , S(O)R ｂ５１ , S(O)NR ｃ５１ R ｄ５１ , S(O) ２ R ｂ５１ , S(O) ２ NR ｃ５１ R ｄ５１ , OS(O)(=NR ｅ５１ )R ｂ５１ , and OS(O) ２ R ｂ５１ selected from, wherein said R ５Ａ C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ５１ , R ｃ５１ , and R ｄ５１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ５１ of R ｃ５１ , R ｄ５１ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or or any R attached to the same N atom ｃ５１ and R ｄ５１ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｂ５１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from alkyl, C ｂ５１ alkyl, C １－６ alkenyl, C ２－６ alkynyl, phenyl, C ２－６ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C ３－７ alkyl-, C １－６ cycloalkyl-C ３－７ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and each of the C １－６ alkyl-, C Ｍ is optionally substituted with 1, 2, 3, or 4 independently selected R substituents, Each R ｅ５１ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from R ６ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ６ , SR ａ６ , NHOR ａ６ , C(O)R ｂ６ , C(O)NR ｃ６ R ｄ６ , C(O)NR ｃ６ (OR ａ６ ), C(O)OR ａ６ , OC(O)R ｂ６ , OC(O)NR ｃ６ R ｄ６ , NR ｃ６ R ｄ６ , NR ｃ６ NR ｃ６ R ｄ６ , NR ｃ６ , C(O)R ｂ６ , NR ｃ６ , C(O)OR ａ６ , NR ｃ６ , C(O)NR ｃ６ R ｄ６ , C(=NR ｅ６ )R ｂ６ , C(=NR ｅ６ )NR ｃ６ R ｄ６ , NR ｃ６ , C(=NR ｅ６ )NR ｃ６ R ｄ６ , NR ｃ６ , C(=NR ｅ６ )R ｂ６ , NR ｃ６ , S(O)R ｂ６ , NR ｃ６ S(O)NR ｃ６ R ｄ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S(O)(=NR ｅ６ ) R ｂ６ , N.R. ｃ６ S (O) ２ N.R. ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , S(O) ２ N.R. ｃ６ R ｄ６ , OS(O)(=NR ｅ６ ) R ｂ６ , and OS(O) ２ R ｂ６ wherein R ６ C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－６ Alkyl-, C ３－１０ Cycloalkyl-C １－６ Alkyl-, (5- to 10-membered heteroaryl)-C １－６ Alkyl- and (4- to 10-membered heterocycloalkyl)-C １－６ Each alkyl- is selected from 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ６Ａ is optionally substituted with a substituent; Each R ａ６ , R ｃ６ , and R ｄ６ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected, said R ａ６ , R ｃ６ and R ｄ６ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ６Ａ substituents, or or any R attached to the same N atom ｃ６ and R ｄ６ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ６Ａ substituents Each R ｂ６ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ６ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ６Ａ substituents, Each R ｅ６ is H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, R ６Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ６１ , SR ａ６１ , NHOR ａ６１ , C(O)R ｂ６１ , C(O)NR ｃ６１ R ｄ６１ , C(O)NR ｃ６１ (OR ａ６１ ), C(O)OR ａ６１ , OC(O)R ｂ６１ , OC(O)NR ｃ６１ R ｄ６１ , NR ｃ６１ R ｄ６１ , NR ｃ６１ NR ｃ６１ R ｄ６１ , NR ｃ６１ , C(O)R ｂ６１ , NR ｃ６１ , C(O)OR ａ６１ , NR ｃ６１ , C(O)NR ｃ６１ R ｄ６１ , C(=NR ｅ６１ )R ｂ６１ , C(=NR ｅ６１ )NR ｃ６１ R ｄ６１ , NR ｃ６１ , C(=NR ｅ６１ )NR ｃ６１ R ｄ６１ , NR ｃ６１ , C(=NR ｅ６１ )R ｂ６１ , NR ｃ６１ , S(O)R ｂ６１ , NR ｃ６１ , S(O)NR ｃ６１ R ｄ６１ , NR ｃ６１ S (O) ２ R ｂ６１ , N.R. ｃ６１ S(O)(=NR ｅ６１ ) R ｂ６１ , N.R. ｃ６１ S (O) ２ N.R. ｃ６１ R ｄ６１ , S(O)R ｂ６１ , S(O)NR ｃ６１ R ｄ６１ , S(O) ２ R ｂ６１ , S(O) ２ N.R. ｃ６１ R ｄ６１ , OS(O)(=NR ｅ６１ ) R ｂ６１ , and OS(O) ２ R ｂ６１ wherein R ６Ａ C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, phenyl, C ３－７ Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ Alkyl-, C ３－７ Cycloalkyl-C １－６ Alkyl-, (5- to 6-membered heteroaryl)-C １－６ Alkyl- and (4- to 7-membered heterocycloalkyl)-C １－６ Each alkyl- is selected from 1, 2, 3, or 4 independently selected R Ｍ is optionally substituted with a substituent; Each R ａ６１ 、R ｃ６１ 、and R ｄ６１ are each independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and said R ａ６１ 、R ｃ６１ and R ｄ６１ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or any R attached to the same N atom ｃ６１ and R ｄ６１ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents Each R ｂ６１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the said R