Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors

Abstract

To provide inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.SOLUTION: A compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided. The compound inhibits cyclin-dependent kinase 2 (CDK2), and is useful in treating cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 886,735, filed August 14, 2019, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on August 12, 2020, is named 20443-0628WO1_SEQ.txt and is 16 kilobytes in size.

[0003] Technical Field The present application relates to imidazolylpyrimidinylamine compounds that inhibit cyclin-dependent kinase 2 (CDK2) and are useful for treating cancer. [Background technology]

[0004] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. When CDKs heterodimerize with regulatory subunits known as cyclins, they become fully activated and regulate key cellular processes, including cell cycle progression and cell division (Morgan, DO, Annu Rev Cell Dev Biol, 1997.13:261-91). Uncontrolled proliferation is a hallmark of cancer cells. Deregulation of CDK activity is associated with aberrant cell cycle regulation and is detected in nearly all forms of human cancer (Sherr, CJ, Science, 1996.274(5293):1672-7).

[0005] CDK2 is of particular interest because deregulation of CDK2 activity frequently occurs in various human cancers. CDK2 plays a key role in promoting the G1 / S transition and S-phase progression. In complex with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, and pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and transition from G1 to S phase (Henley, SA and FA Dick, Cell Div, 2012, 7(1):p.10). This results in activation of CDK2 / cyclin A, which phosphorylates endogenous substrates that enable DNA synthesis, replication, and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000, 12(6):676-84). The CDK2 pathway has been reported to influence tumorigenesis primarily through amplification and / or overexpression of CCNE1 and mutations that inactivate endogenous CDK2 inhibitors (e.g., p27) (Xu, X., et al., Biochemistry, 1999.38(27):8713-22).

[0006] Increased CCNE1 copy number and overexpression have been identified in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcomes in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002. 347(20): 1566-75; Nakayama, N., et al., Cancer, 2010. 116(11): 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017. 23(7): 1862-1874; Rosen, DG, et al., Cancer, 2006. 106(9): 1925-32). Amplification and / or overexpression of CCNE1 has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011. 108(9):3761-6; Herrera-Abreu, MT, et al., Cancer Res, 2016. 76(8):2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and tumor growth inhibition (Chen, YN, et al., Proc Natl Acad Sci USA, 1999. 96(8):4325-9; Mendoza, N., et al., Cancer Res, 2003. 63(5):1020-4). Inhibition of CDK2 has also been reported to restore sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in preclinical models (Scaltriti, supra).

[0007] These data provide evidence for considering CDK2 as a potential target for new drug development in cancers associated with deregulated CDK2 activity. Over the past decade, there has been growing interest in the development of CDK-selective inhibitors. Despite significant efforts, no approved drugs targeting CDK2 have been approved to date (Cicenas, J., et al., Cancers (Basel), 2014.6(4):p.2224-42). Thus, there remains a need to discover CDK inhibitors with novel activity profiles, particularly those targeting CDK2. The present application addresses this and other needs. Summary of the Invention

[0008] The present invention relates in particular to compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0009] The present invention further provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] The present invention further provides a method of inhibiting CDK2, comprising contacting CDK2 with a compound described herein, or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides a method of inhibiting CDK2 in a patient, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0013] The present invention further provides a method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising administering to the human subject a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the human subject has previously been determined to: (i) (a) have a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) have a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and / or deletions, (ii) (a) have an amplification of the cyclin E1 (CCNE1) gene, and / or (b) have an expression level of CCNE1 in a biological sample obtained from the human subject that is greater than a control expression level of CCNE1.

[0014] The present invention further provides a method for treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising: (i) identifying, in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions; (ii) identifying, in a biological sample obtained from the human subject, (a) amplification of the cyclin E1 (CCNE1) gene, and / or (b) an expression level of CCNE1 that is higher than a control expression level of CCNE1; and (iii) administering to the human subject a compound described herein, or a pharmaceutically acceptable salt thereof.

