Tricyclic triazolo compounds as DGK inhibitors

Abstract

The present application provides tricyclic triazolo compounds that modulate the activity of diacylglycerol kinase (DGK), which compounds are useful in the treatment of a variety of diseases, including cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention provides tricyclic triazolo compounds that modulate the activity of diacylglycerol kinase (DGK) and are useful for treating diseases associated with diacylglycerol kinase, including cancer. Background Art

[0002] Diacylglycerol kinase (DGK) is an enzyme family that regulates a variety of biological processes, including cell proliferation, migration, immunity, and the pathogenesis of diseases such as cancer. In mammalian systems, 10 DGK family members are classified into five subtypes based on shared common domains (Sakane F. et al., Int. J. Mol. Sci., 2020.21: Pages 6794-6829). The diversification of individual DGK isoforms and specific cell functions are regulated by their tissue-restricted expression, intracellular localization, and interaction with regulatory proteins (Joshi, RP and Koretzky, GA, Int. J. Mol. Sci., 2013.14: Pages 6649-6673).

[0003] In T lymphocytes, DGKα and ζ are the main DGK isoforms expressed (Kris hna, S. and Zhong, X.-P., Front Immunol., 2013.4:178). In particular, in response to T cell receptor (TCR) activation, phospholipase Cγ1 (PLCγ1) hydrolyzes membrane phospholipid PIP2 to produce diacylglycerol (DAG) (Krishna, S. and Zhong, X.-P., Front Immunol., 2013.4:178; Riese, MJ et al., Front Cell Dev Biol., 2016.4:108). Subsequently, DAG acts as a second messenger to recruit RasGRP1 and PKCθ to the cell membrane, thereby initiating multiple downstream signaling events, leading to T cell activation. In order to prevent T cell overactivation, DGKα and ζ strictly regulate the level of intracellular DAG by phosphorylating DAG to produce phosphatidic acid (PA). Mouse and human cell line genetic studies all support the important regulatory role of DGKα and ζ in T cell activation. It is reported that the knockout or depletion of DGKα and ζ enhances T cell activation, cytokine production and hyperplasia. In addition, the knockout of both DGKα and ζ shows greater T cell activation than individual knockouts, indicating the non-redundant effects of these two isotypes (Riese, MJ et al., Cancer Res., 2013.73: pp. 3566-3577; Jung, I.-Y. et al., Cancer Res., 2018.78: pp. 4692-4703). Therefore, DGKα and ζ link lipid metabolism to intracellular signal transduction cascades by regulating cell DAG levels, and act as key regulators of T cell activation.

[0004] Cytotoxic T lymphocytes (CTL) are the main components of the adaptive immune system, which recognize and kill cells with bacterial or viral infections, or cells presenting abnormal proteins (such as tumor antigens). However, cancer cells can evolve to utilize a variety of mechanisms that simulate peripheral immune tolerance to avoid CTL immune surveillance and killing. Such mechanisms include lowering antigen presentation, suppressing T cell function by increasing the expression of inhibitory molecules, and increasing immunosuppressive protein production in the tumor microenvironment (Speiser, DE et al., Nat. Rev. Immunol., 2016.16: 599-611 pages, Gonzalez H. et al., Genes & Dev., 2018.32: 1267-1284 pages). Immune checkpoint therapy (ICT) performed by blocking inhibitory molecules such as PD (L) -1 and CTLA4 can restore T cell activity, and has been used clinically to treat a variety of different types of cancer. However, only a subset of patients respond to ICT due to primary or acquired resistance (Sharma, P. et al., Cell. 2017.168: pp. 707-723). Therefore, despite the recent significant clinical success of immunotherapy in treating cancer, resistance remains a challenge (Sharma, P. et al., Cancer Discov., 2021.11: pp. 838-857).

[0005] Overexpression of DGKα and ζ has been observed in tumor-infiltrating lymphocytes (TILs) of human tumors, and is thought to inhibit T cell function. Importantly, significant immune-mediated anti-tumor activity was shown in DGKα and DGKζ deficient mouse models (Merida, I. et al., Adv. Biol. Regul., 2017. 63: pp. 22-31, Prinz, PU et al., J. Immunol., 2012. 188: pp. 5990-6000). In addition, DGKα and DGKζ-deficient T cells are resistant to several immunosuppressive factors (such as TGFβ, PGE2 and adenosine) within the tumor microenvironment and other T cell inhibitory pathways (such as PD(L)-1-mediated immunosuppression) (Riese, MJ et al., Cancer Res., 2013.73: 3566-77; Jung, I.-Y. et al. (2018) Cancer Res., 2018.78: 4692-4703; Arranz-Nicolas, J. et al., Cancer Immunol. Immunother., 2018.67: 965-980; Riese, MJ et al., Front. Cell Dev. Biol., 2016.4: 108). Therefore, DGKα and DGKζ are attractive targets as single immunotherapy or in combination with current ICT therapies (such as PD(L)-1 and CTLA4). By targeting T cell lipid metabolism, DGKα and DGKζ inhibition can potentially restore antitumor immunity in a subset of patients with primary or acquired immune resistance and therefore difficult to treat with current ICT. In addition to its function in T lymphocytes, DGKα and DGKζ are reported to directly promote cancer proliferation, migration, invasion and survival by regulating DAG levels in cancer cells. Therefore, DGK inhibition can have a direct antitumor effect by interfering with tumor-intrinsic oncogenic survival pathways (Cooke, M. and Kaznietz, MG, Sci. Signal., 2022.15:eabo0264).

[0006] The compounds in the present application may have selective activity against one or both of DGKα and DGKζ. These DGK inhibitors can be used alone or in combination with other therapeutic agents to treat cancer. Summary of the invention

[0007] The present invention particularly relates to compounds of formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0010] The present invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] The present invention also provides a method for inhibiting the activity of diacylglycerol kinase (DGK), which comprises contacting the kinase with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides a method for treating a disease or condition 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.

[0013] The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0014] The present invention also 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

[0015] The present application provides a compound of formula I:

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein:

[0018] each is a single bond or a double bond, at least one of which It is a double bond;

[0019] U is CR 3 or N;

[0020] X is CR 4 , N, NR 4 , S or O;

[0021] Y is CR 5 , N or NR 5 ;

[0022] Z is CR 6 , N, NR 6 , S or O;

[0023] R 1 It's Cy 1 or L-Cy 1 ;

[0024] L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl;

[0025] Cy 1 It is C 3-10 cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1A Substituent substitution;

[0026] Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 , where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution;

[0027] Each R a11 , R c11 and R d11 Independently selected from H, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a11 , R c11 and R d11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution;

[0028] or any R attached to the same N atom c11 and R d11 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution;

[0029] Each R b11 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution;

[0030] Each R e11 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0031] Each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2 、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) 2R b12 、S(O) 2 NR c12 R d12 、OS(O)(=NR e12 )R b12 and OS(O) 2 R b12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution;

[0032] Each R a12 , R c12 and R d12 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a12 , R c12 and R d12 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution;

[0033] or any R attached to the same N atom c12 and R d12 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution;

[0034] Each R b12 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b12 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution;

[0035] Each R e12 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0036] Each R 1C are 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, 5-6 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 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 Rd13 、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 , where R 1C The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution;

[0037] Each R a13 , R c13 and R d13 Independently selected from H, C 1-6 Alkyl, C1-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a13 , R c13 and R d13 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution;

[0038] or any R attached to the same N atom c13 and R d13 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1D Substituent substitution;

[0039] Each R b13 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b13 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C3-7 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution;

[0040] Each R e13 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0041] Each R 1D are 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, 5-6 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 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 Rd14 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 , where R 1D The C 1-6 Alkyl, 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-C1-6 Alkyl-, (5-6 membered heteroaryl)-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0042] Each R a14 , R c14 and R d14 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a14 , R c14 and R d14 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0043] or any R attached to the same N atom c14 and R d14 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0044] Each R b14 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7Cycloalkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b14 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0045] Each R e14 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0046] R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C1-6 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 , S(O)R b2 , NR c2 , S(O)NR c2 R d2 , NR c2 , S(O) 2 R b2 , NR c2 , S(O)(=NR e2 ), R b2 , NR c2 , S(O) 2 , NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , S(O) 2 , NR c2 R d2、OS(O)(=NR e2 )R b2 and OS(O) 2 R b2 , where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution;

[0047] Each R a2 , R c2 and R d2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a2 , R c2 and R d2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution;

[0048] or any R attached to the same N atom c2 and R d2 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution;

[0049] Each R b2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution;

[0050] Each R e2 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, C3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0051] R 2A Selected from halogen, 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 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 Rd21 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 , where R 2A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0052] Each R a21 , R c21 and R d21 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, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 Alkyl-, C 3-7 Cycloalkyl-C1-6 Alkyl-, (5-6 membered heteroaryl)-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a21 , R c21 and R d21 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0053] or any R attached to the same N atom c21 and R d21 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0054] Each R b21 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b21 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0055] Each R e21 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0056] R 3 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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)Rb3 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 S(O)NR 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 , where R 3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution;

[0057] Each R a3 , R c3 and R d3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a3 , R c3 and R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution;

[0058] or any R attached to the same N atom c3 and R d3 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution;

[0059] Each R b3 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution;

[0060] Each R e3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0061] R 3A Selected from halogen, 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 1-6Alkyl-, 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 c31R 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 , where R 3A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0062] Each R a31 , R c31 and R d31 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a31 , R c31 and R d31 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected RM Substituent substitution;

[0063] or any R attached to the same N atom c31 and R d31 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0064] Each R b31 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b31 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0065] Each R e31 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C1-6 alkyl-;

[0066] R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 S(O)NRc4 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 , where R 4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution;

[0067] Each R a4 , R c4 and R d4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a4 , R c4 and R d4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution;

[0068] or any R attached to the same N atom c4 and R d4 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution;

[0069] Each R b4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution;

[0070] Each R e4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0071] R 4A Selected from halogen, 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 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 Rd41 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 , where R 4A The C 1-6 Alkyl, 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)-C1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0072] Each R a41 , R c41 and R d41 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a41 , R c41 and R d41 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0073] or any R attached to the same N atom c41 and R d41 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0074] Each R b41 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, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5-6 membered heteroaryl)-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b41 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0075] Each R e41 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0076] R 5 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO 2 , ORa5 、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) 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 )Rb5 and OS(O) 2 R b5 , where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution;

[0077] Each R a5 , R c5 and R d5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a5 , R c5 and R d5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5ASubstituent substitution;

[0078] or any R attached to the same N atom c5 and R d5 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution;

[0079] Each R b5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution;

[0080] Each R e5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0081] R 5A Selected from halogen, 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 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 , where R 5A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0082] Each R a51 , R c51 and R d51 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, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5-6 membered heteroaryl)-C 1-6Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a51 , R c51 and R d51 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0083] or any R attached to the same N atom c51 and R d51 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0084] Each R b51 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b51 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R MSubstituent substitution;

[0085] Each R e51 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0086] R 6 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 NRc6 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 NR c6 S(O) 2 R b6 NR c6 S(O)(=NR e6 )R b6 NR c6 S(O) 2 NR c6 R d6 、S(O)R b6 、S(O)NR c6 R d6 、S(O) 2 R b6 、S(O) 2 NR c6 R d6 、OS(O)(=NR e6 )R b6 and OS(O) 2 R b6 , where R 6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution;

[0087] Each R a6 , R c6 and R d6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a6 , R c6 and R d6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution;

[0088] or any R attached to the same N atom c6 and R d6 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution;

[0089] Each R b6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution;

[0090] Each R e6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0091] R 6A Selected from halogen, 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 1-6alkyl-, (4-7 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 , NR c61 S(O)(=NR e61 )R b61 , NR c61 S(O) 2 NR c61 R d61 , S(O)R b61 , S(O)NR c61 R d61 , S(O) 2 R b61 , S(O) 2NR c61 R d61 、OS(O)(=NR e61 )R b61 and OS(O) 2 R b61 , where R 6A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0092] Each R a61 , R c61 and R d61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a61 , R c61 and R d61 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0093] or any R attached to the same N atom c61and R d61 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0094] Each R b61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b61 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0095] Each R e61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0096] R c7 Selected from H, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R c7 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl - optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7A Substituent substitution;

[0097] Each R 7A are independently selected from 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, 5-15 membered heteroaryl, 4-15 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 (ORa71 )、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 和OS(O) 2 R b71 , where R7A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution;

[0098] Each R a71 , R c71 and R d71 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a71 , R c71 and R d71 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution;

[0099] or any R attached to the same N atomc71 and R d71 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution;

[0100] Each R b71 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b71 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution;

[0101] Each R e71 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-;

[0102] Each R 7B are 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, 5-6 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 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)Rb72 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 , where R 7B The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0103] Each R a72 , R c72 and R d72 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a72, R c72 and R d72 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0104] or any R attached to the same N atom c72 and R d72 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0105] Each R b72 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b72 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution;

[0106] Each R e72Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-; and

[0107] Each R M 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 Halogenated alkoxy, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-.

[0108] In some embodiments, U is CR 3 .

[0109] In some embodiments, R 3 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0110] In some embodiments, R 3 Selected from H and C 1-6 alkyl.

[0111] In some embodiments, U is CH or N.

[0112] In some embodiments, U is CH.

[0113] In some embodiments, U is N.

[0114] In some embodiments, X is CR 4 or NR 4 .

[0115] In some embodiments, X is CR 4 .

[0116] In some embodiments, X is NR 4 .

[0117] In some embodiments, R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0118] In some embodiments, R 4 Is H or C 1-6 alkyl.

[0119] In some embodiments, R 4 Is H or C 1-3 alkyl.

[0120] In some embodiments, R 4 It is H, methyl or ethyl.

[0121] In some embodiments, X is CH, CCH 3 , N or -NCH 2 CH 3 .

[0122] In some embodiments, X is N.

[0123] In some embodiments, X is S.

[0124] In some embodiments, X is O.

[0125] In some embodiments, X is CH, CCH 3 、N、-NCH 2 CH 3 , S or O.

[0126] In some embodiments, Y is CR 5 or N.

[0127] In some embodiments, Y is N.

[0128] In some embodiments, Y is CR 5 .

[0129] In some embodiments, R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 S(O)NR c5 R d5 NRc5 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 , where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution.

[0130] In some embodiments, R 5 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0131] In some embodiments, R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0132] In some embodiments, R 5 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0133] In some embodiments, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0134] In some embodiments, R 5 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0135] In some embodiments, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0136] In some embodiments, R 5 is selected from H, D, methyl, ethyl, difluoromethyl and pyrazolyl, wherein R 5 The methyl, ethyl and pyrazolyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0137] In some embodiments, R 5 is selected from H, methyl, ethyl, difluoromethyl and pyrazolyl, wherein R 5 The methyl, ethyl and pyrazolyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0138] In some embodiments, R 5 is selected from H, D, ethyl, difluoromethyl and pyrazolyl, wherein R 5 The ethyl and pyrazolyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0139] In some embodiments, R 5 is selected from H, ethyl, difluoromethyl and pyrazolyl, wherein R 5 The ethyl and pyrazolyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0140] In some embodiments, each R 5A independently selected from halogen, 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- and CN, where R 5A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution.

[0141] In some embodiments, each R 5A independently selected from halogen, C 1-6 Alkyl, C1-6 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- and CN.

[0142] In some embodiments, each R 5A independently selected from halogen, 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 and CN.

[0143] In some embodiments, each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0144] In some embodiments, each R 5A It is CN.