ｂ６１ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｅ６１ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from R ｃ７ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is selected from alkyl, C ｃ７ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ３－１０ aryl-C ６－１０ alkyl-, C １－６ cycloalkyl-C ３－１０ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R １－６ substituents, ７Ａ ​ Each R ７Ａ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１５ aryl, C ３－１５ cycloalkyl, 5- to 15-membered heteroaryl, 4- to 15-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ７１ , SR ａ７１ , NHOR ａ７１ , C(O)R ｂ７１ , C(O)NR ｃ７１ R ｄ７１ , C(O)NR ｃ７１ (OR ａ７１ ), C(O)OR ａ７１ , OC(O)R ｂ７１ , OC(O)NR ｃ７１ R ｄ７１ , NR ｃ７１ R ｄ７１ , NR ｃ７１ NR ｃ７１ R ｄ７１ , NR ｃ７１ , C(O)R ｂ７１ , NR ｃ７１ , C(O)OR ａ７１ , NR ｃ７１ , C(O)NR ｃ７１ R ｄ７１ , C(=NR ｅ７１ )R ｂ７１ , C(=NR ｅ７１ )NR ｃ７１ R ｄ７１ , C(=NOR ａ７１ )R ｂ７１ , C(=NOR ａ７１ )OR ａ７１ , NR ｃ７１ , C(=NR ｅ７１ )NR ｃ７１ R ｄ７１ , NR ｃ７１ , C(=NR ｅ７１ ), R ｂ７１ , NR ｃ７１ S(O)R ｂ７１ , NR ｃ７１ S(O)NR ｃ７１ R ｄ７１ , NR ｃ７１ S(O) ２ R ｂ７１ , NR ｃ７１ S(O)(=NR ｅ７１ )R ｂ７１ , NR ｃ７１ S(O) ２ NR ｃ７１ R ｄ７１ , S(O)R ｂ７１ , S(O)NR ｃ７１ R ｄ７１ , S(O) ２ R ｂ７１ , S(O) ２ NR ｃ７１ R ｄ７１ , OS(O)(=NR ｅ７１ )R ｂ７１ , and OS(O) ２ R ｂ７１ independently selected from, said R ７Ａ C of １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ７Ｂ substituents, Each R ａ７１ , R ｃ７１ , and R ｄ７１ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and the R ａ７１ , R ｃ７１ and R ｄ７１ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ７Ｂ substituents, or or any R attached to the same N atom ｃ７１ and R ｄ７１ together with the N atom to which they are attached form a 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ７Ｂ substituents Each R ｂ７１ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is independently selected from alkyl-, C ｂ７１ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R ７Ｂ substituents, Each R ｅ７１ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from Each R ７Ｂ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , OR ａ７２ , SR ａ７２ , NHOR ａ７２ , C(O)R ｂ７２ , C(O)NR ｃ７２ R ｄ７２ , C(O)NR ｃ７２ (OR ａ７２ ), C(O)OR ａ７２ , OC(O)R ｂ７２ , OC(O)NR ｃ７２ R ｄ７２ , NR ｃ７２ R ｄ７２ , NR ｃ７２ NR ｃ７２ R ｄ７２ , NR ｃ７２ , C(O)R ｂ７２ , NR ｃ７２ , C(O)OR ａ７２ , NR ｃ７２ , C(O)NR ｃ７２ R ｄ７２ , C(=NR ｅ７２ )R ｂ７２ , C(=NR ｅ７２ )NR ｃ７２ R ｄ７２ , NR ｃ７２ , C(=NR ｅ７２ )NR ｃ７２ R ｄ７２ , NR ｃ７２ , C(=NR ｅ７２ )R ｂ７２ , NR ｃ７２ , S(O)R ｂ７２ , NR ｃ７２ , S(O)NR ｃ７２ R ｄ７２ , NR ｃ７２ S(O) ２ R ｂ７２ , NR ｃ７２ S(O)(=NR ｅ７２ )R ｂ７２ , NR ｃ７２ S(O) ２ NR ｃ７２ R ｄ７２ , S(O)R ｂ７２ , S(O)NR ｃ７２ R ｄ７２ , S(O) ２ R ｂ７２ , S(O) ２ NR ｃ７２ R ｄ７２ , OS(O)(=NR ｅ７２ )R ｂ７２ , and OS(O) ２ R ｂ７２ is independently selected from, said R ７Ｂ C of １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ａ７２ 、R ｃ７２ 、and R ｄ７２ are each independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C ａ７２ of said R ｃ７２ 、R ｄ７２ and R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, or any R attached to the same N atom ｃ７２ and R ｄ７２ together with the N atom to which they are attached form a 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group, and the 5- or 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents Each R ｂ７２ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the R ｂ７２ C of １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R Ｍ substituents, Each R ｅ７２ is independently selected from H, OH, CN, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, C １－６ haloalkoxy, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from Each R Ｍ is independently selected from H, OH, halo, oxo, CN, C(O)OH, NH ２ , NO ２ , SF ５ , C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkoxy, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the compound, or a pharmaceutically acceptable salt thereof, independently selected from the foregoing.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein U is CH or N.