[0015] The present invention also provides a method for assessing the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) to a compound described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) administering a compound or salt to a human subject, wherein the human subject has previously been determined to have amplification of the cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 higher than the control expression level of CCNE1; and (b) measuring the level of retinoblastoma (Rb) protein phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the subject after administration of step (a), wherein a decrease in the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the human subject is responsive to the compound or salt.

[0016] The present invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0017] The present invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, to prepare a medicament for use in any of the methods described herein. [Brief explanation of the drawings]

[0018] [Figure 1] Characterization of ovarian and endometrial cell lines. A: Cell lines used in the study included four cell lines with CCNE1 amplification and three cell lines without CCNE1 amplification. CCNE1 amplification copy numbers are indicated. B: CCNE1 expression was determined by Western blot in the indicated cell lines. The blot shows that cell lines with CCNE1 gain of function by copy number (CN>2) have higher levels of CCNE1 protein compared to cell lines with neutral or loss of function copies of the gene (CN≦2). GAPDH was detected as a loading control. No Amp, non-amplified; Amp, amplified. [Figure 2A] siRNA-mediated CDK2 knockdown inhibits proliferation in CCNE1-amplified cell lines. 72 hours after transfection with either scrambled siRNA ("Ctl") or CDK2 siRNA, CCNE1-amplified Fu-ov1 (top) and KLE (bottom) cells were harvested and subjected to cell cycle analysis. Cell cycle phase distribution was assessed by FACS. Representative images of three separate experiments are shown. [Figure 2B] siRNA-mediated CDK2 knockdown inhibits proliferation in CCNE1-amplified cell lines. After transfection with CDK2 siRNA, CDK2 knockdown was confirmed by Western blot analysis. GAPDH was used as a loading control. [Figure 3A] CDK2 knockdown does not inhibit the growth of CCNE1-non-Amp strains. Seventy-two hours after transfection with Ctl siRNA and CDK2 siRNA, CCNE1-non-amplified COV504 and Igrov1 cells were harvested and subjected to cell cycle analysis. Cell cycle phase distribution was assessed by FACS. Representative images from three separate experiments are shown. [Figure 3B] CDK2 knockdown does not inhibit the growth of CCNE1 non-Amp strains. CDK2 knockdown was confirmed by Western blot analysis after transfection with CDK2 siRNA. GAPDH was used as a loading control. [Figure 4] CDK2 knockdown by siRNA inhibits proliferation of CCNE1-amplified but not CCNE1-non-amplified human cancer cell lines. Percentage of cells in S phase 3 days after transfection of CDK2 siRNA versus Ctl siRNA. Cell cycle phase distribution was assessed by FACS. Means represent three independent experiments in four CCNE1Amp cell lines and three non-Amp lines. [Figure 5]Palbociclib treatment induces a dose-dependent inhibition of proliferation in CCNE1-non-amplified cell lines, but not in CCNE1-amplified cell lines. Cell cycle analysis of CCNE1-non-amplified cell line COV504 (top) and CCNE1-amplified OVCAR3 cells (bottom) after 16 hours of palbociclib treatment. Cell cycle phase distribution was assessed by FACS. [Figure 6] Palbociclib treatment selectively inhibits proliferation of CCNE1-non-amplified cancer cell lines. Percentage of cells in S phase after 16 hours of palbociclib at the indicated doses relative to DMSO. [Figure 7A] CDK2 knockdown by siRNA blocks RB phosphorylation at S780 in CCNE1-amplified but not non-amplified ovarian cells. Four CCNE1Amp cell lines, COV318, Fu-OV1, OVCAR3, and KLE cells, were transfected with CDK2 siRNA for 72 hours. [Figure 7B] CDK2 knockdown by siRNA blocks RB phosphorylation at S780 in CCNE1-amplified but not non-amplified ovarian cells. Three CCNE1-non-Amp cell lines, COV504, OV56, and Igrov1, were transfected with CDK2 siRNA for 72 hours. Total protein was extracted from CDK2 siRNA- or Ctl siRNA-transfected cells and subjected to Western blotting. GAPDH was used as a loading