[0145] In some embodiments, R 5 Selected from H, D, 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 and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0146] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C3-7 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- and CN.

[0147] In some embodiments, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0148] Each R 5A independently selected from halogen, 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- and CN.

[0149] In some embodiments, R 5 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0150] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0151] In some embodiments, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0152] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0153] In some embodiments, R 5 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl group is optionally substituted with cyano.

[0154] In some embodiments, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl group is optionally substituted with cyano.

[0155] In some embodiments, R 5 is selected from H, D, methyl, cyanoethyl, difluoromethyl and pyrazolyl.

[0156] In some embodiments, R 5 is selected from H, methyl, cyanoethyl, difluoromethyl and pyrazolyl.

[0157] In some embodiments, R 5 is selected from H, cyanoethyl, difluoromethyl and pyrazolyl.

[0158] In some embodiments, Z is CR 6 NR 6 or S.

[0159] In some embodiments, Z is CR 6 .

[0160] In some embodiments, Z is NR 6.

[0161] In some embodiments, Z is S.

[0162] In some embodiments, R 6 H, halogen, 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 (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein 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 (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution.

[0163] In some embodiments, R 6 H, halogen, 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 (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the 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 (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution.

[0164] In some embodiments, R 6 H, halogen, 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 (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1 or 2 independently selected R 6A Substituent substitution.

[0165] In some embodiments, R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution.

[0166] In some embodiments, R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1 or 2 independently selected R 6A Substituent substitution.

[0167] In some embodiments, each R 6A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and NR c61 R d61 .

[0168] In some embodiments, each R 6A Independently selected from NR c61 R d61 .

[0169] In some embodiments, each R a61 , R b61 , R c61 and R d61 Independently selected from H, C1-6 Alkyl and C 1-6 Halogenated alkyl.

[0170] In some embodiments, each R a61 , R b61 , R c61 and R d61 Independently selected from H and C 1-6 alkyl.

[0171] In some embodiments, each R c61 and R d61 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0172] In some embodiments, each R c61 and R d61 Independently selected from H and C 1-6 alkyl.

[0173] In some embodiments, each R 6A Independently selected from NR c61 R d61 , where each R c61 and R d61 Independently selected from H and C 1-6 alkyl.

[0174] In some embodiments, each R 6A Independently selected from NR c61 R d61 , where each R c61 and R d61 C for independent selection 1-6 alkyl.

[0175] In some embodiments, R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 The alkyl group is optionally replaced by NR c61 R d61 Substitution, where R c61 and R d61 Each independently selected from H and C 1-6 alkyl.

[0176] In some embodiments, R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C1-6 Alkyl-, wherein the C 1-6 The alkyl group is optionally replaced by NR c61 R d61 Substitution, where R c61 and R d61 Each is an independent choice of C 1-6 alkyl.

[0177] In some embodiments, R 6 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0178] In some embodiments, R 6 Is H or C 1-6 alkyl.

[0179] In some embodiments, R 6 Is H or C 1-3 alkyl.

[0180] In some embodiments, R 6 It is H, methyl, cyclopropylmethyl, tetrahydrofuranylmethyl and dimethylaminoethyl.

[0181] In some embodiments, R 6 It is H or methyl.

[0182] In some embodiments, R 6 It's H.

[0183] In some embodiments, R 6 It's methyl.

[0184] In some embodiments, R 6 It is cyclopropylmethyl.

[0185] In some embodiments, R 6 It is tetrahydrofuranylmethyl.

[0186] In some embodiments, R 6 It is dimethylaminoethyl.

[0187] In some embodiments, Z is CH, NCH 3 、NCH 2 CH 2 N(CH 3 ) 2 、NCH 2 -Cyclopropyl, NCH 2 -tetrahydrofuranyl or S.

[0188] In some embodiments, Z is CH, NCH 3 or S.

[0189] In some embodiments, Z is CH.

[0190] In some embodiments, Z is NCH 3 .

[0191] In some embodiments, Z is NCH 2 CH 2 N(CH 3 ) 2 .

[0192] In some embodiments, Z is NCH 2 -cyclopropyl.

[0193] In some embodiments, Z is NCH 2 -tetrahydrofuranyl.

[0194] In some embodiments, Z is S.

[0195] In some embodiments, R 1 It's Cy 1 .

[0196] In some embodiments, R 1 It is L-Cy 1 .

[0197] In some embodiments, Cy 1 It is C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1A Substituent substitution.

[0198] In some embodiments, Cy 1 It is C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0199] In some embodiments, Cy 1 It is C 3-7 Cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the C 3-7Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0200] In some embodiments, Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0201] In some embodiments, Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group being substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0202] In some embodiments, Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group being composed of 2 or 3 independently selected R 1A Substituent substitution.

[0203] In some embodiments, Cy 1 is piperazinyl, which is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0204] In some embodiments, Cy 1 is piperazinyl, which is optionally substituted by 2 or 3 independently selected R 1A Substituent substitution.

[0205] In some embodiments, Cy 1 is piperazinyl, the piperazinyl being substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

[0206] In some embodiments, Cy 1 is piperazinyl, the piperazinyl being substituted by 2 or 3 independently selected R 1A Substituent substitution.

[0207] In some embodiments, Cy 1 yes:

[0208]

[0209] In some embodiments, Cy 1 yes:

[0210]

[0211] In some embodiments, Cy 1 yes:

[0212]

[0213] In some embodiments, Cy 1 yes:

[0214]

[0215] In some embodiments, each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0216] In some embodiments, each R 1A independently selected from halo, oxo 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0217] In some embodiments, each R 1A are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0218] In some embodiments, each R 1A Independently selected from C 1-6 Alkyl and C 1-6 A haloalkyl group, wherein R 1A The C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0219] In some embodiments, each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0220] In some embodiments, Cy 1 yes:

[0221]

[0222] In some embodiments, Cy 1 yes:

[0223]

[0224]

[0225] In some embodiments, Cy 1 yes:

[0226] In some embodiments, Cy 1 yes:

[0227]

[0228] In some embodiments, Cy 1 yes:

[0229]

[0230] In some embodiments, Cy 1 yes:

[0231]

[0232] In some embodiments, Cy 1 yes:

[0233]

[0234]

[0235] In some embodiments, Cy 1 yes:

[0236] In some embodiments, Cy 1 yes:

[0237]

[0238]

[0239] In some embodiments, Cy 1 yes:

[0240] In some embodiments, Cy 1 yes:

[0241] In some embodiments, Cy 1 yes:

[0242] In some embodiments, Cy 1 yes:

[0243]

[0244] In some embodiments, Cy 1 yes:

[0245]

[0246] In some embodiments, Cy 1 yes:

[0247]

[0248] In some embodiments, Cy 1 yes:

[0249]

[0250] In some embodiments, each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO 2 OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0251] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C1-6 Alkyl-, CN and OR a12 , where R 1B The C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0252] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0253] In some embodiments, each R 1B Independently selected from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0254] In some embodiments, each R 1B Independently selected from C 1-6 Aryl, 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 and OR a12 , where R 1B The C 1-6 Aryl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0255] In some embodiments, each R 1B Independently selected from C 1-6 Aryl, 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 1-6Alkyl-, CN and OR a12 , where R 1B The phenyl group, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0256] In some embodiments, each R 1B Independently selected from 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 and OR a12 , where R 1B The phenyl group, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0257] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0258] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The phenyl group, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0259] In some embodiments, each R 1B Independently selected from phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The phenyl group, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0260] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0261] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, CN and OR a12 , where R 1B The phenyl groups are each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

[0262] In some embodiments, each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C Substituent substitution.

[0263] In some embodiments, each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, CN and OR a13 , where R 1C The C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1D Substituent substitution.

[0264] In some embodiments, each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 .

[0265] In some embodiments, each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 .

[0266] In some embodiments, each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ;and

[0267] Each R a13 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Halogenated alkyl.

[0268] In some embodiments, each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 ;and

[0269] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0270] In some embodiments, each R 1C Independently selected from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy and hydroxy.

[0271] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, pyridyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl and pyridyl are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 R 1C Substituent substitution.

[0272] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, pyridyl, CN and OR a12 , where R 1B The phenyl and pyridyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected halogen or OR a13 Group substitution.

[0273] In some embodiments, each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C Substituents are substituted, the substituents being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 .

[0274] In some embodiments, each R a12 , R b12 , R c12 and R d12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0275] In some embodiments, each R a12 , R b12 , R c12 and R d12 Independently selected from H and C 1-6 alkyl.

[0276] In some embodiments, each R a13 , Rb13 , R c13 and R d13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0277] In some embodiments, each R a13 , R b13 , R c13 and R d13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0278] In some embodiments, each R a13 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0279] In some embodiments, each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0280] In some embodiments, each R a13 Independently selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0281] In some embodiments, each R a13 It is C 1-6 Halogenated alkyl.

[0282] In some embodiments, each R a13 It is C 1-3 Halogenated alkyl.

[0283] In some embodiments, each R a13 It is trifluoromethyl.

[0284] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, pyridyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl and pyridyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0285] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ;

[0286] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl; and

[0287] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0288] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, 5-6 membered heteroaryl, CN and OR a12 , where R 1B The phenyl groups are each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituents are substituted; and

[0289] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0290] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, pyridyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl and pyridyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0291] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 ;

[0292] Each R a12 Independently selected from H and C 1-6 Alkyl; and

[0293] Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0294] In some embodiments, each R 1B Independently selected from C 1-6 Alkyl, phenyl, pyridyl, CN and OR a12 , where R 1B The phenyl and pyridyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected halogen or OR a13 group substitution;

[0295] Each R a12 Independently selected from H and C 1-6 Alkyl; and

[0296] Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0297] In some embodiments, each R 1B Independently selected from phenyl, CN and OR a12 ; where R 1B The phenyl groups are each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituents are substituted; and

[0298] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0299] In some embodiments, R 1B Independently selected from phenyl, CN and OR a12 ; where R 1B The phenyl groups are each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituents are substituted; and

[0300] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0301] In some embodiments, each R 1B Independently selected from phenyl, CN and OR a12 ; where R 1BThe phenyl groups of are each optionally substituted with 1, 2, 3 or 4 independently selected halo groups; and

[0302] Each R a12 Independently selected from H and C 1-6 alkyl.

[0303] In some embodiments, each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN, hydroxyl and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C Substituents are substituted, the substituents being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 ;and

[0304] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0305] In some embodiments, each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C Substituents are substituted, the substituents being independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 ;and

[0306] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0307] In some embodiments, each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN, hydroxyl and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C The methyl group is substituted with a substituent independently selected from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy and hydroxy.

[0308] In some embodiments, each R 1Bare independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C The methyl group is substituted with a substituent independently selected from chloro, fluoro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, methoxy, difluoromethoxy, trifluoromethoxy and hydroxy.

[0309] In some embodiments, each R 1B are 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, trifluoromethylpyridyl, (trifluoromethyl)(fluoro)pyridyl, trifluoromethoxypyridyl, CN, hydroxy and methoxy.

[0310] In some embodiments, each R 1B are 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, trifluoromethylpyridyl, (trifluoromethyl)(fluoro)pyridyl, trifluoromethoxypyridyl, CN and methoxy.

[0311] In some embodiments, each R 1B are independently selected from isopropyl, CN, methoxy, hydroxy, hydroxymethyl,

[0312]

[0313] In some embodiments, each R 1B Independently selected from CN, methoxy, hydroxyl,

[0314]

[0315]

[0316] In some embodiments, each R 1B Independently selected from isopropyl, fluorophenyl, trifluoromethoxypyridyl, CN and methoxy.

[0317] In some embodiments, each R 1B Independently selected from fluorophenyl, CN and methoxy.

[0318] In some embodiments, R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

[0319] In some embodiments, R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

[0320] In some embodiments, R 2 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein R 2 The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

[0321] In some embodiments, R 2 Selected from H, C 1-6 Alkyl and C 3-7 Cycloalkyl.

[0322] In some embodiments, R 2 Selected from H, methyl and cyclopropyl.

[0323] In some embodiments, R 2 It's H.

[0324] In some embodiments, R 2 It's methyl.

[0325] In some embodiments, R 2 It is cyclopropyl.

[0326] In some embodiments:

[0327] each is a single bond or a double bond, at least one of which It is a double bond;

[0328] U is CH or N;

[0329] X is CR 4 , N, NR 4 , S or O;

[0330] Y is CR 5 or N;

[0331] Z is CR 6 NR 6 or S;

[0332] R 1 It's Cy 1 or L-Cy 1 ;

[0333] L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl;

[0334] Cy 1 It is C 3-10 cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0335] Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0336] Each R 1B are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO 2 OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0337] Each R 1C are 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, 5-6 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 and OR a13 ;

[0338] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0339] R 2 Selected from H, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution;

[0340] Each R 2A independently selected from halogen, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0341] R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0342] R 5 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0343] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0344] R 6 H, halogen, 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 (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein 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 (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution;

[0345] Each R 6A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and NR c61 R d61 ;

[0346] Each R c61 and R d61 Independently selected from H and C 1-6 Alkyl; and

[0347] R c7 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.

[0348] In some embodiments of the preceding embodiment, R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0349] In some embodiments:

[0350] each is a single bond or a double bond, at least one of which It is a double bond;

[0351] U is CH or N;

[0352] X is CR 4 , N, NR 4 , S or O;

[0353] Y is CR 5 or N;

[0354] Z is CR 6 NR 6 or S;

[0355] R 1 It's Cy 1 or L-Cy 1 ;

[0356] L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl;

[0357] Cy 1 It is C 3-10 cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0358] Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0359] Each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO 2 OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1CSubstituent substitution;

[0360] Each R 1C are 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, 5-6 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- and CN;

[0361] R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution;

[0362] Each R 2A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C3-7 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0363] R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0364] R 5 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0365] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0366] R 6 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl; and

[0367] R c7 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.

[0368] In some embodiments of the preceding embodiment, R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R5A Substituent substitution.

[0369] In some embodiments:

[0370] U is CH or N;

[0371] X is CR 4 , N, NR 4 , S or O;

[0372] Y is CR 5 or N;

[0373] Z is CR 6 NR 6 or S;

[0374] R 1 It's Cy 1 ;

[0375] Cy 1 It is C 3-7 Cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0376] Each R 1A are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0377] Each R 1B Independently selected from C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 1-6Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0378] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ;

[0379] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0380] Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0381] R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution;

[0382] R 4 Is H or C 1-6 alkyl;

[0383] R 5Selected from H, D, 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 and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0384] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0385] R 6 H, halogen, 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 (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl- each optionally substituted by NR c61 R d61 replace; and

[0386] Each R c61 and R d61 Independently selected from H and C 1-6 alkyl.

[0387] In some embodiments of the preceding embodiment, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0388] In some embodiments:

[0389] each is a single bond or a double bond, at least one of which It is a double bond;

[0390] U is CH or N;

[0391] X is CR 4 , N, NR 4 , S or O;

[0392] Y is CR 5 or N;

[0393] Z is CR 6 NR 6 or S;

[0394] R 1 It's Cy 1 or L-Cy 1 ;

[0395] L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl;

[0396] Cy 1 It is C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0397] Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0398] Each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO 2 OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0399] Each R 1Care 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, 5-6 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- and CN;

[0400] R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution;

[0401] Each R 2A independently selected from halogen, 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-C1-6 Alkyl-, C 3-7 Cycloalkyl-C 1-6 Alkyl-, (5-6 membered heteroaryl)-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;

[0402] R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0403] R 5 Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0404] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0405] R 6 H, halogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl; and

[0406] R c7 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.