3. R ４ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from alkynyl.

4. R ４ is H or C １－６ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

5. X is CH, CCH ３ , N, -NCH ２ CH ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is S or O.

6. Y is CR ５ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is CR or N.

7. R ５ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ selected from alkyl-, and R ５ wherein the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ５ But, H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, wherein R ５ C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, phenyl, C ３－７ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl each have 1, 2, 3, or 4 independently selected R ５Ａ 7. The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

9. R ５ is selected from H, C １－６ alkyl, C １－６ haloalkyl, and 5- to 6-membered heteroaryl, and the C ５ of said R １－６ alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

10. R ５ is selected from H, methyl, ethyl, difluoromethyl, and pyrazolyl, and the methyl, ethyl, and pyrazolyl of said R ５ are each optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

11. Each R ５Ａ is independently selected from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, and CN, and the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Each R ５Ａ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each R is CN.

13. R ５ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, methyl, cyanoethyl, difluoromethyl, and pyrazolyl.

14. Z is CR ６ , NR ６ , or S, the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R ６ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl-C １－６ alkyl-, or (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and the C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted by 1, 2, 3, or 4 independently selected R ６Ａ substituents, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. R ６ is H, C １－６ alkyl, C ３－７ cycloalkyl-C １－６ alkyl-, or (4-7 membered heterocycloalkyl)-C １－６ alkyl-, and the C １－６ alkyl, C ３－７ cycloalkyl-C １－６ alkyl-, or (4-7 membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted by 1, 2, 3, or 4 independently selected R ６Ａ substituents, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. Each R ６Ａ is independently selected from NR ｃ６１ R ｄ６１ and each R ｃ６１ and R ｄ６１ are independently selected from H and C １－６ alkyl, a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