control. [Figure 8A] Palbociclib blocks RB phosphorylation at S780 in CCNE1 non-amplified but not amplified ovarian cells. CCNE1AmpOVCAR3 and COV318 cells were treated with palbociclib at various concentrations as indicated for 1 or 15 hours. [Figure 8B]Palbociclib blocks RB phosphorylation at S780 in CCNE1-non-amplified ovarian cells, but not in amplified ovarian cells. CCNE1-non-AmpCOV504 and OV56 were treated with various concentrations of palbociclib as indicated for 1 hour or 15 hours. Total protein was extracted from these palbociclib- or DMSO-treated cells and subjected to Western blotting. p-RB, phosphorylated retinoblastoma protein. GAPDH was used as a loading control. [Figure 9A] Degradation of CDK2 by dTAG reduces RB phosphorylation at S780. Chemical structure of dTAG. [Figure 9B] Degradation of CDK2 by dTAG reduces RB phosphorylation at S780. Degradation of CDK2-FKBP12(F36V) by 14 hours of CDK2-dTAG treatment inhibited RB phosphorylation at S780 in CDK2 knockout OVCAR3 cells (right, Cas9+, CDK2-FKBP12(F36V)-HA+, CDK2-gRNA) but not in OVCAR3 cells with endogenous CDK2 (left, Cas9+, CDK2-FKBP12(F36V)-HA+, Ctl-gRNA). [Figure 10] p-RB S780 HTRF cell assay for identification of CDK2 inhibitors. A: IC50 in CDK2 biochemical kinase activity assay. B: Concentration-response analysis of reference compounds tested in p-RB S780 HTRF cell assay. HTRF, homogeneous time-resolved fluorescence. IC50 from HTRF cell assay correlates with IC50 in CDK2 enzymatic assay. [Figure 11] Bioinformatics analysis of the CCLE dataset reveals that sensitivity to CDK2 inhibition in CCNE1-amplified cells depends on functional p16. p16 status in CDK2-sensitive versus -insensitive cell lines is shown. CCLE: Broad Institute Cancer Cell Line Encyclopedia (hereafter referred to as Barretina). [Figure 12]CCNE1-amplified cells with impaired p16 function do not respond to CDK2 inhibition. A: Western blot analysis of p16 in three gastric cell lines with CCNE1Amp. B: Percentage of cells in S phase 3 days after transfection of CDK2 siRNA versus Ctl siRNA. Cell cycle phase distribution was assessed by FACS. [Figure 13] p16 knockdown by siRNA abolishes CDK2 inhibition-induced cell cycle arrest in CCNE1-amplified cells. The percentage of S-phase cells after p16 knockdown and CDK2 inhibitor treatment was normalized to that of Ctl siRNA and DMSO-treated cells. CCNE1-amplified COV318 cells were transfected with either Ctl siRNA or p16 siRNA. 72 hours after transfection, cells were treated with 100 nM of the CDK2 inhibitor Compound A. 16 hours after treatment, cells were harvested and subjected to cell cycle analysis. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present application relates inter alia to compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; ring moiety A is a 4- to 14-membered heterocycloalkyl, and ring moiety A is attached to the —NH— group of formula (I) at a ring member of the saturated or partially saturated ring of the 4- to 14-membered heterocycloalkyl; R 1 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 2 , R 3 , and R 4 is defined as shown in group (a), group (b), or group (c), Group (a): R 2 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-4 Alkoxy, C 1-4 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 3 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)OR a4 , C(=NR e4 )R b4 , C(=NR e4 )NR c4 R d4 , S(O)2R b4 , and S(O)NR c4 R d4 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A is optionally substituted by a substituent; Group (b): R 2 H, D, Halo, NO2, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 NR c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )R b2 , N.R. c2 S(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)(=NR e2 )R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 Rd2 , S(O)2R b2 , S(O)NR c2 R d2 , OS(O)(=NR e2 )R b2 , OS(O)2R b2 , S(O)(=NR e2 )R b2 , SF5, P(O)R f2 R g2 , OP(O)(OR h2 )(OR i2 ), P(O)(OR h2 )(OR i2 ), and BR j2 R k2 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2A is optionally substituted by a substituent; R 3 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 4 is H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; Group (c): R 2 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; R 3 and R 4 are 1, 2, 3, or 4 independently selected R's together with the atoms to which they are attached. 