[0407] In some embodiments of the preceding embodiment, R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

[0408] In some embodiments:

[0409] U is CH or N;

[0410] X is CH, CCH 3 、N、-NCH 2 CH 3 , S or O;

[0411] Y is CR 5 or N;

[0412] Z is CH, NCH 3 、NCH 2 CH 2 N(CH 3 ) 2 、NCH 2 -Cyclopropyl, NCH 2 -tetrahydrofuranyl or S;

[0413] R 1 It's Cy 1 ;

[0414] Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0415] Each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0416] Each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 ; where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0417] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ;

[0418] Each Ra12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0419] Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0420] R 5 Selected from H, D, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0421] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0422] In some embodiments:

[0423] U is CH or N;

[0424] X is CH, CCH 3 、N、-NCH 2 CH 3 , S or O;

[0425] Y is CR 5 or N;

[0426] Z is CH, NCH 3 、NCH 2 CH 2 N(CH 3 ) 2 、NCH 2 -Cyclopropyl, NCH 2 -tetrahydrofuranyl or S;

[0427] R 1 It's Cy 1 ;

[0428] Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0429] Each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0430] Each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 ; where R 1B The phenyl group, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0431] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ;

[0432] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0433] Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0434] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0435] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0436] In some embodiments:

[0437] U is CH or N;

[0438] X is CR 4 , N, NR 4 , S or O;

[0439] Y is CR 5 or N;

[0440] Z is CR 6 NR 6 or S;

[0441] R 1 It's Cy 1 ;

[0442] Cy 1 It is C 3-7 Cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0443] Each R 1A are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0444] Each R 1B Independently selected from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0445] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0446] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0447] R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution;

[0448] R 4 Is H or C 1-6 alkyl;

[0449] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution;

[0450] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0451] R 6 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0452] In some embodiments:

[0453] U is CH or N;

[0454] X is CH, CCH 3 、N、-NCH 2 CH 3 , S or O;

[0455] Y is CR 5 or N;

[0456] Z is CH, NCH 3 or S;

[0457] R 1 It's Cy 1 ;

[0458] Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution;

[0459] Each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution;

[0460] Each R 1B Independently selected from phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The phenyl group, C 3-7Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution;

[0461] Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN;

[0462] Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0463] R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and

[0464] Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

[0465] In some embodiments, the compound of formula I is a compound of formula II:

[0466]

[0467] or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound of formula I is a compound of formula IIa:

[0469]

[0470] or a pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound of Formula I is a compound of Formula IIb:

[0472]

[0473] or a pharmaceutically acceptable salt thereof.

[0474] In some embodiments, the compound of formula I is a compound of formula III:

[0475]

[0476] or a pharmaceutically acceptable salt thereof.

[0477] In some embodiments, the compound of Formula I is a compound of Formula IIIa:

[0478]

[0479] or a pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the compound of Formula I is a compound of Formula IIIb:

[0481]

[0482] or a pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the compound of formula I is a compound of formula IV:

[0484]

[0485]

[0486] or a pharmaceutically acceptable salt thereof.

[0487] In some embodiments, the compound of Formula I is a compound of Formula IVa:

[0488]

[0489] or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the compound of Formula I is a compound of Formula IVb:

[0491]

[0492] or a pharmaceutically acceptable salt thereof.

[0493] In some embodiments, the compound of formula I is a compound of formula V:

[0494]

[0495] or a pharmaceutically acceptable salt thereof.

[0496] In some embodiments, the compound of formula I is a compound of formula Va:

[0497]

[0498] or a pharmaceutically acceptable salt thereof.

[0499] In some embodiments, the compound of Formula I is a compound of Formula Vb:

[0500]

[0501]

[0502] or a pharmaceutically acceptable salt thereof.

[0503] In some embodiments, the compound of formula I is a compound of formula VI:

[0504]

[0505] or a pharmaceutically acceptable salt thereof.

[0506] In some embodiments, the compound of Formula I is a compound of Formula VIa:

[0507]

[0508] or a pharmaceutically acceptable salt thereof.

[0509] In some embodiments, the compound of Formula I is a compound of Formula VIb:

[0510]

[0511] or a pharmaceutically acceptable salt thereof.

[0512] In some embodiments, the compound of formula I is a compound of formula VII:

[0513]

[0514] or a pharmaceutically acceptable salt thereof.

[0515] In some embodiments, the compound of Formula I is a compound of Formula VIIa:

[0516]

[0517] or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, the compound of Formula I is a compound of Formula VIIb:

[0519]

[0520] or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the compound of Formula I is a compound of Formula VIII:

[0522]

[0523] or a pharmaceutically acceptable salt thereof.

[0524] In some embodiments, the compound of Formula I is a compound of Formula VIIIa:

[0525]

[0526] or a pharmaceutically acceptable salt thereof.

[0527] In some embodiments, the compound of Formula I is a compound of Formula VIIIb:

[0528]

[0529] or a pharmaceutically acceptable salt thereof.

[0530] In some embodiments, the compound of Formula I is a compound of Formula IX:

[0531]

[0532] or a pharmaceutically acceptable salt thereof.

[0533] In some embodiments, the compound of Formula I is a compound of Formula IXa:

[0534]

[0535] or a pharmaceutically acceptable salt thereof.

[0536] In some embodiments, the compound of Formula I is a compound of Formula IXb:

[0537]

[0538] or a pharmaceutically acceptable salt thereof.

[0539] In some embodiments, the compound of formula I is a compound of formula X:

[0540]

[0541] or a pharmaceutically acceptable salt thereof.

[0542] In some embodiments, the compound of Formula I is a compound of Formula Xa:

[0543]

[0544] or a pharmaceutically acceptable salt thereof, wherein:

[0545] m is 0, 1, 2, 3, 4 or 5; and

[0546] n is 0, 1, 2, 3, 4 or 5.

[0547] In some embodiments, the compound of formula I is a compound of formula Xb:

[0548]

[0549] or a pharmaceutically acceptable salt thereof, wherein:

[0550] In some embodiments, the compound of formula I is a compound of formula Xc:

[0551]

[0552] or a pharmaceutically acceptable salt thereof, wherein:

[0553] m is 0, 1, 2, 3, 4 or 5; and

[0554] n is 0, 1, 2, 3, 4 or 5.

[0555] In some embodiments, the compound of formula I is a compound of formula Xd:

[0556]

[0557] or a pharmaceutically acceptable salt thereof, wherein:

[0558] m is 0, 1, 2, 3, 4 or 5; and

[0559] n is 0, 1, 2 or 3.

[0560] In some embodiments, the compound of formula I is a compound of formula Xe:

[0561]

[0562] or a pharmaceutically acceptable salt thereof, wherein:

[0563] m is 0, 1, 2, 3, 4 or 5; and

[0564] n is 0, 1, 2, 3, 4 or 5.

[0565] In some embodiments, the compound of formula I is a compound of formula XI:

[0566]

[0567] or a pharmaceutically acceptable salt thereof.

[0568] In some embodiments of Formulas X, Xa, Xb, Xc, Xd, Xe, and XI, each R 1A Independently selected from C 1-6 Alkyl and C 1-6 A haloalkyl group, wherein R 1A The C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0569] In some embodiments of Formulas X, Xa, Xb, Xc, Xd, Xe, and XI, each R 1A Independently selected from C 1-6 Alkyl, where R 1A The C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

[0570] In some embodiments, the compounds provided herein are selected from:

[0571] 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;

[0572] 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;

[0573] 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;

[0574] 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)propionitrile;

[0575] 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;

[0576] 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;

[0577] 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;

[0578] 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;

[0579] 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-methyl-1H-[1,2,4]triazolo[3,4-b]purine;

[0580] 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;

[0581] 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;

[0582] 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;

[0583] 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;

[0584] 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;

[0585] 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;

[0586] 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;

[0587] (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;

[0588] 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]purine;

[0589] 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;

[0590] 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;

[0591] 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-diethylpiperazin-1-yl)-1-(cyclopropylmethyl)-1H-[1,2,4]triazolo[3,4-b]purine;

[0592] 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;

[0593] 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;

[0594] 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;

[0595] 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;

[0596] 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;

[0597] 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;

[0598] 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-dimethylethan-1-amine;

[0599] 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;

[0600] 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;

[0601] 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;

[0602] 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;

[0603] 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;

[0604] 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-dimethylethan-1-amine;

[0605] 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-dimethylethan-1-amine;

[0606] 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-dimethylethan-1-amine;

[0607] 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-dimethylethan-1-amine;

[0608] 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;

[0609] 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;

[0610] 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;

[0611] 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;

[0612] 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;

[0613] 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;

[0614] 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;

[0615] 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;

[0616] 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;

[0617] 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;

[0618] 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;

[0619] 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;

[0620] 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;

[0621] 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;

[0622] 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;

[0623] 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;

[0624] 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;

[0625] 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;

[0626] 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;

[0627] 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;

[0628] 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;

[0629] 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;

[0630] 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;

[0631] 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;

[0632] 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;

[0633] 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-dimethylethan-1-amine;

[0634] 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-dimethylethan-1-amine;

[0635] 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-dimethylethan-1-amine;

[0636] 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;

[0637] 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;

[0638] 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;

[0639] 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;

[0640] 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;

[0641] 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;

[0642] 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;

[0643] 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;

[0644] 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;

[0645] 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;

[0646] 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;

[0647] 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;

[0648] 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;

[0649] 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;

[0650] 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;

[0651] 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;

[0652] 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;

[0653] 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;

[0654] 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;

[0655] 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;

[0656] 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;

[0657] 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;

[0658] 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;

[0659] 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-dimethylethan-1-amine;

[0660] 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-dimethylethan-1-amine;

[0661] 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;

[0662] 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;

[0663] 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;

[0664] 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;

[0665] 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;

[0666] 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;

[0667] 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;

[0668] 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;

[0669] 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-dimethylethan-1-amine;

[0670] 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-dimethylethan-1-amine;

[0671] 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-dimethylethan-1-amine;

[0672] 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;

[0673] 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;

[0674] 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;

[0675] 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;

[0676] 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-dimethylethan-1-amine;

[0677] 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;

[0678] 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-dimethylethan-1-amine;

[0679] 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;

[0680] 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;

[0681] 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-dimethylethan-1-amine;

[0682] 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;

[0683] 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-dimethylethan-1-amine;

[0684] 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;

[0685] 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-dimethylethan-1-amine;

[0686] 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;

[0687] 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;

[0688] 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;

[0689] 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;

[0690] 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;

[0691] ((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;

[0692] (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;

[0693] (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;

[0694] 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;

[0695] 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;

[0696] 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;

[0697] 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;

[0698] 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;

[0699] 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;

[0700] 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;

[0701] 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;

[0702] 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;

[0703] 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;

[0704] 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;

[0705] 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-dimethylethan-1-amine;

[0706] ((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;

[0707] 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;

[0708] 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;

[0709] 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

[0710] 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;

[0711] or a pharmaceutically acceptable salt thereof.

[0712] In some embodiments, the compounds provided herein are selected from:

[0713] 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-dimethylethan-1-amine;

[0714] 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;

[0715] 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-dimethylethan-1-amine;

[0716] 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;

[0717] 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;

[0718] 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;

[0719] 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;

[0720] 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;

[0721] 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;

[0722] 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;

[0723] 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

[0724] 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;

[0725] 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;

[0726] 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-dimethylethan-1-amine;

[0727] 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-dimethylethan-1-amine;

[0728] 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;

[0729] 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;

[0730] 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-dimethylethan-1-amine;

[0731] 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-dimethylethan-1-amine;

[0732] 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

[0733] 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;

[0734] or a pharmaceutically acceptable salt thereof.

[0735] In some embodiments, the compound provided herein 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)-N,N-dimethylethan-1-amine or a pharmaceutically acceptable salt thereof.

[0736] In some embodiments, the compound provided herein 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)-N,N-dimethylethan-1-amine.

[0737] In some embodiments, the compound provided herein 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.

[0738] In some embodiments, the compound provided herein 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.

[0739] In some embodiments, the compound provided herein 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-dimethylethan-1-amine or a pharmaceutically acceptable salt thereof.

[0740] In some embodiments, the compound provided herein 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-dimethylethan-1-amine.

[0741] It should be further understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity may also be provided separately or in any suitable sub-combination.

[0742] At various locations in this specification, divalent linking substituents are described. It is expressly intended that each divalent linking substituent includes both the forward and backward forms of the linking substituent. For example, -NR(CR'R") n -Including-NR(CR'R") n -and-(CR'R") n NR - both. Where a structure explicitly requires a linking group, the Markush variables listed for that group are to be understood as linking groups.

[0743] The term "n-membered" (where n is an integer) generally describes 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, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

[0744] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected, and substitutions may be in any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) may replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence.

[0745] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "at each occurrence the 'variable' is selected from".

[0746] Throughout this definition, the term “C n-m” and “C m-n " indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C 1-3 , C 1-4 , C 1-6 wait.

[0747] As used herein, the term “C n-m "Alkyl" refers to a saturated hydrocarbon group which may be straight or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, 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, and the like. 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.

[0748] As used herein, “C n-m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0749] As used herein, “C n-m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0750] As used herein, the term “C n-m "Alkoxy" refers to a radical of the formula -O-alkyl, wherein the alkyl has n to m carbons. Example 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 has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0751] As used herein, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group which may be monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings). n-m"Aryl" refers to an aromatic group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0752] 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.

[0753] As used herein, “C n-m "Haloalkoxy" refers to a radical of the formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy radicals include OCF 3 and OCHF 2 In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0754] As used herein, the term “C n-m "Haloalkyl" refers to an alkyl group having from 1 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, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F、CCl 3 , CHCl 2 , C 2 Cl 5 wait.

[0755] As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. Cycloalkyl can include monocyclic or polycyclic (e.g., with 2 fused rings) groups, spirocyclic and bridged rings (e.g., bridged bicycloalkyl). The ring-forming carbon atoms of cycloalkyl can be optionally substituted by oxo or sulfide ion groups (e.g., C (O) or C (S)). The definition of cycloalkyl also includes parts having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond with it), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. The cycloalkyl containing fused aromatic rings can be connected by any ring-forming atoms (including ring-forming atoms of fused aromatic rings). Cycloalkyl can have 3, 4, 5, 6, 7, 8, 9 or 10 ring-forming carbons (i.e., C 3-10In some embodiments, the cycloalkyl group is C 3-10 In some embodiments, the cycloalkyl group is C 3-7 In some embodiments, the cycloalkyl group is C 4-7 In some embodiments, the cycloalkyl group is C 4-10 Spirocyclic or bridged cycloalkyl (e.g., bridged bicycloalkyl). Example cycloalkyls 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]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0756] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle 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, the heteroaryl is a 5-10-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, the 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 5-10 or 5-15 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 5-6 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, 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, heteroaryl 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 more than one heteroatom ring member, the heteroatoms may be the same or different.Example heteroaryl groups include, but are not limited to, thienyl / thiophenyl, furyl / 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-azaborolane, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, triazolyl, thiadiazolyl, quinolyl, isoquinolyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazine, 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, furano[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, and the like.