18. R ６ is H, C １－６ alkyl, C ３－７ cycloalkyl-C １－６ alkyl-, or (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C １－６ alkyl is optionally substituted by NR ｃ６１ R ｄ６１ and R ｃ６１ and R ｄ６１ are each independently selected from H and C １－６ alkyl, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

19. R ６ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, cyclopropylmethyl, tetrahydrofuranylmethyl, or dimethylaminoethyl.

20. Z is CH, NCH ３ , NCH ２ CH ２ N(CH ３ ) ２ , NCH ２ -cyclopropyl, NCH ２ -tetrahydrofuranyl, or S, a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. R １ is Cy １ The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R is Cy.

22. Cy １ is C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, and said C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ａ substituents, a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

23. Cy １ is a 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R １Ａ substituents, a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

24. Cy １ is piperazinyl which is optionally substituted with one, two, three or four independently selected R １Ａ substituents, a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

25. Cy １ is piperazinyl which is substituted with 1, 2, 3 or 4 independently selected R １Ａ substituents, a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

26. Cy １ is [Chemical Formula 4] The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is.

27. Cy １ is 【Chemical Formula 5】 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is.

28. Each R １Ａ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- and is independently selected from, and the C １Ａ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｂ substituents, a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

29. Each R １Ａ is independently selected from halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, and the C １Ａ of said R １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｂ substituents, a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

30. Each R １Ａ is independently selected from C １－６ alkyl and C １－６ haloalkyl, and the C １Ａ of said R １－６ alkyls are each optionally substituted with one, two, three or four independently selected R １Ｂ substituents, a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

31. Each R １Ａ is independently selected from C １－６ alkyl, each of which is optionally substituted with one, two, three, or four independently selected R １Ｂ substituents, a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

32. Cy １ is [Chemical Formula 6] The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is.

33. Each R １Ｂ is independently selected from halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , and OR ａ１２ and is independently selected from the group consisting of, said R １Ｂ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

34. Each R １Ｂ But, C １－６ Alkyl, C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－６ Alkyl-, C ３－１０ Cycloalkyl-C １－６ Alkyl-, (5- to 10-membered heteroaryl)-C １－６ Alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ Alkyl-, CN, and OR ａ１２ Independently selected from the group consisting of R １Ｂ C ６－１０ Aryl, C ３－１０ Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl-C １－６ Alkyl-, C ３－１０ Cycloalkyl-C １－６ Alkyl-, (5- to 10-membered heteroaryl)-C １－６ Alkyl- and (4- to 10-membered heterocycloalkyl)-C １－６ Each alkyl- is selected from 1, 2, 3, or 4 independently selected R １Ｃ 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

35. Each R １Ｂ But, C １－６ Alkyl, phenyl, C ３－７ Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ Alkyl-, C ３－７ Cycloalkyl-C １－６ Alkyl-, (5- to 6-membered heteroaryl)-C １－６ Alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ Alkyl-, CN, and OR ａ１２ Independently selected from the group consisting of R １Ｂ Phenyl, C ３－７ Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ Alkyl-, C ３－７ Cycloalkyl-C １－６ Alkyl-, (5- to 6-membered heteroaryl)-C １－６ Alkyl- and (4- to 7-membered heterocycloalkyl)-C １－６ Each alkyl- is selected from 1, 2, 3, or 4 independently selected R １Ｃ 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, optionally substituted with a substituent.