4A forming a 5- to 7-membered heterocycloalkyl ring optionally substituted by substituents, Each R a2 , R c2 , and R d2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2A optionally substituted with substituents, or any R bonded to the same N atom c2 and R d2 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 2A forming a 4- to 10-membered heterocycloalkyl group optionally substituted with substituents, Each R b2 are independently selected from 1, 2, 3, or 4 independently selected R 2A C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R e2 are independently H, OH, CN, and C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R f2 and R g2 are independently H, 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R h2 and R i2 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C1-4 alkyl, Each R j2 and R k2 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j2 and R k2 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 2A are independently D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a21 , S.R. 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 , N.R. c21 R d21 , N.R. c21 NR c21 R d21 , N.R. c21 C(O)R b21 , N.R. c21 C(O)OR a21 , N.R. c21C(O)NR c21 R d21 , C(=NR e21 )R b21 , C(=NR e21 )NR c21 R d21 , N.R. c21 C(=NR e21 )NR c21 R d21 , N.R. c21 C(=NR e21 )R b21 , N.R. c21 S(O)NR c21 R d21 , N.R. c21 S(O)R b21 , N.R. c21 S(O)2R b21 , N.R. c21 S(O)(=NR e21 )R b21 , N.R. c21 S(O)NR c21 R d21 , S(O)R b21 , S(O)NR c21 R d21 , S(O)2R b21 , S(O)NR c21 R d21 , OS(O)(=NR e21 )R b21 , OS(O)2R b21 , S(O)(=NR e21 )R b21 , SF5, P(O)R f21 R g21 , OP(O)(OR h21 )(OR i21 ), P(O)(OR h21 )(OR i21 ), and BR j21 R k21 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2B optionally substituted with substituents, Each R a21 , R c21 , and R d21 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2B optionally substituted with substituents, or any R bonded to the same N atom c21 and R d21 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 2Bforming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b21 are independently selected from 1, 2, 3, or 4 independently selected R 2B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R e21 are independently H, OH, CN, and 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R f21 and R g21 are independently H, 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 3-10Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R h21 and R i21 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R j21 and R k21 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j21 and R k21 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 2B are independently D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a22 , S.R. a22 , NHOR a22 , C(O)R b22 , C(O)NR c22 R d22 , C(O)NR c22 (OR a22 ), C(O)OR a22 ,OC(O)R b22 , OC(O)NR c22 R d22 , N.R. c22 R d22 , N.R. c22 NR c22 R d22 , N.R. c22 C(O)R b22 , N.R. c22 C(O)OR a22 , N.R. c22 C(O)NR c22 R d22 , C(=NR e22 )R b22 , C(=NR e22 )NR c22 R d22 , N.R. c22 C(=NR e22 )NR c22 R d22 , N.R. c22 C(=NR e22 )R b22 , N.R. c22 S(O)NR c22 R d22 , N.R. c22 S(O)R b22 , N.R. c22 S(O)2R b22 , N.R. c22 S(O)(=NR e22 )R b22 , N.R. c22 S(O)NR c22 R d22 , S(O)R b22 , S(O)NR c22 R d22, S(O)2R b22 , S(O)NR c22 R d22 , OS(O)(=NR e22 )R b22 , OS(O)2R b22 , S(O)(=NR e22 )R b22 , SF5, P(O)R f22 R g22 , OP(O)(OR h22 )(OR i22 ), P(O)(OR h22 )(OR i22 ), and BR j22 R k22 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2C optionally substituted with substituents, Each R a22 , R c22 , and R d22 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 2C optionally substituted with substituents, or any R bonded to the same N atom c22 and R d22 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 2C forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b22 are independently selected from 1, 2, 3, or 4 independently selected R 2C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e22 are independently H, OH, CN, and 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 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f22 and R g22 are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h22 and R i22 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j22 and R k22 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j22 and R k22 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 2C are independently