[0757] As used herein, "heterocycloalkyl" refers to 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 heteroatoms selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may be optionally replaced by one or more oxo or sulfide groups (e.g., C(O), S(O), C(S) or S(O)). 2The heterocycloalkyl group may be substituted with one or more oxo groups or sulfides. When the ring-forming carbon atoms or heteroatoms of the heterocycloalkyl group are optionally substituted with one or more oxo groups or sulfides, the O or S of the group is (for example, 1-methyl-6-oxo-1,6-dihydropyridazine-3-base is a 6-membered heterocycloalkyl group, wherein the ring-forming carbon atoms are substituted with oxo groups, and wherein the 6-membered heterocycloalkyl group is further substituted with methyl groups) except the number of ring-forming atoms specified herein. Heterocycloalkyl groups include monocyclic and polycyclic (for example, with 2 condensed rings) systems. Heterocycloalkyl groups include monocyclic and polycyclic 3 to 15, 3 to 10, 4 to 10, 4 to 15, 5 to 10, 4 to 7, 5 to 7 or 5 to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings and bridged rings (for example, 5 to 10 or 4 to 15-membered bridged biheterocycloalkyl rings, wherein one or more ring-forming carbon atoms are replaced by heteroatoms independently selected from N, O, S and B). Heterocycloalkyl groups may be connected by ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

[0758] The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused to (i.e., having a bond in common with) a non-aromatic heterocyclic ring, such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings may be attached via any ring-forming atom, including a ring-forming atom of the fused aromatic ring.

[0759] In some embodiments, heterocycloalkyl contains 3 to 10 ring atoms, 4 to 15 ring atoms, 4 to 10 ring atoms, 4 to 8 ring atoms, 3 to 7 ring atoms or 5 to 6 ring atoms. In some embodiments, heterocycloalkyl has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl with 1 or 2 heteroatoms independently selected from N, O, S and B and with one or more oxidized ring members. In some embodiments, heterocycloalkyl is a monocyclic or bicyclic 5-10 or 5-15 membered heterocycloalkyl with 1, 2, 3 or 4 heteroatoms independently selected from N, O, S and B and with one or more oxidized ring members. In some embodiments, heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl with 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and with one or more oxidized ring members. In some embodiments, 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 oxygenated ring members.

[0760] Example heterocycloalkyl groups include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, benzazepine (be nzazapene), azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxobicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxobicyclo[2.2.2]octyl, azaadamantyl, diaza adamantyl, oxo-adamantyl, azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, oxo-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxo-azaspiro[3.4]octyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxo- azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxo-diazaspiro[4.4]nonyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octyl, oxohexahydropyrrolo[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridyl, diazaspiro[5.5]undecyl, diazaspiro[5.6]dodecyl, diazaspiro[6.6]tridecyl, and the like.

[0761] As used herein, “C o-p Cycloalkyl-C n-m "Alkyl-" refers to a radical of the formula cycloalkyl-alkylene- wherein the cycloalkyl has o to p carbon atoms and the alkylene linking radical has n to m carbon atoms.

[0762] As used herein, “C o-p Aryl-C n-m "Alkyl-" refers to a radical of the formula aryl-alkylene- wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0763] As used herein, "heteroaryl-C n-m"Alkyl-" refers to a radical of the formula heteroaryl-alkylene- wherein the alkylene linking group has n to m carbon atoms.

[0764] As used herein, "heterocycloalkyl-C n-m "Alkyl-" refers to a radical of the formula heterocycloalkyl-alkylene- wherein the alkylene linking group has n to m carbon atoms.

[0765] As used herein, an "alkyl linking group" or "alkylene linking group" is a divalent straight or branched chain alkyl linking group ("alkylene"). 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-" contains an alkyl linking group. Examples of "alkyl linking group" or "alkylene" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propylene-1,3-diyl, propylene-1,2-diyl, propylene-1,1-diyl, and the like.

[0766] In certain positions, the definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings may be attached to any ring member, subject to the proviso that the valence of the atom is not exceeded. For example, the azetidine ring may be attached at any position of the ring, while the pyridin-3-yl ring is attached at the 3-position.

[0767] As used herein, the term "oxo" refers to an oxygen atom (i.e., =0) as a divalent substituent, forming a carbonyl when attached to carbon (e.g., C=O or C(O)), or attached to a nitrogen or sulfur heteroatom to form a nitroso, sulfinyl, or sulfonyl group.

[0768] As used herein, the term "independently selected" means that each occurrence of a variable or substituent (e.g., each R M ) is independently selected at each occurrence from the applicable list.

[0769] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are encompassed in the present invention. The cis and trans geometric isomers of the compounds disclosed herein are described and can be separated into mixtures of isomers or individual isomeric forms. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration. The various formulas provided herein (e.g., Formula I, Formula II, etc.) include stereoisomers of the compound.

[0770] The resolution of the racemic mixture of compound can be carried out by any one of various methods known in the art. Example method includes using chiral resolution acid to carry out fractional recrystallization, and the chiral resolution acid is a kind of optically active, salified organic acid. Suitable resolution agent for fractional recrystallization method is for example optically active acid, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acid, such as β-camphorsulfonic acid, such as D and L forms. Other resolution agents suitable for fractional crystallization method include stereoisomer pure form (such as S and R form, or diastereoisomer pure form) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane etc.

[0771] Resolution of the racemic mixture can also be carried out by elution on a column filled with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by those skilled in the art.

[0772] Compounds provided herein also include tautomeric forms. Tautomeric forms are produced by the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms in which protons can occupy two or more positions of heterocyclic systems, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, 2-hydroxypyridines and 2-pyridones and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into a form by appropriate substitution.

[0773] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0774] In some embodiments, preparation of the compounds may involve the addition of an acid or base to effect, for example, catalysis of a desired reaction or the formation of a salt form such as an acid addition salt.

[0775] In some embodiments, the compound or its salt provided herein is separated substantially. "Separated substantially" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition rich in the compound provided herein. Separation substantially can include a composition containing at least about 50 % by weight, at least about 60 % by weight, at least about 70 % by weight, at least about 80 % by weight, at least about 90 % by weight, at least about 95 % by weight, at least about 97 % by weight or at least about 99 % by weight of the compound or its salt provided herein.

[0776] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise specified, compounds identified herein as one particular tautomeric form by name or structure are intended to include the other tautomeric forms.

[0777] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0778] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by converting the acid or base moiety present into 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); basic or organic salts of acidic residues (such as carboxylic acids); etc. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of parent compounds formed by, for example, non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties. Typically, 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 or in an organic solvent or in a mixture of the two; typically, 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 may 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.

[0779] synthesis

[0780] As will be appreciated by those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes.

[0781] Compounds of Formula I can be synthesized using the process shown in Scheme 1. As depicted in Scheme 1, compounds of Formula 1-2 can be obtained using a variety of methods (e.g., nucleophilic aromatic substitution or suitable cross-coupling reactions). For example, compounds of Formula 1-1 (i.e., each Hal can be independently F, Cl, Br or I) can be reacted 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 minutes to several days) to produce compounds of Formula 1-2. Alternatively, transition metal (e.g., Pd, Cu, Ni) catalyzed reactions of Compound 1-1 with suitable coupling partners (e.g., primary or secondary amines, nitrogen heterocycles or heteroaryl boronic acids / esters, trialkyltin or zinc reagents) (including but not limited to Buchwald, Ullman, Suzuki, Stille, Negishi couplings) provide compounds of Formula 1-2. Compounds of Formula 1-1 are commercially available or can be readily synthesized according to methods known to those skilled in the art. Under appropriate conditions (e.g., in the presence of a palladium catalyst such as methanesulfonate (2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) ("tBuBrettPhos Pd G3") and a catalyst such as Cs 2 CO 3 In the presence of a base such as NaOt-Bu, in a suitable solvent such as THF or 1,4-dioxane), a CN bond forming reaction (e.g., transition metal catalyzed or nucleophilic aromatic substitution) between a compound of Formula 1-2 and hydrazine produces a compound of Formula 1-3. Under appropriate conditions (e.g., in the presence of AcOH), the reaction of a compound of Formula 1-3 with a compound of Formula 1-4 (e.g., trimethyl orthoformate or triethyl orthoacetate) provides a compound of Formula I.

[0782] Solution 1.

[0783]

[0784] Compounds of Formula I can also be prepared using the process shown in Scheme 2. As shown in Scheme 2, compounds of Formula 2-1 can be converted to compounds of Formula 2-2 by a variety of methods. For example, halogenation of compounds of Formula 2-1 (e.g., by deprotonation with an appropriate base such as 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride ("TMPMgCl.LiCl") followed by addition of an appropriate electrophile such as 1-chloro-2-iodoethane) followed by a suitable cross-coupling provides compounds 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), and the like. Alternatively, the compound of formula 2-2 can be obtained by converting the compound of formula 2-1 to a carbonyl intermediate (e.g., by deprotonation with an appropriate base such as TMPMgCl.LiCl, followed by addition of an appropriate electrophile such as DMF), followed by reaction with an appropriate fluorinating agent (e.g., diethylaminosulfur trifluoride). Under appropriate conditions (e.g., in the presence of a palladium ring precatalyst such as tBuBrettPhos Pd G3 and a catalyst such as Cs 2 CO 3 In the presence of a base), a CN bond formation reaction (e.g., transition metal catalyzed or nucleophilic aromatic substitution) between the compound of formula 2-2 and hydrazine produces a compound of formula 2-2. Under appropriate conditions (e.g., in the presence of AcOH), the reaction of the compound of formula 2-2 with a compound of formula 2-3 (e.g., triethyl orthoformate) provides a compound of formula I.

[0785] Solution 2.

[0786]

[0787] Compounds of formula 3-8 can be synthesized, for example, according to the process shown in Scheme 3. As shown in Scheme 3, protection of the amino compound of formula 3-1 produces a compound of formula 3-2 under appropriate conditions (e.g., including but not limited to, reductive amination with an appropriate aldehyde such as benzaldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride). Compounds of formula 3-1 are commercially available or can be readily synthesized according to methods known to those skilled in the art. Under appropriate conditions (e.g., in the presence of a coupling reagent such as HATU and a base such as N-ethyl-N-isopropylpropan-2-amine in an appropriate solvent such as N,N-dimethylformamide), an amide coupling reaction of a compound of formula 3-2 with a compound of formula 3-3 provides a compound of formula 3-4. Deprotection of the tert-butyloxycarbonyl group in the compound of formula 3-4 under appropriate conditions (e.g., using an acid such as trifluoroacetic acid) followed by intramolecular cyclization under appropriate conditions (e.g., using an appropriate solvent such as MeOH) provides a compound of formula 3-5. The compound of formula 3-5 is reduced under suitable conditions (e.g., using a reducing agent such as borane in a suitable solvent such as THF) to produce a compound of formula 3-6. Protection of the compound of formula 3-6 provides a compound of formula 3-7 under suitable conditions (e.g., by reaction with di-tert-butyl dicarbonate in the presence of a base such as N-ethyl-N-isopropylpropan-2-amine). Selective deprotection of PG (e.g., wherein PG is a protecting group such as benzyl) in the compound of formula 3-7 under suitable conditions (e.g., using a suitable catalyst such as palladium / carbon in the presence of hydrogen) provides a compound of formula 3-8.

[0788] Solution 3.

[0789]

[0790] Compounds of formula 4-4 can be prepared, for example, using the process shown in Scheme 4. In the process shown in Scheme 4, under appropriate conditions (for example, in the presence of a base such as N-ethyl-N-isopropylpropan-2-amine, in an aqueous solution such as CH 3 CN in a suitable solvent), a nucleophilic substitution reaction between the compound of formula 4-1 and the compound of formula 4-2 generates a compound of formula 4-3. Under appropriate conditions (for example, in the presence of an acid such as HCl or trifluoroacetic acid, in an aqueous solution such as tetrahydrofuran, 1-4-dioxane or CH 2 Cl 2 Removal of a suitable protecting group (eg, wherein PG is a group such as tert-butyloxycarbonyl) from a compound of Formula 4-3 provides a compound of Formula 4-4.

[0791] Solution 4.

[0792]

[0793] Alternatively, compounds of Formula 4-4 can be prepared, for example, using the process shown in Scheme 5. In the process shown in Scheme 5, an amide coupling reaction of a compound of Formula 5-1 with a compound of Formula 5-2 provides a compound of Formula 5-3. The compound of Formula 5-3 is subjected to reductive alkylation conditions (e.g., by using an appropriate transition metal catalyst such as IrCl(CO)(PPh) in the presence of a silane such as 1,1,3,3-tetramethyldisiloxane). 3 ) 2 , followed by addition of a suitable organometallic reagent, such as a Grignard reagent), provides a compound of Formula 5-4. Under appropriate conditions (e.g., in the presence of an acid such as HCl or trifluoroacetic acid in an aqueous solution such as tetrahydrofuran, 1-4-dioxane or CH 2 Cl 2 Removal of a suitable protecting group (eg, wherein PG is a group such as tert-butyloxycarbonyl) from a compound of Formula 5-4 provides a compound of Formula 4-4.

[0794] Solution 5.

[0795]

[0796] The reactions for preparing the compounds described herein can be carried out in suitable solvents that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents generally do not react with 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 solidification 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 a particular reaction step can be selected by a skilled person.

[0797] As used herein, the expression "ambient temperature" or "room temperature" or "rt" is understood in the art and generally refers to a temperature about the temperature of the room in which the reaction is carried out (e.g., reaction temperature), for example a temperature of about 20°C to about 30°C.

[0798] The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. One skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999).

[0799] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light) or mass spectrometry) or by chromatographic methods (such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC)) to monitor product formation. Compounds can be purified by various methods (including high performance liquid chromatography (HPLC) and normal phase silica chromatography) by those skilled in the art.

[0800] How to use

[0801] The compounds described herein can inhibit the activity of DGK. Compounds that inhibit DGK can be used to provide a means of preventing cancer cell growth or inducing apoptosis of cancer cells. Such compounds can also be used to treat cancer cells that exhibit changes in diacylglycerol-regulated enzymes and effectors. Therefore, it is expected that the compounds of the present disclosure can be used to treat or prevent cancer, such as solid tumors.

[0802] In certain embodiments, the present disclosure provides a method for treating a DGK-related disorder in a patient in need thereof, comprising the step of administering to the patient a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0803] The compounds or salts described herein may be selective. "Selectivity" means that the compound binds to or inhibits DGKα or DGKζ with greater affinity or potency, respectively, compared to at least one other DGK isoform or kinase, etc. In some embodiments, the selectivity may be at least about 2 times, 5 times, 10 times, at least about 20 times, at least about 50 times, at least about 100 times, at least about 200 times, at least about 500 times, or at least about 1000 times. The compounds disclosed herein may 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., more than 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., more than one or more other DGK isoforms or kinases, etc.). Selectivity may be measured by conventional methods in the art. In some embodiments, the K of each enzyme may be measured by a selective inhibitor of DGKζ. m Selectivity is tested at ATP concentrations. In some embodiments, the selectivity of the compounds of the invention can be determined by cellular assays associated with specific DGK kinase activity.

[0804] Based on the strong evidence that DGKα and DGKζ negatively regulate signaling pathways downstream of the T cell receptor, the development of DGK inhibitors may enhance T cell effector function and inhibit tumor progression. DGK inhibitors can be used alone or in combination with other therapies to treat cancer, including solid tumors and hematological malignancies, including renal cell carcinoma, mesothelioma, glioblastoma multiforme, colorectal cancer, melanoma, and pancreatic cancer (Chen, SS 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: pp. 4692-4703; Sitaram, P. et al., Int. J Mol. Sci., 2019. 20: pp. 5821-5848; Wesley, EM et al., Immunohorizons, 2018. 2: pp. 107-118). In addition, pharmacological inhibition of DGK provides benefits in controlling viral infections and can be used to treat such viral infections including coronavirus infection, HIV infection, and hepatitis virus infection in preclinical models (Harabuchi, S. et al., Front. Immunol., 2022.13:1032113).