36. Each R １Ｂ is selected independently from C １－６ alkyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR ａ１２ and the C １Ｂ alkyl, phenyl, C １－６ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R ３－７ are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

37. Each R １Ｂ is selected independently from C １－６ alkyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, CN, and OR ａ１２ and the C １Ｂ alkyl, C １－６ cycloalkyl, phenyl, and 5- to 6-membered heteroaryl of said R ３－７ are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, Each R ａ１２ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, and the compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

38. Each R １Ｂ is independently selected from C １－６ alkyl, C ３－７ cycloalkyl, phenyl, pyridinyl, CN, and OR ａ１２ and the C １Ｂ alkyl, phenyl, C １－６ cycloalkyl, and pyridinyl of said R ３－７ are each optionally substituted with 1, 2, 3, or 4 R １－６ substituents independently selected from halo, C １－６ alkyl, C ａ１３ haloalkyl, CN, and OR １Ｃ and is optionally substituted with substituents, Each R ａ１２ is independently selected from H and C １－６ alkyl, Each Ｒａ１３ is independently H, C １－６ alkyl, or C １－６ haloalkyl, the compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

39. Each Ｒ１Ｂ is independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridinyl, CN, and methoxy, and each methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, and pyridinyl of R １Ｂ is optionally substituted with one, two, three, or four independently selected R １Ｃ substituents, a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

40. Each R １Ｃ is selected independently from halo, C １－６ alkyl, C １－６ haloalkyl, CN, and OR ａ１３ and is selected independently therefrom each Ｒａ１３ is independently H, C １－６ alkyl, or C １－６ haloalkyl, a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof.

41. Each R １Ｂ is independently selected from isopropyl, hydroxymethyl, difluorocyclobutyl, trifluoromethylcyclobutyl, difluorocyclohexyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, bromofluorophenyl, chlorofluorophenyl, (fluoro)(difluoromethyl)phenyl, (fluoro)(trifluoromethyl)phenyl, (chloro)(methyl)phenyl, difluoromethylphenyl, trifluoromethylphenyl, (trifluoromethyl)(methyl)phenyl, (trifluoromethyl)(difluoro)phenyl, (chloro)(trifluoromethyl)phenyl, (chloro)(difluoro)phenyl, (trifluoromethoxy)(fluoro)phenyl, trifluoromethoxyphenyl, methoxyphenyl, cyanophenyl, trifluoromethylpyridinyl, (trifluoromethyl)(fluoro)pyridinyl, trifluoromethoxypyridinyl, CN, and methoxy, the compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

42. R ２ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is selected from alkyl, C ２ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R ２Ａ substituents, a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

43. R ２ is selected from H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and said R ２ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ２Ａ substituents, a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

44. R ２ is H, C １－６ alkyl, C １－６ haloalkyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the C ２ of said R １－６ alkyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ２Ａ substituents, a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

45. R ２ wherein R is selected from H, C １－６ alkyl, and C ３－７ cycloalkyl, the compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.

46. R ２ The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, methyl, and cyclopropyl.

47. each [Chemical Formula 7] is a single bond or a double bond, and at least one 【Chemical 8】 is a double bond, U is CH or N, X is CR ４ , N, NR ４ , S, or O, and Y is CR ５ or N, and Z is CR ６ , NR ６ , or S, and R １ is Cy １ or L-Cy １ and L is NR ｃ７ , O, C １－３ alkyl, C ２－３ alkenyl, or C ２－３ alkynyl, and Cy １ is C ３－１０ cycloalkyl, 5- to 15-membered heteroaryl, or 4- to 15-membered heterocycloalkyl, wherein said C ３－１０ cycloalkyl, 5- to 15-membered heteroaryl or 4- to 15-membered heterocycloalkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ａ substituents, Each R １Ａ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is independently selected from, and the R １Ａ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｂ substituents, Each R １Ｂ is halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, NO ２ , and OR ａ１２ and is independently selected from, said R １Ｂ of C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, Each R １Ｃ is independently selected from halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, CN, and OR ａ１３ and is independently selected from Each R ａ１３ is independently selected from H, C １－６ alkyl, and C １－６ haloalkyl, R ２ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ is selected from alkyl-, C ２ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ３－１０ aryl-C ６－１０ alkyl-, C １－６ cycloalkyl-C ３－１０ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R １－６ substituents, ２Ａ ​ Each R ２Ａ is halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, phenyl-C １－６ alkyl-, C ３－７ cycloalkyl-C １－６ alkyl-, (5- to 6-membered heteroaryl)-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ is independently selected from R ４ is selected from H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, and R ５ wherein R is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ selected from alkyl, C ５ wherein each of the C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- is optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, Each R ５Ａ is independently selected from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, and CN R ６ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl-C １－６ alkyl-, or (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, and wherein said C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted by 1, 2, 3, or 4 independently selected R ６Ａ substituents, Each R ６Ａ is selected independently from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, CN, and NR ｃ６１ R ｄ６１ and is selected independently therefrom Each R ｃ６１ and R ｄ６１ are each independently selected from H and C １－６ alkyl, R ｃ７ is H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