D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a23 , S.R. a23 , NHOR a23 , C(O)R b23 , C(O)NR c23 R d23 , C(O)NR c23 (OR a23 ), C(O)OR a23 ,OC(O)R b23 , OC(O)NR c23 R d23 , N.R. c23 R d23 , N.R. c23 NR c23 R d23 , N.R. c23 C(O)R b23 , N.R. c23 C(O)OR a23 , N.R. c23 C(O)NR c23 R d23 , C(=NR e23 )R b23 , C(=NR e23 )NR c23 R d23 , N.R. c23 C(=NR e23)NR c23 R d23 , N.R. c23 C(=NR e23 )R b23 , N.R. c23 S(O)NR c23 R d23 , N.R. c23 S(O)R b23 , N.R. c23 S(O)2R b23 , N.R. c23 S(O)(=NR e23 )R b23 , N.R. c23 S(O)NR c23 R d23 , S(O)R b23 , S(O)NR c23 R d23 , S(O)2R b23 , S(O)NR c23 R d23 , OS(O)(=NR e23 )R b23 , OS(O)2R b23 , S(O)(=NR e23 )R b23 , SF5, P(O)R f23 R g23 , OP(O)(OR h23 )(OR i23 ), P(O)(OR h23 )(OR i23 ), and BR j23 R k23 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, Each R a23 , R c23 , and R d23 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, or any R bonded to the same N atom c23 and R d23 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R G forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b23 are independently selected from 1, 2, 3, or 4 independently selected R G C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e23 are independently H, OH, CN, and 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f23 and R g23 are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h23 and R i23 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j23 and R k23 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j23 and R k23 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R a4 , R c4 , and R d4 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A optionally substituted with substituents, or any R bonded to the same N atom c4 and R d4 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 4A forming a 4- to 10-membered heterocycloalkyl group optionally substituted with substituents, Each R b4 are independently selected from 1, 2, 3, or 4 independently selected R 4A C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R e4 are independently H, OH, CN, and 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R 4A are independently D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. 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 , N.R. c41 R d41 , N.R. c41 NR c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , C(=NR e41 )R b41 , C(=NR e41 )NR c41 R d41 , N.R. c41 C(=NR e41 )NRc41 R d41 , N.R. c41 C(=NR e41 )R b41 , N.R. c41 S(O)NR c41 R d41 , N.R. c41 S(O)R b41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)(=NR e41 )R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)R b41 , S(O)NR c41 R d41 , S(O)2R b41 , S(O)NR c41 R d41 , OS(O)(=NR e41 )R b41 , OS(O)2R b41 , S(O)(=NR e41 )R b41 , SF5, P(O)R f41 R g41 , OP(O)(OR h41 )(OR i41 ), P(O)(OR h41 )(OR i41 ), and BR j41 R k41 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4B optionally substituted with substituents, or any R bonded to the same N atom c41 and R d41 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 4B forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b41 are independently selected from 1, 2, 3, or 4 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R e41 are independently H, OH, CN, and 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R f41 and R g41 are independently H, 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R h41and R i41 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R j41 and R k41 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j41 and R k41 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 4B are independently D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , S.R. a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 Rd42 、C(O)NR c42 (OR a42 )、C(O)OR a42 、OC(O)R b42 、OC(O)NR c42 R d42 、NR c42 R d42 、NR c42 NR c42 R d42 、NR c42 C(O)R b42 、NR c42 C(O)OR a42 、NR c42 C(O)NR c42 R d42 、C(=NR e42 )R b42 、C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )NR c42 R d42 、NR c42 C(=NR e42 )R b42 、NR c42 S(O)NR c42 R d42 、NR c42 S(O)R b42 、NR c42 S(O)2R b42 、NR c42 S(O)(=NR e42 )R b42 、NR c42 S(O)2NR c42 R d42 、S(O)R b42 、S(O)NR c42 R d42 、S(O)2R b42 、S(O)2NR c42 R d42 、OS(O)(=NR e42 )R b42 、OS(O)2R b42 、S(O)(=NR e42 )R b42 、SF5、P(O)R f42 R g42 、OP(O)(OR h42 )(ORi42 ), P(O)(OR h42 )(OR i42 ), and BR j42 R k42 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4C optionally substituted with substituents, or any R bonded to the