[0805] In addition, DGKα has been shown to enhance esophageal squamous cell carcinoma (ESCC) and human hepatocellular carcinoma (HCC) progression (Chen, J. et al., Oncogene, 2019. 38: pp. 2533-2550; Takeishi, K. et al., J. Hepatol., 2012. 57: pp. 77-83), support colon cancer and breast cancer growth in three-dimensional (3D) culture (Torres-Ayuso, P. et al., Oncotarget, 2014. 5: pp. 9710-9726), enhance breast cancer invasiveness (Rainero, E. et al., PLOS ONE, 2014. 9(6): e97144) and promote metastasis of non-small cell lung cancer (NSCLC) (Fu, L. et al., Cancer Cell, 2014 ...). letters, 2022.532:215585), and DGKζ is considered a potential oncogene for osteosarcoma proliferation (Yu, W. et al., Front. Oncol., 2019.8:655) and promotes enhanced invasion of human metastatic colon cancer cells (Cai, K. et al., BMC Cancer, 2014.14:208). It is also reported that DGK inhibition has the potential to reduce immunopathology in patients with X-linked lymphoproliferative diseases (Velnati, S. et al., Eur. J. Med. Chem., 2019.164:378-390; Ruffo, E. et al., Sci. Transl. Med. 2016.8(321):321ra7).

[0806] In some embodiments, DGK-related disorders are solid tumors. Example solid tumors include, but are not limited to, breast cancer, colorectal cancer, gastric cancer, and glioblastoma (see, e.g., Cooke and Kazanietz, Sci. Signal, 2022, 15, eabo0264: 1-26). Example cancers associated with changes in DAG-regulated enzymes and effectors include, but are not limited to, uveal melanoma, myelodysplastic syndrome (MDS), angiosarcoma, perilymph node 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 myeloid leukemia (CML), colon cancer, prostate cancer, hepatocellular carcinoma (HCC), blue nevus, NK / T cell lymphoma, glioma, ovarian cancer, liver cancer, melanoma, liver cancer, bone and flesh Tumors, chordoid gliomas, pigment epithelioid melanocytoma, papillary glioneuronal tumors, fibrous histiocytomas, pituitary tumors, 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-associated (EBV)-associated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and cervical cancer (see, e.g., Cooke and Kazanietz, Sci. Signal, 2022, 15, eabo0264: 1-26).

[0807] In some embodiments, the cancer is selected from lung cancer, bladder cancer, urothelial carcinoma, esophageal cancer, gastric cancer, mesothelioma, liver cancer, diffuse large B-cell lymphoma, kidney cancer, head and neck cancer, bile duct cancer, cervical cancer, endocervical cancer, melanoma, Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), melanoma, MSI-high tumors, ICI-sensitive tumors, and viral infection-related cancers such as HPV-related anal cancer, vaginal cancer, vulvar cancer, cervical cancer, and oropharyngeal cancer.

[0808] In some embodiments, the cancer is selected from lung cancer, bladder cancer, urothelial carcinoma, esophageal cancer, gastric cancer, mesothelioma, liver cancer, diffuse large B-cell lymphoma, kidney cancer, head and neck cancer, bile duct cancer, cervical cancer, endocervical carcinoma, and melanoma.

[0809] In some embodiments, the cancer is selected from non-small cell lung cancer (lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD)), bladder urothelial carcinoma, esophageal cancer, gastric adenocarcinoma, mesothelioma, hepatocellular carcinoma, diffuse large B-cell lymphoma (DLBCL), renal clear cell carcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and metastatic melanoma.

[0810] In some embodiments, cancer is myelodysplastic syndrome. As used herein, myelodysplastic syndrome is intended to cover heterogeneous and clonal hematopoietic disorders, characterized by ineffective hematopoiesis on one or more major myeloid cell lineages. Myelodysplastic syndrome is associated with bone marrow failure, peripheral blood cell reduction and a tendency to progress to acute myeloid leukemia (AML). In addition, clonal cell genetic abnormalities can be detected in about 50% of MDS cases. In 1997, the World Health Organization (WHO) jointly with the Society of Hematopathology (SH) and the European Society of Hematopathology (EAHP) proposed a new classification of hematopoietic tissue neoplasms (Harris et al., J Clin Oncol 1999; 17: 3835-3849; Vardiman et al., Blood 2002; 100: 2292-2302). For MDS, WHO not only used morphological criteria from the French-American-British (FAB) classification, but also combined available genetic, biological and clinical features 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., WHOClassification ofTumours of Haematopoietic and Lymphoid Tissues . 4th edition Lyon France: IARC Press; 2008: 88-103; Bunning and Germing, "Myelodysplastic syndromes / neoplasms", Chapter 5, Swerdlow et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues .(4th edition):Lyon,France:IARC Press;2008:88-103).

[0811] Table 1. 2008 WHO classification of new-onset myelodysplastic syndromes

[0812]

[0813]

[0814] In some embodiments, the myelodysplastic syndrome is refractory cytopenias with single lineage dysplasia (RCUD).

[0815] In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS).

[0816] In some embodiments, the myelodysplastic syndrome is refractory anemia associated with thrombocythaemia with ring sideroblasts (RARS-T).

[0817] In some embodiments, the myelodysplastic syndrome is refractory cytopenias with multilineage dysplasia.

[0818] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1).

[0819] In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2).

[0820] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome unclassified (MDS-U).

[0821] In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome associated with isolated del(5q).

[0822] In some embodiments, the myelodysplastic syndrome is refractory to treatment with an erythropoiesis stimulating agent.

[0823] In some embodiments, the compounds of the present disclosure may be used to treat myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome).

[0824] In some embodiments, there is provided herein a method for increasing the survival or progression-free survival of a patient, the method comprising administering a compound provided herein to the patient. In some embodiments, the patient suffers from cancer. In some embodiments, the patient suffers from a disease or condition as described herein. As used herein, progression-free survival refers to the length of time during and after the treatment of solid tumors, during which the patient coexists with the disease but the disease has not yet deteriorated. Progression-free survival may refer to the length of time from the first administration of a compound until death or early stage of disease progression. The progression of the disease may be defined by RECIST v.1.1 (response evaluation criteria for solid tumors), as assessed by an independent centralized radiology review committee. In some embodiments, the administration of a compound results in a progression-free survival 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, the administration of the compound results in 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 of progression-free survival. In some embodiments, the administration of the compound results in 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 of progression-free survival increase.

[0825] The present disclosure also provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0826] The present disclosure also 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.

[0827] As used herein, the term "cell" is intended to refer to a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be a portion of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism, such as a mammal.

[0828] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" a DGK with a compound described herein includes administering a compound described herein to an individual or patient (such as a human) having a DGK, and, for example, introducing a compound described herein into a sample containing a cell or purified preparation containing a DGK.

[0829] As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0830] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or agent, such as any solid form or salt thereof disclosed herein, that elicits the biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human. The appropriate "effective" amount in any individual case can be determined using techniques known to those skilled in the art.

[0831] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0832] 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 and biologically or otherwise desirable, and include excipients or carriers acceptable for veterinary use as well as human medical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmaceuticals, 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.

[0833] As used herein, the terms "treating" or "treatment" refer to inhibiting a disease; e.g., inhibiting the disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms), or ameliorating a disease; e.g., ameliorating the disease, disorder or condition in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0834] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition but does not yet experience or display the pathology or symptoms of the disease.

[0835] It will be appreciated 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 (and the embodiments are intended to be combined as if written in multiple related form). Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0836] Combination therapy

[0837] I. Immune Checkpoint Therapy

[0838] In some embodiments, the DGKα and DGKζ inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors to treat cancers as described herein.

[0839] The compounds disclosed herein can be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infection. Exemplary immune checkpoint inhibitors include inhibitors for immune checkpoint molecules (such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, 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 compounds disclosed herein can be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infection. In the embodiment, 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 compound 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 TGFRβ inhibitors.

[0840] In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0841] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0842] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as 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, cemiplimab, tislelizumab, spartalizumab (PDR001), silizumab (JNJ-63723283), toripalizumab (JS001), carrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-06 80. BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SH R-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 an inhibitor disclosed in U.S. Pat. Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 0174679, 2017 / 0320875, 2017 / 0342060, 2017 / 0362253, 2018 / 0016260, 2018 / 005748 6. 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 publication number WO 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO2011066342, WO 2011159877, WO 2011082400 or WO 2011161699, each of which is herein incorporated by reference in its entirety. In some embodiments, the inhibitor of PD-L1 is INCB086550. In some embodiments, the inhibitor of PD-L1 is INCB099280.

[0843] In some embodiments, the antibody is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cimiprilimab, spartalizumab, carrelizumab, cilizumab, toripalimab, sindilimab, 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, cimiprilimab, spartalizumab, carrelizumab, cilizumab, toripalimab or sindilimab. 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 cemiplizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is carrelizumab. In some embodiments, the anti-PD-1 antibody is silizumab. In some embodiments, the anti-PD-1 antibody is toripalizumab. In some embodiments, the anti-PD-1 antibody is sindilimab. 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; Ruifulimab). In some embodiments, the anti-PD1 antibody is SHR-1210. Other anticancer agents 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.

[0844] In some embodiments, the inhibitor of immune checkpoint molecules is a small molecule or a pharmaceutically acceptable salt thereof that is bound to PD-L1. In some embodiments, the inhibitor of immune checkpoint molecules is a small molecule or a pharmaceutically acceptable salt thereof that is bound to and internalizes PD-L1. In some embodiments, the inhibitor of immune checkpoint molecules is a compound selected from US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US 16 / 369,654 (filed on March 29, 2019) and US No. 62 / 688,164, or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in its entirety.

[0845] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRβ.

[0846] In some embodiments, the inhibitor is MCLA-145.

[0847] 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.

[0848] 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 Itiramude α (IMP321).

[0849] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is olerumab.

[0850] 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.

[0851] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0852] 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 enoxicam, MGD009 or 8H9.

[0853] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirelumab or IPH4102.

[0854] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0855] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TGF-β. In some embodiments, the inhibitor of TGF-β is trabedecanoic acid, galusertinib or M7824.

[0856] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-γ. In some embodiments, the inhibitor of PI3K-γ is IPI-549.

[0857] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0858] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0859] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0860] 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.

[0861] 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 obinutuzumab or rituximab.

[0862] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0863] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is umetropumab.

[0864] 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, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (taliximab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178 or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0865] 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.

[0866] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0867] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is theralizumab.

[0868] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0869] 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.

[0870] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF.β. 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.

[0871] 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. Inhibitors of arginase inhibitors include INCB1158.

[0872] As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0873] II. Cancer Therapy

[0874] Cancer cell growth and survival can be affected by multiple signal transduction pathways. Therefore, it may be useful to combine different enzyme / protein / receptor inhibitors to treat such diseases, and the different enzyme / protein / receptor inhibitors show different preferences in the targets of their regulating activities. Examples of agents that can be combined with compounds of the present disclosure or their solid forms or salts include inhibitors of PI3K-AKT-mTOR pathways, inhibitors of Raf-MAPK pathways, inhibitors of JAK-STAT pathways, inhibitors of β-chain protein pathways, inhibitors of notch pathways, inhibitors of hedgehog pathways, Pim kinase inhibitors, and protein chaperones and inhibitors of cell cycle progression. Targeting more than one signal transduction pathway (or more than one biomolecule involved in a given signal transduction pathway) can reduce the possibility of drug resistance in a cell population, and / or reduce the toxicity of treatment.

[0875] 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 to treat 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 combined with one or more inhibitors 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, CSFIR, 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 solid forms or salts thereof, may be combined with one or more of the following kinases for the treatment of cancer.Non-limiting examples of inhibitors that can be used in combination with the compounds of the present disclosure, or solid forms or salts thereof, for treating cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, deritinib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (e.g., icaridostat and NLG919), LSD1 inhibitors Inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., INCB50797 and INCB50465), PI3K-γ inhibitors (such as PI3K-γ 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 extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329, and INCB57643), and adenosine receptor antagonists or combinations thereof. Inhibitors of HDAC, such as panobinostat and vorinostat. Inhibitors of c-Met, such as onazolizumab, tivantinib, and 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, and GDC-0973. Inhibitors of Hsp90 (e.g., tanspiramycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and Pim kinases (LGH447, INCB053914, and SGI-1776) may also be combined with the compounds of the present disclosure.

[0876] The compounds disclosed herein or their solid forms or salts can be used in combination with one or more agents for treating diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid or an immunomodulator. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil nitrogen mustard, methenyl chloride, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, nitrogen mustard phenylbutyric acid, pipobroman, triethylene-melamine, 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 immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0877] The compound of the present disclosure or its solid form or salt can be further used in combination with other methods for treating cancer, for example, by 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 dose of T cell activation, oncolytic virus therapy and immunomodulatory small molecules, including thalidomide (thalidomide) or JAK1 / 2 inhibitors, etc. The compound can be administered in combination with one or more anticancer drugs (such as chemotherapeutic agents). Example chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezomib, bortezomib, brivanib, buparlisib, intravenous busulfan intravenous, oral busulfan, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, nitrogen mustard, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparinsodium), dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin-toxin conjugate, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib, estramustine, etoposide phosphate phosphate), etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin CC), mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilasib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab zumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine oguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, voristastat, and zoledronate.

[0878] Other anticancer agents include antibody therapeutics such as trastuzumab (Herceptin), co-stimulatory molecules (such as CTLA-4) antibodies (e.g., ipilimumab or tremelimumab), 4-1BB, PD-1 and PD-L1 antibodies, or cytokine (IL-10, TGF-β, etc.) antibodies. Examples of PD-1 and / or PD-L1 antibodies that can be used in combination with the compounds of the present disclosure for the treatment of cancer or infection (such as viral, bacterial, fungal and parasitic infections) include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

[0879] Other anticancer agents include inhibitors of kinase-associated cell proliferative disorders. These kinases include, but are not limited to, Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, adrenergic 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.

[0880] Other anti-cancer agents also include those that block the migration of immune cells, such as antagonists of chemokine receptors, including CCR2 and CCR4.

[0881] 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, immunosuppressants or therapeutic antibodies. The steroids include but are not limited to 17α-ethinylestradiol, diethylstilbestrol, testosterone, prisone, fluoxymethyltestosterone, methylprednisolone, methyltestosterone, prisone, triamcinolone acetonide, chlorethoxyquin, hydroxyprogesterone, aminoglutethimide and medroxyprogesterone acetate.

[0882] The compounds of the present disclosure, or solid forms or salts thereof, may also be used in combination with lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS214662, tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox, and amidox.

[0883] The compounds of the present disclosure or their solid forms or salts can be combined 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 gp100, MAGE antigens, Trp-2, MARTI and / or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

[0884] The compounds of the present disclosure or their solid forms or salts can be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses involved in human cancers, such as human papilloma virus (HPV), hepatitis viruses (HBV and HCV) and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the present disclosure or their solid forms or salts can 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 can be combined with dendritic cell immunization to activate an effective anti-tumor response.

[0885] The compounds of the present disclosure, or solid forms or salts thereof, can be used in combination with bispecific macrocyclic peptides that target effector cells expressing Fcα or Fcγ receptors to tumor cells. The compounds of the present disclosure, or solid forms or salts thereof, can also be combined with macrocyclic peptides that activate host immune responses.

[0886] The compounds of the present disclosure, or solid forms or salts thereof, can be used in combination with bone marrow transplantation to treat various tumors of hematopoietic origin.