48. U is CH or N, X is CR ４ , N, NR ４ , S, or O, and Y is CR ５ or N, and Z is CR ６ , NR ６ , or S, and R １ is Cy １ and Cy １ is C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl, wherein said C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ａ substituents, Each R １Ａ is independently selected from halo, oxo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, and the C １Ａ of said R １－６ alkyl, C ２－６ alkenyl, and C ２－６ alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｂ substituents, Each R １Ｂ is C １－６ alkyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, (4- to 10-membered heterocycloalkyl)-C １－６ alkyl-, CN, and OR ａ１２ and is independently selected from, said R １Ｂ of C １－６ alkyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C ６－１０ aryl-C １－６ alkyl-, C ３－１０ cycloalkyl-C １－６ alkyl-, (5- to 10-membered heteroaryl)-C １－６ alkyl-, and (4- to 10-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, Each R １Ｃ is selected independently from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, CN, and OR ａ１３ and is selected independently therefrom, Each R ａ１２ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, Each R ａ１３ is independently selected from H, C １－６ alkyl, and C １－６ haloalkyl, R ２ is selected from H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ６－１０ aryl, C ３－１０ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, and the C of said R ２ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ aryl, C ６－１０ cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ３－１０ substituents, ２Ａ ​ R ４ is H or C １－６ is alkyl, R ５ is selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and the C ５ of said R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, Each R ５Ａ is independently selected from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, and CN, R ６ is H, halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－７ cycloalkyl-C １－６ alkyl-, or (4- to 7-membered heterocycloalkyl)-C １－６ alkyl-, and the C １－６ alkyl, C ３－７ cycloalkyl-C １－６ alkyl-, and (4- to 7-membered heterocycloalkyl)-C １－６ alkyl- are each optionally substituted by NR ｃ６１ R ｄ６１ and Each R ｃ６１ and R ｄ６１ is independently selected from H and C １－６ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

49. U is CH or N, X is CH, CCH ３ , N, -NCH ２ CH ３ , S, or O, and Y is CR ５ or N, and Z is CH, NCH ３ , NCH ２ CH ２ N(CH ３ ) ２ , NCH ２ -cyclopropyl, NCH ２ -tetrahydrofuranyl, or S, and R １ is Cy １ and Cy １ is a 4- to 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R １Ａ substituents Each R １Ａ is independently selected from C １－６ alkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R １Ｂ substituents, Each R １Ｂ is selected independently from C １－６ alkyl, phenyl, C ３－７ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, and OR ａ１２ and the C １Ｂ alkyl, phenyl, C １－６ cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl of said R ３－７ are each optionally substituted with 1, 2, 3, or 4 independently selected R １Ｃ substituents, Each R １Ｃ is selected independently from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, CN, and OR ａ１３ and is selected independently therefrom, Each R ａ１２ is independently selected from H, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, and C ２－６ alkynyl, Each Ｒａ１３ is independently H, C １－６ alkyl, or C １－６ haloalkyl, and R ５ is selected from H, C １－６ alkyl, C １－６ haloalkyl, and 5- to 6-membered heteroaryl, and the C ５ of said R １－６ alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R ５Ａ substituents, Each R ５Ａ is selected independently from halo, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, and CN, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