same N atom c42 and R d42 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R 4C forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b42 are independently selected from 1, 2, 3, or 4 independently selected R 4C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e42 are independently H, OH, CN, and 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f42 and R g42are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h42 and R i42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j42 and R k42 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j42 and R k42 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 4C are independently D, halo, CN, NO2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a43 , S.R. a43 , NHOR a43 , C(O)R b43 , C(O)NR c43 R d43 , C(O)NR c43 (OR a43 ), C(O)OR a43 ,OC(O)R b43 , OC(O)NR c43 R d43 , N.R. c43 R d43 , N.R. c43 NR c43 R d43 , N.R. c43 C(O)R b43 , N.R. c43 C(O)OR a43 , N.R. c43 C(O)NR c43 R d43 , C(=NR e43 )R b43 , C(=NR e43 )NR c43 R d43 , N.R. c43 C(=NR e43 )NR c43 R d43 , N.R. c43 C(=NR e43 )R b43 , N.R. c43 S(O)NR c43 R d43 , N.R. c43 S(O)R b43 , N.R. c43 S(O)2R b43 , N.R. c43 S(O)(=NR e43)R b43 , N.R. c43 S(O)NR c43 R d43 , S(O)R b43 , S(O)NR c43 R d43 , S(O)2R b43 , S(O)NR c43 R d43 , OS(O)(=NR e43 )R b43 , OS(O)2R b43 , S(O)(=NR e43 )R b43 , SF5, P(O)R f43 R g43 , OP(O)(OR h43 )(OR i43 ), P(O)(OR h43 )(OR i43 ), and BR j43 R k43 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, Each R a43 , R c43 , and R d43 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, or any R bonded to the same N atom c43 and R d43 together with the N atoms to which they are attached, may be one, two, three, or four independently selected R G forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R b43 are independently selected from 1, 2, 3, or 4 independently selected R G C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e43 are independently H, OH, CN, and C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f43 and R g43 are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h43 and R i43 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j43 and R k43 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j43 and R k43 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; R Z is R 5 and NR 5 R 5Z is selected from R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R5A is optionally substituted by a substituent; R 5Z is H, C 1-6 Alkyl, and C 1-6 haloalkyl; Or, alternatively, R 5 and R 5Z together with the nitrogen atom to which they are attached, may be one, two, three, or four independently selected R 5A forming a 4- to 7-membered heterocycloalkyl ring optionally substituted with substituents, Each R 5A are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. 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 , N.R. c51 R d51 , N.R. c51 NR c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 C(O)OR a51 , N.R. c51 C(O)NR c51 R d51 , C(=NR e51)R b51 , C(=NR e51 )NR c51 R d51 , N.R. c51 C(=NR e51 )NR c51 R d51 , N.R. c51 C(=NR e51 )R b51 , N.R. c51 S(O)NR c51 R d51 , N.R. c51 S(O)R b51 , N.R. c51 S(O)2R b51 , N.R. c51 S(O)(=NR e51 )R b51 , N.R. c51 S(O)NR c51 R d51 , S(O)R b51 , S(O)NR c51 R d51 , S(O)2R b51 , S(O)NR c51 R d51 , OS(O)(=NR e51 )R b51 , OS(O)2R b51 , S(O)(=NR e51 )R b51 , SF5, P(O)R f51 R g51 , OP(O)(OR h51 )(OR i51 ), P(O)(OR h51 )(OR i51 ), and BR j51 R k51 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5B optionally substituted with substituents, Each R a51 , R c51 , and R d51 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5B optionally substituted with substituents, or any R bonded to the same N atom c51 and R d51 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R 5B optionally substituted with substituents, Each R b51are independently selected from 1, 2, 3, or 4 independently selected R 5B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R e51 are independently H, OH, CN, and 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 3-7 Cycloalkyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R f51 and R g51 are independently H, 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 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R h51 and R i51 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R j51 and R k51 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j51 and R k51 