[0887] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0888] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil (1592U89); dipivoxil, bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated β-L-2',3'-dicleoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6,-diamino-purine dioxolane); and lodenosine (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 (+)-curcumolactone A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lanavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentavir, and isamyl project number 11607.

[0889] When more than one agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for more than two agents).

[0890] In some embodiments, the compounds of the present disclosure, or solid forms or salts thereof, may be used in combination with INCB086550.

[0891] Drug preparations and dosage forms

[0892] When used as a medicament, the compounds of the present disclosure can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in pharmaceutical technology, and can be administered by a variety of routes, depending on whether local treatment or systemic treatment is required and the area to be treated. Administration can be surface (including transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal or intranasal), 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 may be in the form of a single bolus dose, or may be achieved, for example, by a continuous infusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desired.

[0893] The present disclosure also includes pharmaceutical compositions, which contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient, combined with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. When preparing the composition of the present disclosure, the active ingredient is usually mixed with an excipient, diluted by an excipient, or packaged in such a carrier, in the form of, for example, a capsule, a medicine bag, paper or other container. When an excipient acts as a diluent, it can be a solid, semisolid or liquid material, which is used as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the following forms: tablets, pills, powders, lozenges, medicine bags, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0894] When preparing a formulation, the active compound may be ground to provide an appropriate particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0895] The compounds of the present disclosure may be ground using known milling procedures such as wet milling to obtain particle sizes suitable for tablet formation and other formulation types. Finely dispersed (nanoparticulate) formulations of the compounds of the present disclosure may be prepared by methods known in the art, for example, see International Application No. WO 2002 / 000196.

[0896] 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 additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxy-benzoate and propyl hydroxy-benzoate; sweeteners; and flavoring agents. The compositions of the present disclosure may be formulated using procedures known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

[0897] The composition can be formulated in unit dosage form, each dose containing about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0898] In some embodiments, the compositions of the present disclosure contain about 5 to about 50 mg of active ingredient. Those skilled in the art will appreciate that this embodies compositions containing 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 active ingredient.

[0899] In some embodiments, the compositions of the present disclosure contain about 50 to about 500 mg of active ingredient. Those skilled in the art will appreciate that this embodies compositions containing 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 active ingredient.

[0900] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. Those skilled in the art will appreciate that this embodies compositions containing 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 active ingredient.

[0901] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0902] The active compound can be effective within a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0903] To prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When these preformulation compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed in the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0904] Tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form with an advantage of prolonged action. For example, tablets or pills may include an inner dosage component and an outer dosage component, the latter being in the form of a film coating above the former. The two components may be separated by an enteric layer that is used to resist disintegration in the stomach and allows the inner component to enter the duodenum intact or to delay release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and a mixture of polymeric acids and materials such as shellac, hexadecanol, and cellulose acetate.

[0905] Liquid forms in which the compounds and compositions of the present disclosure may be incorporated for oral administration or by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0906] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to produce local or systemic effects. The composition may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from an atomizing device, or the atomizing device may be attached to a mask, curtain, or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0907] The topical preparation may contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers, and the one or more hydrophobic carriers are selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, etc. The carrier composition of the cream may be based on a combination of water with glycerol and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate and cetostearyl alcohol). Gels may be prepared using isopropyl alcohol and water, in combination with other components (such as glycerol, hydroxyethyl cellulose, etc.) as appropriate. In some embodiments, the topical preparation 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 5wt% of the compound of the present disclosure. The topical preparation may be suitably packaged in, for example, a 100g tube, and the tube may optionally be accompanied by instructions for treating selected indications (e.g., psoriasis or other skin disorders).

[0908] The amount of the compound or composition administered to the patient will vary depending on what is being administered, the purpose of administration (such as prevention or therapy), the patient's condition, the mode of administration, etc. In therapeutic applications, the composition can be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially prevent the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated, as well as the judgment of the attending physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0909] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be aseptically filtered. The aqueous solution may be packaged for use as is, or lyophilized, and the lyophilized preparation may be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will generally be between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients, carriers or stabilizers will result in the formation of a pharmaceutical salt.

[0910] The therapeutic dose of the compounds of the present disclosure may vary according to, for example, the specific use to be achieved by the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present disclosure in the pharmaceutical composition may vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, the compounds of the present disclosure may be provided in a physiological buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on the following variables, such as the type and degree of progression of the disease or condition, the overall health of a particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be inferred from a dose-response curve derived from an in vitro or animal model test system.

[0911] The compositions of the present disclosure may also include one or more additional agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are listed herein.

[0912] Labeled compounds and analytical methods

[0913] Another aspect of the disclosure relates to labeled compounds of the disclosure (radioactive labels, fluorescent labels, etc.), which can be used not only for imaging techniques, but also for in vitro and in vivo analysis, which is used to locate and quantify DGK in tissue samples (including humans), and to identify DGK inhibitors by binding of labeled compounds. Substitution of one or more atoms of the compounds of the disclosure can also be used to generate differential ADME (adsorption, distribution, metabolism and excretion). Therefore, the disclosure includes DGK analysis containing such labeled or substituted compounds.

[0914] The present disclosure also includes isotopically labeled compounds of the present disclosure. An "isotopically" or "radiolabeled" compound is a compound of the present disclosure in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present disclosure include, but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 18F. 35 S. 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I. 124 I. 125 I and 131 I. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced by deuterium atoms to allow the mixture to be deuterated (e.g., C 1-6 One or more hydrogen atoms of the alkyl group may be optionally replaced by a deuterium atom, such as with -CD 3 Substitute -CH 3 ). In some embodiments, the alkyl groups of the disclosed formulae (eg, Formula I) can be perdeuterated.

[0915] One or more constituent atoms of the compounds provided herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds provided herein can be replaced or substituted with deuterium (e.g., C 1-6 One or more hydrogen atoms of the alkyl group may be replaced by a deuterium atom, such as with -CD 3 Substitute -CH 3 ). In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 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 or substituted by deuterium atoms.

[0916] In some embodiments, each hydrogen atom of the compounds provided herein (such as in conjunction with an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent as described herein or a -C 1-4 The hydrogen atoms to which the carbon atoms of the alkyl-, alkylene, alkenylene and alkynylene linking groups are attached are optionally replaced by deuterium atoms.

[0917] In some embodiments, each hydrogen atom of the compounds provided herein (such as in conjunction with an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituent as described herein or a -C 1-4 The hydrogen atom attached to the carbon atom of the alkyl-, alkylene, alkenylene and alkynylene linking groups) is replaced by a deuterium atom (i.e., an alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl substituent or a -C 1-4 Alkyl-, alkylene, alkenylene and alkynylene linking groups are perdeuterated).

[0918] In some embodiments, the alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents described herein or -C 1-4 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hydrogen atoms attached to the carbon atoms of the alkyl-, alkylene, alkenylene and alkynylene linking groups are optionally replaced with deuterium atoms.

[0919] In some embodiments, the alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents described herein or -C 1-4 1, 2, 3, 4, 5, 6, 7 or 8 hydrogen atoms attached to the carbon atoms of the alkyl-, alkylene, alkenylene and alkynylene linking groups are optionally replaced by deuterium atoms.

[0920] In some embodiments, a compound provided herein (eg, a compound of any one of Formulae I-XI) or a pharmaceutically acceptable salt thereof comprises at least one deuterium atom.

[0921] In some embodiments, the compounds provided herein (eg, compounds of any one of Formulae I-XI) or pharmaceutically acceptable salts thereof contain two or more deuterium atoms.

[0922] In some embodiments, the compounds provided herein (eg, compounds of any one of Formulae I-XI) or pharmaceutically acceptable salts thereof contain three or more deuterium atoms.

[0923] In some embodiments, for a compound provided herein (eg, a compound of any one of Formulae I-XI) or a pharmaceutically acceptable salt thereof, all hydrogen atoms are replaced with deuterium atoms (ie, the compound is "perdeuterated").

[0924] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. 2007 edition, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments and / or analysis.

[0925] Substitution with heavier isotopes (such as deuterium) may offer certain therapeutic advantages due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. (See, for example, 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 offer one or more therapeutic advantages.

[0926] The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro DGK labeling and competition assays, incorporation of 3 H. 14 C. 82 Br, 125 I. 131 I or 35 Compounds of S may be useful. For radiographic applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br can be useful.

[0927] It is understood that a "radiolabeled" or "labeled compound" is a compound into which at least one radionuclide has been incorporated. In some embodiments, the radionuclide is selected from 3 H. 14 C. 125 I. 35 S and 82 The group composed of Br.

[0928] The present disclosure may also include synthetic methods for incorporating radioisotopes into 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.

[0929] The labeled compounds of the present disclosure can be used in screening analysis to identify / evaluate compounds. For example, the concentration change of the newly synthesized or identified labeled compound (i.e., test compound) when in contact with DGK can be monitored by tracking the label, thereby evaluating the ability of the compound to bind to DGK. For example, the ability of the test compound (labeled) to reduce the binding of another compound (i.e., standard compound) known to bind to DGK can be evaluated. Therefore, the ability of the test compound to compete with the standard compound for binding to DGK is directly related to its binding affinity. In contrast, in some other screening analyses, the standard compound is labeled and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and thus determine the relative binding affinity of the test compound.

[0930] Pill Box

[0931] The present disclosure also includes a pharmaceutical kit that can be used, for example, to treat or prevent a DGK-related disease or condition as described herein, the pharmaceutical kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. The kit may also include one or more of various conventional pharmaceutical kit components, such as a container containing one or more pharmaceutically acceptable carriers, other containers, etc., as will be readily apparent to those skilled in the art. The kit may also include instructions as inserts or labels indicating the amount of the components to be administered, administration instructions, and / or instructions for mixing the components.

[0932] The present invention will be described in more detail by means of specific embodiments. 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 that various non-critical parameters that may be changed or modified to produce substantially the same results.

[0933] Example

[0934] Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass directed fractionation system. The basic equipment setup, protocols, and control software for operating these systems have been described in detail in the literature (see, e.g., “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 isolated compounds were usually subjected to analytical liquid chromatography mass spectrometry (LCMS) under the following conditions for purity analysis: Instrument: Agilent 1100 series, LC / MSD, Column: Waters Sunfire TM C 18 5 μm, 2.1×50 mm, buffer: mobile phase A: water containing 0.025% TFA and mobile phase B: acetonitrile; gradient 2% to 80% B in 3 minutes, flow rate 2.0 mL / min.

[0935] Additionally as indicated in the Examples, some of the prepared compounds were separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) and MS detection or flash chromatography (silica gel). Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0936] pH = 2, purification: Waters Sunfire TM C 185 μm, 19×100 mm, eluted with mobile phase A: water containing 0.1% TFA (trifluoroacetic acid) and mobile phase B: acetonitrile; the flow rate was 30 mL / min, and the separation gradient of each compound was optimized using the compound-specific method optimization scheme 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.

[0937] pH = 10, purification: Waters XBridge TM C 18 5 μm, 19 × 100 mm column, with mobile phase A containing 0.15% NH 4 OH water and mobile phase B: acetonitrile elution; the flow rate was 30 mL / min, and the separation gradient of each compound was optimized using the compound-specific method optimization scheme 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.

[0938] Intermediate 1. (2R,5S)-1-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride

[0939]

[0940] Step 1. Tert-butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[0941]

[0942] Tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (15.0 g, 70 mmol, Combi-Blocks OR-8588), 4,4′-(chloromethylene)bis(fluorobenzene) (19.2 g, 80 mmol, Combi-Blocks QA-4728) and N-ethyl-N-isopropylpropan-2-amine (37 mL, 210 mmol) were stirred in CH 3 CN (175 mL) overnight. After cooling to rt, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine. The organic phase was purified by MgSO 4 Dry, filter, and concentrate and use flash column chromatography (330 g SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to afford tert-butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine-1-carboxylate (26.0 g, 89% yield) as a light yellow waxy solid. 24 H 31 F 2 N 2 O 2 LC-MS calculated value (M+H) + : m / z = 417.2; Exp. value 417.1.

[0943] Step 2. (2R,5S)-1-(Bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride

[0944] 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 solution of HCl in 1,4-dioxane (6.25 mL, 25.0 mmol) and stirred with N 2 The reaction mixture was purged and stirred at 80° C. for 4 h. After cooling to rt, the mixture was washed with Et 2 The reaction mixture was diluted with 4% CO (25 mL) and hexanes (50 mL) and slurrying was continued for 30 min. The solid precipitate was collected by filtration and washed with Et 2 O and hexane, and dried under vacuum to afford the desired product as a white solid (1.34 g, 85% yield). 19 H 23 F 2 N 2 LC-MS calculated value (M+H) + : m / z = 317.2; experimental value 317.2.

[0945] Intermediate 2. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine

[0946]

[0947] To a mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (618 mg, 3.0 mmol, PharmaBlock PB03220) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 1.06 g, 3.0 mmol) in 1-butanol (15.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.57 mL, 9.0 mmol) and the mixture was stirred at rt overnight. 2 Cl 2 The reaction mixture was diluted and washed with saturated NaHCO 3 The combined organic layers were purified by MgSO 4 Dry, concentrate, and use flash column chromatography (SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to afford the desired product as a very light yellow waxy solid (1.42 g, 97% yield). 24 H 23 CIF 2 N 5 LC-MS calculated for S (M+H) + : m / z = 486.1; Exp. value 486.2.

[0948] Intermediate 3. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-iodothiazolo[5,4-d]pyrimidine

[0949]

[0950] In an oven-dried vial with a stir bar, a mixture of 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine (Intermediate 2, 761 mg, 1.57 mmol) in anhydrous THF (7.8 mL) was cooled to -78 °C, then a 1 M solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex in THF / toluene (2.5 mL, 2.5 mmol, Aldrich 703540) was added dropwise, and the mixture was stirred at -78 °C for 30 min, then 1-chloro-2-iodoethane (571 μL, 6.3 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for another 30 min. The reaction mixture was warmed to 0 °C and stirred for 30 min, then saturated NH 4 The mixture was quenched with aqueous Cl solution. After warming to rt, CH 2 Cl 2 The mixture was extracted. The combined organic layers were purified by MgSO 4 Dry, concentrate, and purify by flash column chromatography (40 g SiO 2 The crude residue was purified by HPLC-MS / MS (EtOAc / hexanes) to afford the desired product (843 mg, 88% yield) as a very light yellow waxy solid. 24 H 22 CIF 2 IN 5 LC-MS calculated for S (M+H) + : m / z = 612.0; Found 612.1.

[0951] Intermediate 4. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-(difluoromethyl)thiazolo[5,4-d]pyrimidine

[0952]

[0953] Step 1. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine-2-carbaldehyde

[0954]

[0955] In a dried vial with a stir bar, a mixture of 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine (Intermediate 2, 200.0 mg, 0.412 mmol) in THF (2.1 mL) was cooled to -78 °C, then a 1 M solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex in THF / toluene (0.66 mL, 0.66 mmol, Aldrich 703540) was added dropwise, and the reaction mixture was stirred at -78 °C for 30 min, then N,N-dimethylformamide (301 mg, 4.12 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for another 30 min. The reaction mixture was warmed to 0 °C and stirred for 30 min, then saturated NH 4 The mixture was quenched with aqueous Cl solution. After warming to rt, CH 2 Cl 2 The combined organic layers were purified by MgSO 4 Dry, concentrate, and purify by flash column chromatography (12 g SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to afford the desired product as a very light yellow waxy solid. 25 H 23 CIF 2 N 5 LC-MS calculated value of OS (M+H) + : m / z = 514.1; Exp. value 514.2.