50. The compound of formula I is a compound of formula II: 【Chemical Formula 9】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

51. The compound of formula I is a compound of formula III: 【Chemical Formula 10】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

52. The compound of formula I is a compound of formula IV: 【Chemical 11】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

53. The compound of formula I is a compound of formula V: 【Chemical Formula 12】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

54. The compound of formula I is a compound of formula VI: 【Chemical 13】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

55. The compound of formula I is a compound of formula VII: 【Chemical 14】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

56. The compound of formula I is a compound of formula VIII: 【Chemical 15】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

57. The compound of formula I is a compound of formula IX: 【Chemical 16】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

58. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-8-methylthiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-(difluoromethyl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 3-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-2-yl)propanenitrile, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-(1H-pyrazol-4-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)furo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-1H-[1,2,4]triazolo[3,4-b]purine, 5-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-6-ethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine, 5-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1,3-dimethyl-1H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyridine, 4-((2S,5S)-4-(bis(4-fluorophenyl)methyl)-5-(methoxymethyl)-2-methylpiperazin-1-yl)thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)piperazin-2-yl)acetonitrile, 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-4-(8-cyclopropylthiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)-5-methylpiperazin-2-yl)acetonitrile, 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(1-methyl-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)acetonitrile, and (R)-3-(1-(bis(4-fluorophenyl)methyl)-4-(thiazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidin-4-yl)piperazin-2-yl)propanenitrile, or a pharmaceutically acceptable salt thereof, a compound according to claim 1.

59. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 1-(cyclopropylmethyl)-4-((2S,5R)-4-((S)-1-(4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 1-(cyclopropylmethyl)-4-((2S,5R)-4-((R)-1-(4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 1-(cyclopropylmethyl)-4-((2S,5R)-4-((S)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 1-(cyclopropylmethyl)-4-((2S,5R)-4-((R)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-((2S,5R)-4-((S)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-(4-fluorophenyl)(5-(trifluoromethoxy)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, and 4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