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5B are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a52 , S.R. a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)NR c52 (OR a52 ), C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , N.R. c52 R d52 , N.R. c52 NR c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , C(=NR e52 )R b52 , C(=NR e52 )NR c52 R d52 , N.R. c52 C(=NR e52 )NR c52 R d52 , N.R. c52 C(=NR e52 )R b52 , N.R. c52 S(O)NR c52 R d52 , N.R. c52 S(O)R b52 , N.R. c52 S(O)2R b52 , N.R. c52 S(O)(=NR e52 )R b52 , N.R. c52 S(O)NR c52 R d52 , S(O)R b52 , S(O)NR c52 R d52 , S(O)2R b52 , S(O)NR c52 R d52, OS(O)(=NR e52 )R b52 , OS(O)2R b52 , S(O)(=NR e52 )R b52 , SF5, P(O)R f52 R g52 , OP(O)(OR h52 )(OR i52 ), P(O)(OR h52 )(OR i52 ), and BR j52 R k52 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5C optionally substituted with substituents, Each R a52 , R c52 , and R d52 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5C optionally substituted with substituents, or any R bonded to the same N atom c52 and R d52 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R 5C optionally substituted with substituents, Each R b52 are independently selected from 1, 2, 3, or 4 independently selected R 5C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e52 are independently H, OH, CN, and 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f52 and R g52 are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h52 and R i52 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j52 and R k52 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j52 and R k52together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 5C are independently H, D, halo, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a53 , S.R. a53 , NHOR a53 , C(O)R b53 , C(O)NR c53 R d53 , C(O)NR c53 (OR a53 ), C(O)OR a53 ,OC(O)R b53 , OC(O)NR c53 R d53 , N.R. c53 R d53 , N.R. c53 NR c53 R d53 , N.R. c53 C(O)R b53 , N.R. c53 C(O)OR a53 , N.R. c53 C(O)NR c53 R d53 , C(=NR e53 )R b53 , C(=NR e53 )NR c53 R d53 , N.R. c53 C(=NR e53 )NR c53 R d53 , N.R. c53C(=NR e53 )R b53 , N.R. c53 S(O)NR c53 R d53 , N.R. c53 S(O)R b53 , N.R. c53 S(O)2R b53 , N.R. c53 S(O)(=NR e53 )R b53 , N.R. c53 S(O)NR c53 R d53 , S(O)R b53 , S(O)NR c53 R d53 , S(O)2R b53 , S(O)NR c53 R d53 , OS(O)(=NR e53 )R b53 , OS(O)2R b53 , S(O)(=NR e53 )R b53 , SF5, P(O)R f53 R g53 , OP(O)(OR h53 )(OR i53 ), P(O)(OR h53 )(OR i53 ), and BR j53 R k53 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, Each R a53 , R c53 , and R d53are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, or any R bonded to the same N atom c53 and R d53 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R G optionally substituted with substituents, Each R b53 are independently selected from 1, 2, 3, or 4 independently selected R G C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R e53 are independently H, OH, CN, and 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R f53 and R g53 are independently H, 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 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R h53 and R i53 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R j53 and R k53 are independently OH, C 1-6 Alkoxy, and C 1-6 haloalkoxy; or any R bonded to the same B atom j53 and R k53 together with the B atoms to which they are bonded, C 1-6 Alkyl and C 1-6 forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R 6 are independently H, D, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl R 7 H, D, Halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, OH, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C1-3 Alkyl)amino, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-3 Alkoxy-C 1-4 Alkyl, and C 3-4 cycloalkyl; Each R G are independently OH, NO2, CN, halo, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Haloalkyl, Cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, C 1-3 Alkoxy-C 1-3 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3 Alkyl sulfonyl, carbamyl, C 1-3 Alkylcarbamyl, di(C 1-3 Alkyl) carbamyl, carboxy, C 1-3 Alkyl carbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonyloxy, C 1-3 Alkylcarbonylamino, C 1-3 Alkoxycarbonylamino, C 1-3 Alkylaminocarbonyloxy, C 1-3 Alkyl sulfonyl amino, amino sulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino, and di(C 1-3alkyl)aminocarbonylamino.