[0956] Step 2: 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-(difluoromethyl)thiazolo[5,4-d]pyrimidine

[0957] In a dried vial with a stir bar, 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidine-2-carbaldehyde (Step 1) was added to CH 2 Cl 2 (Diethylamino)sulfur trifluoride (163 μL, 1.2 mmol, Aldrich 235253) was added dropwise to the mixture in 4% paraformaldehyde (2.1 mL) and the reaction mixture was stirred at rt for 4 h. The mixture was then quenched by dropwise addition of saturated NaHCO 3 The reaction mixture was slowly quenched with aqueous solution and washed with CH 2 Cl 2 The combined organic phases were purified by MgSO 4Dry, concentrate, and purify by flash column chromatography (12 g SiO 2 The crude residue was purified by HPLC (5% by mass 4% by weight, EtOAc / hexanes) to afford the desired product. 25 H 23 CIF 4 N 5 LC-MS calculated for S (M+H) + : m / z = 536.1; Exp. value 536.1.

[0958] Intermediate 5. 3-(7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothiazolo[5,4-d]pyrimidin-2-yl)propionitrile

[0959]

[0960] In an oven-dried vial with a stir bar, 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chloro-2-iodothiazolo[5,4-d]pyrimidine (Intermediate 3, 122.4 mg, 0.200 mmol) and Pd(PPh 3 ) 4 To a mixture of (46.2 mg, 0.040 mmol, Aldrich 216666) in DMF (1.0 mL) was added a 0.5 M solution of (2-cyanoethyl)zinc(II) bromide in THF (0.48 mL, 0.24 mmol, Aldrich 497908) and the mixture was heated with N 2 The mixture was purged and stirred at 85° C. for 4 h. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (12 g SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to afford the desired product (87.9 mg, 82% yield) as a yellow waxy solid. 27 H 26 CIF 2 N 6 LC-MS calculated for S (M+H) + : m / z = 539.2; Exp. value 539.2.

[0961] 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

[0962]

[0963] To a mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (102 mg, 0.50 mmol, Combi-Blocks QB-6771) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 177 mg, 0.50 mmol) in 1-butanol (2.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.26 mL, 1.5 mmol) and the reaction mixture was stirred at 60° C. for 2 h. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (24 g SiO 2 The crude residue was purified by HPLC-MS / MS (EtOAc / hexanes) to provide the desired product (224 mg, 92% yield) as a colorless waxy solid. 25 H 26 CIF 2 N 6 LC-MS calculated value (M+H) + : m / z = 483.2; Exp. value 483.2.

[0964] Intermediate 7. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chlorofuro[3,2-d]pyrimidine

[0965]

[0966] This compound was prepared according to the procedure described in Intermediate 6, substituting 2,4-dichlorofuro[3,2-d]pyrimidine for 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine. 25 H 24 CIF 2 N 4 LC-MS calculated for O (M+H) + : m / z = 469.2; Exp. value 469.1.

[0967] Intermediate 8. 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chlorothieno[3,2-d]pyrimidine

[0968]

[0969] This compound was prepared according to the procedure described in Intermediate 6, substituting 2,4-dichlorothieno[3,2-d]pyrimidine for 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine. 25 H 24 CIF 2 N 4LC-MS calculated for S (M+H) + : m / z = 485.1; Exp. value 485.2.

[0970] Intermediate 9. 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-9-methyl-9H-purine

[0971]

[0972] To a mixture of 2,6-dichloro-9-methyl-9H-purine (203 mg, 1.00 mmol, Combi-Blocks ST-3696) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 353 mg, 1.00 mmol) in 1-butanol (5.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.52 mL, 3.0 mmol) and the mixture was stirred at 85 °C for 2 h. After cooling to rt, the mixture was heated with CH 2 Cl 2 The reaction mixture was diluted and washed with saturated NaHCO 3 The combined organic layers were purified by MgSO 4 Dry, concentrate, and purify by flash column chromatography (40 g SiO 2 , EtOAc / hexane). 25 H 26 CIF 2 N 6 LC-MS calculated value (M+H) + : m / z = 483.2; Exp. value 483.2.

[0973] 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

[0974]

[0975] To a mixture of 2,4-dichloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (54 mg, 0.25 mmol, Ambeed A478597) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 88 mg, 0.25 mmol) in 1-butanol (1.25 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.75 mmol) and the reaction mixture was stirred at 110° C. for 4 h. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (12 g SiO 2 The crude residue was purified by HPLC (5% by mass 4% by weight, EtOAc / hexanes). 27 H 29 CIF 2 N 5 LC-MS calculated value (M+H) + : m / z = 496.2; Found 496.1.

[0976] Intermediate 11. 7-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-5-chlorothieno[3,2-b]pyridine

[0977]

[0978] To a mixture of 5,7-dichlorothieno[3,2-b]pyridine (103 mg, 0.50 mmol, AstaTech 26642) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 177 mg, 0.50 mmol) in 1-butanol (2.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.26 mL, 1.5 mmol) and the reaction mixture was stirred at 160° C. for 5 d. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (12 g SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to afford the desired product (31 mg, 13% yield) as a brown waxy solid. 26 H 25 CIF 2 N 3 LC-MS calculated for S (M+H) + : m / z = 484.1; Exp. value 484.1.

[0979] 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

[0980]

[0981] This compound was prepared according to the procedure described in Intermediate 11, substituting 4,6-dichloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine (Enamine EN300-295293) for 5,7-dichlorothieno[3,2-b]pyridine. 27 H 29 CIF 2 N 5 LC-MS calculated value (M+H) + : m / z = 496.2; Exp. value 496.3.

[0982] Intermediate 13. (2S,5S)-tert-butyl 4-(bis(4-fluorophenyl)methyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

[0983]

[0984] A mixture of tert-butyl (2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (921.2 mg, 4.00 mmol, AstaTech AT10033), 4,4′-(chloromethylene)bis(fluorobenzene) (955 mg, 4.00 mmol, Combi-Blocks QA-4728) and N-ethyl-N-isopropylpropan-2-amine (2.1 mL, 12 mmol) was stirred in CH 3 CN (10.0 mL) overnight. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (40 g SiO 2 The crude residue was purified by HPLC (4% by weight, EtOAc / hexanes) to afford the desired product (854 mg, 49% yield) as a colorless waxy solid. 24 H 31 F 2 N 2 O 3 LC-MS calculated value (M+H) + : m / z = 433.2; Exp. value 433.2.

[0985] Intermediate 14. (2S,5S)-1-(bis(4-fluorophenyl)methyl)-2-(methoxymethyl)-5-methylpiperazine hydrochloride

[0986]

[0987] Step 1. Tert-butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-5-(methoxymethyl)-2-methylpiperazine-1-carboxylate

[0988]

[0989] To a mixture of tert-butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (Intermediate 13, 143 mg, 0.33 mmol) in a 1:1 mixture of THF / DMF (1.65 mL) was added sodium hydride (26.4 mg, 0.66 mmol) (60% dispersion in mineral oil, Aldrich 452912) in an oven-dried vial with a stir bar and stirred with N 2 The mixture was purged and stirred at rt for 15 min, then iodomethane (141 mg, 0.99 mmol) was added and the reaction mixture was stirred at rt overnight. 2 Cl 2 The reaction mixture was diluted and saturated NaHCO 3 The organic layer was taken out and washed with CH 2 Cl 2 The aqueous layer was extracted. The combined organic layers were purified by MgSO 4 Dry, concentrate, and purify by flash column chromatography (12 g SiO 2 , EtOAc / hexanes) to provide the desired product (69 mg, 47% yield) as a colorless waxy solid. 25 H 33 F 2 N 2 O 3 LC-MS calculated value (M+H) + : m / z = 447.2; experimental value 447.3.

[0990] Step 2. (2S,5S)-1-(bis(4-fluorophenyl)methyl)-2-(methoxymethyl)-5-methylpiperazine hydrochloride

[0991] To 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 a 4 M solution of HCl in 1,4-dioxane (0.4 mL, 1.6 mmol) and stirred with N 2 The reaction mixture was purged and stirred at 85° C. for 2 h. After cooling to rt, the reaction mixture was concentrated to 1 / 2 volume and washed with Et 2 O (3 mL) and hexane (5 mL), and slurrying was continued for 30 min. The solid precipitate was allowed to settle, the supernatant solvent was decanted, and the remaining solid was dried under vacuum to provide the desired product as a white solid. 20 H25 F 2 N 2 LC-MS calculated for O (M+H) + : m / z = 347.2; Exp. value 347.1.

[0992] Intermediate 15. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride

[0993]

[0994] Step 1. tert-Butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-2-methyl-5-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate

[0995]

[0996] A mixture of (2S,5S)-tert-butyl 4-(bis(4-fluorophenyl)methyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (Intermediate 13, 432.5 mg, 1.00 mmol) and N-ethyl-N-isopropylpropan-2-amine (524 μL, 3.00 mmol) in THF (5.0 mL) was cooled in an ice bath, and methanesulfonyl chloride (156 μL, 2.0 mmol) was then added dropwise. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was then concentrated in vacuo and purified by flash column chromatography (24 g SiO 2 The crude residue was purified by HPLC (5% by weight, EtOAc / hexanes) to provide the desired product (481 mg, 94% yield) as a colorless oil. 25 H 33 F 2 N 2 O 5 LC-MS calculated for S (M+H) + : m / z = 511.2; experimental value 511.2.

[0997] Step 2: tert-Butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-(cyanomethyl)-2-methylpiperazine-1-carboxylate

[0998]

[0999] To a mixture of tert-butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-2-methyl-5-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate (481 mg, 0.94 mmol) in dimethylacetamide (4.7 mL) was added potassium cyanide (307 mg, 4.7 mmol) and the reaction mixture was stirred at 55 °C overnight. After cooling to rt, the reaction mixture was diluted with 5% aqueous LiCl solution and washed with CH 2 Cl 2 The combined organic phases were purified by MgSO 4 Dry and concentrate. Use flash column chromatography (40 g SiO 2 The crude residue was purified by HPLC-MS / MS (EtOAc / hexanes) to provide the desired product (370 mg, 89% yield) as a colorless waxy solid. 25 H 29 F 2 N 3 O 2 LC-MS calculated value of Na (M+Na) + : m / z = 464.2; Exp. value 464.1.

[1000] Step 3. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride

[1001]

[1002] To a mixture of tert-butyl (2S,5R)-4-(bis(4-fluorophenyl)methyl)-5-(cyanomethyl)-2-methylpiperazine-1-carboxylate (370 mg, 0.84 mmol) in THF (4.2 mL) was added a 4M solution of HCl in 1,4-dioxane (1.05 mL, 4.2 mmol) and stirred with N 2 The reaction mixture was purged and stirred at 60° C. for 30 min. After cooling to rt, the mixture was washed with Et 2 The reaction mixture was diluted with 4% 2-HNO3 (8 mL) and hexanes (16 mL) and slurrying continued for 30 min. The solid precipitate was allowed to settle, the supernatant solvent was decanted, and the residual solid was dried under vacuum to provide the desired product as a white solid (288 mg, 91% yield). 20 H 22 F 2 N 3 LC-MS calculated value (M+H) + : m / z = 342.2; Exp. value 342.1.

[1003] Intermediate 16. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)-5-methylpiperazin-2-yl)acetonitrile

[1004]

[1005] To a mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (52 mg, 0.25 mmol, PharmaBlock PB03220) and 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride (Intermediate 15, 95 mg, 0.25 mmol) in 1-butanol (1.3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.75 mmol) and the reaction mixture was stirred at 60° C. for 1 h. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by flash column chromatography (24 g SiO 2 The crude residue was purified by HPLC-MS / MS (EtOAc / hexanes) to afford the desired product (85 mg, 66% yield) as a light yellow waxy solid. 25 H 22 CIF 2 N 6 LC-MS calculated for S (M+H) + : m / z = 511.1; experimental value 511.0.

[1006] Intermediate 17. 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-4-(2-chloro-9-methyl-9H-purin-6-yl)-5-methylpiperazin-2-yl)acetonitrile

[1007]

[1008] This compound was prepared according to the procedure described in Intermediate 16, substituting 2,6-dichloro-9-methyl-9H-purine (Combi-Blocks ST-3696) for 5,7-dichlorothiazolo[5,4-d]pyrimidine. 26 H 25 CIF 2 N 7 LC-MS calculated value (M+H) + : m / z = 508.2; Observed value 508.1.

[1009] Intermediate 18. (R)-tert-butyl 4-(bis(4-fluorophenyl)methyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[1010]

[1011] This compound was prepared according to the procedure described in Intermediate 13, substituting (R)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (AstaTech 70239) for (2S,5S)-tert-butyl 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate. 24 H 31 F 2 N 2 O 3 LC-MS calculated value (M+H) + : m / z = 433.2; Exp. value 433.3.

[1012] Intermediate 19. (R)-3-(1-(bis(4-fluorophenyl)methyl)piperazin-2-yl)propionitrile hydrochloride

[1013]

[1014] This compound was prepared according to the procedure described in Intermediate 15, substituting (R)-tert-butyl 4-(bis(4-fluorophenyl)methyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (Intermediate 18) for tert-butyl (2S,5S)-4-(bis(4-fluorophenyl)methyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate. 20 H 22 F 2 N 3 LC-MS calculated value (M+H) + : m / z = 342.2; experimental value 342.2.

[1015] Intermediate 20. (R)-3-(1-(bis(4-fluorophenyl)methyl)-4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)piperazin-2-yl)propionitrile

[1016]

[1017] This compound was prepared according to the procedure described in Intermediate 16, substituting (R)-3-(1-(bis(4-fluorophenyl)methyl)piperazin-2-yl)propionitrile hydrochloride (Intermediate 19) for 2-((2R,5S)-1-(bis(4-fluorophenyl)methyl)-5-methylpiperazin-2-yl)acetonitrile hydrochloride. 25 H 22 CIF 2 N 6 LC-MS calculated for S (M+H) + : m / z = 511.1; experimental value 511.2.

[1018] Intermediate 21. 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-chloro-9H-purine

[1019]

[1020] To a mixture of 2,6-dichloropurine (2.79 g, 14.7 mmol, Ambeed A101242) and (2R,5S)-1-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine hydrochloride (Intermediate 1, 5.20 g, 14.7 mmol) in 2-propanol (73.7 mL) was added N-ethyl-N-isopropylpropan-2-amine (7.72 mL, 44.2 mmol) and the mixture was stirred at 85 °C for 12 h. After cooling to rt, the reaction mixture was concentrated in vacuo and washed with CH 2 Cl 2 The crude residue was diluted and washed with saturated NaHCO 3 The combined organic layers were purified by MgSO 4 The filtrate was dried and concentrated. The crude residue was triturated with cold MeOH (100 mL) and filtered to afford the desired product (5.40 g, 78% yield) as a light brown solid. 24 H 24 CIF 2 N 6 LC-MS calculated value (M+H) + : m / z = 469.2; Exp. value 469.2.

[1021] As will be appreciated by those skilled in the art, the compounds of the present disclosure may exist as tautomers. For example, intermediate 21 may exist as 7H-purine or 9H-purine forms (e.g., 6-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazine-1-yl)-2-chloro-7H-purine).