60. 4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-(((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3-chloro-4-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-(((S)-(3,3-difluorocyclobutyl)(3,4-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-(((R)-(3,3-difluorocyclobutyl)(3,4-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-(((S)-(3,4-dichlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-(((R)-(3,4-dichlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-chloro-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-chloro-3-methylphenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(3,4,5-trifluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(2,5-difluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(3-(difluoromethyl)-4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3,3-difluorocyclobutyl)(3-methyl-4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((2,5-difluoro-4-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3-chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3-chloro-4-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-chloro-3-(trifluoromethyl)phenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-bromophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((3-bromo-4-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-((4-bromo-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((4-bromophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(3-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(3-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-(((2S,5R)-4-((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(4-(difluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(4-(difluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(4-(difluoromethoxy)-2-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(4-(difluoromethoxy)-2-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(4-methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-((2S,5R)-4-((R)-1-(4-methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(4-(difluoromethyl)-3-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-(difluoromethyl)-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-(1-(3-chloro-4-(trifluoromethyl)phenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(3-chloro-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(3-chloro-4-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((S)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((R)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((S)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-4-((R)-1-(4-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(((4-(difluoromethyl)phenyl)(4-methoxyphenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(3-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(3-fluorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(3-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(3-chlorophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((S)-1-(3-methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-((R)-1-(3-methoxyphenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 2-(4-(((2S,5R)-4-(bis(4-(difluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]pyrimidin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-2,5-Dimethyl-4-((S)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 2-(4-((2S,5R)-2,5-Dimethyl-4-((R)-(4-(trifluoromethyl)phenyl)(5-(trifluoromethyl)pyridin-2-yl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((S)-(5-Fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-((R)-(5-Fluoro-6-(trifluoromethyl)pyridin-2-yl)(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 4-((2S,5R)-4-(bis(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, 2-(4-((2S,5R)-4-(bis(5-(trifluoromethyl)pyridin-2-yl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((3-chloro-4-fluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, 4-(((2S,5R)-2,5-dimethyl-4-(((trans)-3-(trifluoromethyl)cyclobutyl)(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 2-(4-(((2S,5R)-2,5-dimethyl-4-(((trans)-3-(trifluoromethyl)cyclobutyl)(4-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine 4-(((2S,5R)-4-(((4,4-difluorocyclohexyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 4-(((2S,5R)-2,5-dimethyl-4-(((S)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 4-(((2S,5R)-2,5-dimethyl-4-(((R)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine 4-(((2S,5R)-4-(((3,3-difluorocyclobutyl)(4-fluorophenyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine 4-(((2S,5R)-4-(((4-chlorophenyl)(3,3-difluorocyclobutyl)methyl)-5-ethyl-2-methylpiperazin-1-yl)-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine ((2S,5S)-1-(((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-5-methyl-4-(2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidin-4-yl)piperazin-2-yl)methanol, (R)-1-(((2S,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidin-4-yl)piperazin-2-yl)ethan-1-ol, (S)-1-(((2S,5S)-1-(bis(4-fluorophenyl)methyl)-5-methyl-4-(2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidin-4-yl)piperazin-2-yl)ethan-1-ol, 2-(((2R,5S)-2-ethyl-5-methyl-4-(2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidin-4-yl)piperazin-1-yl)-2,2-bis(4-fluorophenyl)ethan-1-ol, 4-(((2S,5R)-4-(((S)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-4-(((R)-1-(4-(difluoromethoxy)phenyl)-2-methylpropyl)-5-ethyl-2-methylpiperazin-1-yl)-2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-(((2S,5R)-5-ethyl-2-methyl-4-(((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-((((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]pyrimidine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((S)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-5-Ethyl-2-methyl-4-((R)-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-(((2R,5S)-2-Ethyl-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-1-yl)(4-fluorophenyl)methyl)benzonitrile, 4-(((2R,5S)-2-Ethyl-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-1-yl)(4-fluorophenyl)methyl)benzonitrile, 4-((2S,5R)-4-(Bis(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 4-((2S,5R)-4-((3,3-Difluorocyclobutyl)(4-(difluoromethyl)-3-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, 2-(4-((2S,5R)-4-((4-chloro-3-fluorophenyl)(3,3-difluorocyclobutyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, ((2S,5S)-1-(bis(4-chlorophenyl)methyl)-5-methyl-4-(2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin-4-yl)piperazin-2-yl)methanol, 4-((2S,5R)-4-((S)-1-(4-bromophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-((R)-1-(4-bromophenyl)-2-methylpropyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, and 4-((2S,5R)-4-((3-chloro-4-fluorophenyl)(4-bromophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purin, or a pharmaceutically acceptable salt thereof, a compound according to claim 1.

61. 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl)-N,N-dimethylethane-1-amine, or a pharmaceutically acceptable salt thereof, a compound.

62. A compound that is 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, or a pharmaceutically acceptable salt thereof.

63. A compound that is 2-(4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1H-[1,2,4]triazolo[3,4-b]purin-1-yl-2-d)-N,N-dimethylethane-1-amine, or a pharmaceutically acceptable salt thereof.

64. The compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterated.

65. A pharmaceutical composition comprising the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

66. A method for inhibiting the activity of diacylglycerol kinase, the method comprising contacting the kinase with the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

67. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

68. The method according to claim 67, wherein the cancer is non-small cell lung cancer, urothelial carcinoma of the bladder, esophageal cancer, gastric adenocarcinoma, mesothelioma, hepatocellular carcinoma of the liver, diffuse large B-cell lymphoma, clear cell renal cell carcinoma of the kidney, squamous cell carcinoma of the head and neck, cholangiocarcinoma, squamous cell carcinoma of the cervix, adenocarcinoma of the cervix, and melanoma.

69. The method according to claim 68, wherein the melanoma is metastatic melanoma.

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