[1022] Intermediate 22. (S)-(Tetrahydrofuran-2-yl)methyl methanesulfonate

[1023]

[1024] Use N 2 (S)-(Tetrahydrofuran-2-yl)methanol (2.00 g, 19.6 mmol, BLD Pharmatech BD48351) and N-ethyl-N-isopropylpropan-2-amine (5.12 mL, 29.4 mmol) were purged in CH 2 Cl 2(15 mL) and cooled to 0 °C, followed by the dropwise addition of methanesulfonyl chloride (1.97 mL, 25.5 mmol). The reaction mixture was allowed to warm to rt and stirred for 30 min. The mixture was treated with saturated NaHCO 3 The mixture was quenched with aqueous solution, the organic layer was taken out and washed with CH 2 Cl 2 The aqueous l...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: each is a single bond or a double bond, at least one of which It is a double bond; U is CR 3 or N; X is CR 4 , N, NR 4 , S or O; Y is CR 5 , N or NR 5 ; Z is CR 6 , N, NR 6 , S or O; R 1 It's Cy 1 or L-Cy 1 ; L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl; Cy 1 It is C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1A Substituent substitution; Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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)2R b11 NR c11 S(O)(=NR e11 )R b11 NR c11 S(O)2NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 、S(O)2NR c11 R d11 、OS(O)(=NR e11 )R b11 and OS(O)2R b11 , where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution; Each R a11 , R c11 and R d11 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a11 , R c11 and R d11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution; or any R attached to the same N atom c11 and R d11 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution; Each R b11 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b11 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1B Substituent substitution; Each R e11 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; Each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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)2R b12 NR c12 S(O)(=NR e12 )R b12 NR c12 S(O)2NR c12 R d12 、S(O)R b12 、S(O)NR c12 R d12 、S(O)2R b12 、S(O)2NR c12 R d12 、OS(O)(=NR e12 )R b12 and OS(O)2R b12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution; Each R a12 , R c12 and R d12 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a12 , R c12 and R d12 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution; or any R attached to the same N atom c12 and R d12 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution; Each R b12 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b12 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 1C Substituent substitution; Each R e12 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; Each R 1C are 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, 5-6 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, NO2, 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)2R b13 NR c13 S(O)(=NR e13 )R b13 NR c13 S(O)2NR c13 R d13 、S(O)R b13 、S(O)NR c13 R d13 、S(O)2R b13 、S(O)2NR c13 R d13 、OS(O)(=NR e13 )R b13 and OS(O)2R b13 , where R 1C The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution; Each R a13 , R c13 and R d13 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a13 , R c13 and R d13 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution; or any R attached to the same N atom c13 and R d13 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 1D Substituent substitution; Each R b13 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b13 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1D Substituent substitution; Each R e13 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; Each R 1D are 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, 5-6 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, NO2, 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)2R b14 NR c14 S(O)(=NR e14 )R b14 NR c14 S(O)2NR c14 R d14 、S(O)R b14 、S(O)NR c14 R d14 、S(O)2R b14 、S(O)2NR c14 R d14 、OS(O)(=NR e14 )R b14 and OS(O)2R b14 , where R 1D The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a14 , R c14 and R d14 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a14 , R c14 and R d14 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c14 and R d14 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b14 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b14 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e14 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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 S(O)R b2 NR c2 S(O)NR c2 R d2 NR c2 S(O)2R b2 NR c2 S(O)(=NR e2 )R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 、S(O)2NR c2 R d2 、OS(O)(=NR e2 )R b2 and OS(O)2R b2 , where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution; Each R a2 , R c2 and R d2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a2 , R c2 and R d2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution; or any R attached to the same N atom c2 and R d2 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution; Each R b2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 2A Substituent substitution; Each R e2 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 2A Selected from halogen, 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, NO2, 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)2R b21 NR c21 S(O)(=NR e21 )R b21 NR c21 S(O)2NR c21 R d21 、S(O)R b21 、S(O)NR c21 R d21 、S(O)2R b21 、S(O)2NR c21 R d21 、OS(O)(=NR e21 )R b21 and OS(O)2R b21 , where R 2A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a21 , R c21 and R d21 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a21 , R c21 and R d21 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c21 and R d21 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b21 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b21 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e21 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R 3 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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 S(O)NR c3 R d3 NR c3 S(O)2R b3 NR c3 S(O)(=NR e3 )R b3 NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 、S(O)2NR c3 R d3 、OS(O)(=NR e3 )R b3 and OS(O)2R b3 , where R 3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution; Each R a3 , R c3 and R d3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a3 , R c3 and R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution; or any R attached to the same N atom c3 and R d3 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution; Each R b3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 3A Substituent substitution; Each R e3 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 3A Selected from halogen, 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, NO2, 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)2R b31 NR c31 S(O)(=NR e31 )R b31 NR c31 S(O)2NR c31 R d31 、S(O)R b31 、S(O)NR c31 R d31 、S(O)2R b31 、S(O)2NR c31 R d31 、OS(O)(=NR e31 )R b31 and OS(O)2R b31 , where R 3A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a31 , R c31 and R d31 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a31 , R c31 and R d31 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c31 and R d31 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b31 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b31 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e31 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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 S(O)NR c4 R d4 NR c4 S(O)2R b4 NR c4 S(O)(=NR e4 )R b4 NR c4 S(O)2NR c4 R d4 、S(O)R b4 、S(O)NR c4 R d4 、S(O)2R b4 、S(O)2NR c4 R d4 、OS(O)(=NR e4 )R b4 and OS(O)2R b4 , where R 4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution; Each R a4 , R c4 and R d4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a4 , R c4 and R d4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution; or any R attached to the same N atom c4 and R d4 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution; Each R b4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b4 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 4A Substituent substitution; Each R e4 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 4A Selected from halogen, 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, NO2, 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)2R b41 NR c41 S(O)(=NR e41 )R b41 NR c41 S(O)2NR c41 R d41 、S(O)R b41 、S(O)NR c41 R d41 、S(O)2R b41 、S(O)2NR c41 R d41 、OS(O)(=NR e41 )R b41 and OS(O)2R b41 , where R 4A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a41 , R c41 and R d41 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a41 , R c41 and R d41 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c41 and R d41 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b41 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b41 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e41 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 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 c5 R d5 、OS(O)(=NR e5 )R b5 and OS(O)2R b5 , where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution; Each R a5 , R c5 and R d5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a5 , R c5 and R d5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution; or any R attached to the same N atom c5 and R d5 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution; Each R b5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 5A Substituent substitution; Each R e5 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 5A Selected from halogen, 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, NO2, 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)2R b51 NR c51 S(O)(=NR e51 )R b51 NR c51 S(O)2NR c51 R d51 、S(O)R b51 、S(O)NR c51 R d51 、S(O)2R b51 、S(O)2NR c51 R d51 、OS(O)(=NR e51 )R b51 and OS(O)2R b51 , where R 5A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a51 , R c51 and R d51 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a51 , R c51 and R d51 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c51 and R d51 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b51 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b51 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e51 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R 6 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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 NR c6 S(O)2R b6 NR c6 S(O)(=NR e6 )R b6 NR c6 S(O)2NR c6 R d6 、S(O)R b6 、S(O)NR c6 R d6 、S(O)2R b6 、S(O)2NR c6 R d6 、OS(O)(=NR e6 )R b6 and OS(O)2R b6 , where R 6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution; Each R a6 , R c6 and R d6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a6 , R c6 and R d6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution; or any R attached to the same N atom c6 and R d6 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution; Each R b6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 6A Substituent substitution; Each R e6 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; R 6A Selected from halogen, 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, NO2, 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)2R b61 NR c61 S(O)(=NR e61 )R b61 NR c61 S(O)2NR c61 R d61 、S(O)R b61 、S(O)NR c61 R d61 、S(O)2R b61 、S(O)2NR c61 R d61 、OS(O)(=NR e61 )R b61 and OS(O)2R b61 , where R 6A The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a61 , R c61 and R d61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a61 , R c61 and R d61 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c61 and R d61 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b61 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e61 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R c7 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R c7 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl - optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7A Substituent substitution; Each R 7A are independently selected from 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, 5-15 membered heteroaryl, 4-15 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2, 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)2R b71 NR c71 S(O)(=NR e71 )R b71 NR c71 S(O)2NR c71 R d71 、S(O)R b71 、S(O)NR c71 R d71 、S(O)2R b71 、S(O)2NR c71 R d71 、OS(O)(=NR e71 )R b71 and OS(O)2R b71 , where R 7A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution; Each R a71 , R c71 and R d71 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a71 , R c71 and R d71 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution; or any R attached to the same N atom c71 and R d71 Together with the N atom to which they are attached, they form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution; Each R b71 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b71 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R 7B Substituent substitution; Each R e71 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; Each R 7B are 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, 5-6 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, NO2, 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)2R b72 NR c72 S(O)(=NR e72 )R b72 NR c72 S(O)2NR c72 R d72 、S(O)R b72 、S(O)NR c72 R d72 、S(O)2R b72 、S(O)2NR c72 R d72 、OS(O)(=NR e72 )R b72 and OS(O)2R b72 , where R 7B The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R a72 , R c72 and R d72 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R a72 , R c72 and R d72 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; or any R attached to the same N atom c72 and R d72 Together with the N atom to which they are attached, they form a 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R b72 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, where R b72 The C 1-6 Alkyl, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R M Substituent substitution; Each R e72 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-; and Each R M independently selected from H, OH, halogen, oxo, CN, C(O)OH, NH2, NO2, SF5, 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, 5-6 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-.

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

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

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

5. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, wherein X is CH, CCH3, N, -NCH2CH3, S or O.

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

7. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

8. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 is selected from H, methyl, ethyl, difluoromethyl and pyrazolyl, wherein R 5 The methyl, ethyl and pyrazolyl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

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

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

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

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 6 H, halogen, 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 (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein 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 (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution.

17. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 16, wherein each R 6A Independently selected from NR c61 R d61 , where each R c61 and R d61 Independently selected from H and C 1-6 alkyl.

18. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- or (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 The alkyl group is optionally replaced by NR c61 R d61 Substituted, wherein R c61 and R d61 Each independently selected from H and C 1-6 alkyl.

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

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Z is CH, NCH3, NCH2CH2N(CH3)2, NCH2-cyclopropyl, NCH2-tetrahydrofuranyl or S.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 1 It's Cy 1 .

22. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 It is C 3-7 Cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

23. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

24. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 is piperazinyl, which is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

25. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 is piperazinyl, the piperazinyl being substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution.

26. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 yes:

27. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 yes:

28. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

29. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each R 1A are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

30. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each R 1A Independently selected from C 1-6 Alkyl and C 1-6 A haloalkyl group, wherein R 1A The C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

31. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution.

32. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Cy 1 yes:

33. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2 and OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

34. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B Independently selected from C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

35. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B Independently selected from C 1-6 Alkyl, 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 and OR a12 , where R 1B The phenyl group, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

36. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution.

37. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, CN and OR a12 , where R 1B The C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituents are substituted; and Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

38. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B Independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl, pyridyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl and pyridyl are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 R 1C Substituent substitution; Each R a12 Independently selected from H and C 1-6 Alkyl; and Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

39. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B are independently selected from methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl, pyridyl, CN and methoxy, wherein R 1B Each of the methyl, isopropyl, cyclobutyl, cyclohexyl, phenyl and pyridyl radicals of 1C Substituent substitution.

40. A compound as described in any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a13 ;and Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

41. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 1B are 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, trifluoromethylpyridyl, (trifluoromethyl)(fluoro)pyridyl, trifluoromethoxypyridyl, CN and methoxy.

42. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

43. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

44. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution.

45. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, C 1-6 Alkyl and C 3-7 Cycloalkyl.

46. ​​A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, methyl and cyclopropyl.

47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: each is a single bond or a double bond, at least one of which It is a double bond; 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 It's Cy 1 or L-Cy 1 ; L is NR c7 , O, C 1-3 Alkyl, C 2-3 Alkenyl or C 2-3 Alkynyl; Cy 1 It is C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl, wherein the C 3-10 Cycloalkyl, 5-15 membered heteroaryl or 4-15 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R 1A are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R 1B are 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN, NO2 and OR a12 , where R 1B The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution; Each R 1C are 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, 5-6 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 and OR a13 ; Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 2A Substituent substitution; Each R 2A independently selected from halogen, 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- and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-; R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl; R 5 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN; R 6 H, halogen, 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 (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein 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 (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution; Each R 6A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and NR c61 R d61 ; Each R c61 and R d61 Independently selected from H and C 1-6 Alkyl; and R c7 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, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.

48. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: 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 It's Cy 1 ; Cy 1 It is C 3-7 Cycloalkyl, 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R 1A are independently selected from halo, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, where R 1A The C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R 1B Independently selected from C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 Alkyl-, CN and OR a12 , where R 1B The C 1-6 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl-, C 3-10 Cycloalkyl-C 1-6 Alkyl-, (5-10 membered heteroaryl)-C 1-6 Alkyl- and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-each optionally replaced by 1, 2, 3 or 4 independently selected R 1C Substituent substitution; Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ; Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl; Each R a13 Independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, wherein R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 2A Substituent substitution; R 4 Is H or C 1-6 alkyl; R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, wherein R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituent substitution; Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN; R 6 H, halogen, 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 (4-7 membered heterocycloalkyl)-C 1-6 Alkyl-, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl- and (4-7 membered heterocycloalkyl)-C 1-6 Alkyl- each optionally substituted by NR c61 R d61 replace; and Each R c61 and R d61 Independently selected from H and C 1-6 alkyl.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: 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 It's Cy 1 ; Cy 1 is a 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 independently selected R 1A Substituent substitution; Each R 1A Independently selected from C 1-6 Alkyl, the C 1-6 The alkyl groups are each optionally substituted with 1, 2, 3 or 4 independently selected R 1B Substituent substitution; Each R 1B Independently selected from C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and OR a12 , where R 1B The C 1-6 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 1C Substituent substitution; Each R 1C independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN and OR a13 ; Each R a12 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl; Each R a13 Independently H, C 1-6 Alkyl or C 1-6 Haloalkyl; R 5 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 5-6 membered heteroaryl, wherein R 5 The C 1-6 The alkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 independently selected R 5A Substituents are substituted; and Each R 5A independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and CN.

50. The compound of claim 1, wherein the compound of formula I is a compound of formula II: or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1, wherein the compound of formula I is a compound of formula III: or a pharmaceutically acceptable salt thereof.

52. The compound of claim 1, wherein the compound of formula I is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1, wherein the compound of formula I is a compound of formula V: or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1, wherein the compound of formula I is a compound of formula VI: or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1, wherein the compound of formula I is a compound of formula VII: or a pharmaceutically acceptable salt thereof.

56. The compound of claim 1, wherein the compound of formula I is a compound of formula VIII: or a pharmaceutically acceptable salt thereof.

57. The compound of claim 1, wherein the compound of formula I is a compound of formula IX: or a pharmaceutically acceptable salt thereof.

58. The compound of claim 1, selected from the group consisting of: 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)propionitrile; 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.

59. The compound of claim 1, selected from the group consisting of: 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]purin-1-yl)-N,N-dimethylethan-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.

60. The compound of claim 1, selected from the group consisting of: 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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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-dimethylethan-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.

61. A compound, which 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)-N,N-dimethylethan-1-amine, or a pharmaceutically acceptable salt thereof.

62. A compound, which 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, which 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-dimethylethan-1-amine, or a pharmaceutically acceptable salt thereof.

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

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

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

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

68. The method of claim 67, wherein the cancer is non-small cell lung cancer, bladder urothelial carcinoma, esophageal cancer, gastric adenocarcinoma, mesothelioma, hepatocellular carcinoma, diffuse large B-cell lymphoma, renal clear cell carcinoma, head and neck squamous cell carcinoma, bile duct carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.

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

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