[0020] In some embodiments, R 1 H, halo, CN, C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0021] In some embodiments, R 1 is F, Cl, Br, CN, CF3, CHF2, CH2F, CH2CF3, or CH2CHF2.

[0022] In some embodiments, R 1 is CN or C 1-3 It is haloalkyl.

[0023] In some embodiments, R 1 is CN or CF3.

[0024] In some embodiments, R 1 is CF3.

[0025] In some embodiments, R 1 is CN.

[0026] In some embodiments, R 1 is halo, CN or C 1-3 It is haloalkyl.

[0027] In some embodiments, R 1 is Cl, CN, or CF3.

[0028] In some embodiments, R 7 H, halo, CN, C 1-2 Alkyl, or C 1-2 It is haloalkyl.

[0029] In some embodiments, R 7 is H, halo, or CN.

[0030] In some embodiments, R 7 is H.

[0031] In some embodiments, the ring moiety A is a 4-10 membered heterocycloalkyl, wherein the heterocycloalkyl does not contain an aromatic ring.

[0032] In some embodiments, ring moiety A is a monocyclic 4-7 membered heterocycloalkyl.

[0033] In some embodiments, the ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidine ring, or an azepane ring;

[0034] In some embodiments, ring moiety A is azetidin-3-yl, piperidin-3-yl, or piperidin-4-yl.

[0035] In some embodiments, ring moiety A is piperidin-4-yl.

[0036] In some embodiments, n is 0, 1, or 2.

[0037] In some embodiments, n is 0 or 1.

[0038] In some embodiments, n is 0.

[0039] In some embodiments, each R 6 are independently H, halo, and C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0040] In some embodiments, each R 6 is H, halo, or C 1-3 haloalkyl.

[0041] In some embodiments, each R 6 are independently H, halo, or methyl.

[0042] In some embodiments, each R 6 is H.

[0043] In some embodiments, each R 6 is H, F, or CH3.

[0044] In some embodiments, each R 6 is F or CH3.

[0045] In some embodiments, R Z is NR 5 R 5Z is.

[0046] In some embodiments, R 5Z is H or methyl.

[0047] In some embodiments, R Z is R 5 is.

[0048] In some embodiments, R Z is N(CH3)2, NH(CH3), or NH(cyclopropyl).

[0049] In some embodiments, R 5 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 5A It is optionally substituted with a substituent.

[0050] In some embodiments, R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 5A It is optionally substituted with a substituent.

[0051] In some embodiments, R 5 is C 1-3 Alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heteroaryl, 1-3 Alkyl, the C 3-7 The cycloalkyl and the 5- to 6-membered heteroaryl each have one or two independently selected R 5A It is optionally substituted with a substituent.

[0052] In some embodiments, R 5 is methyl, cyclopropyl, or imidazolyl, each of which is selected from one, two, or three independently selected R 5AIt is optionally substituted by a substituent.

[0053] In some embodiments, R 5 is methyl, cyclopropyl, or 2-methylimidazol-4-yl.

[0054] In some embodiments, R 5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is selected from one, two, or three independently selected R 5A It is optionally substituted by a substituent.

[0055] In some embodiments, R 5 is methyl, ethyl, cyclopropyl, imidazolyl, pyrazolyl, pyridinyl, and pyrimidinyl, each of which is selected from one, two, or three independently selected R 5A It is optionally substituted by a substituent.

[0056] In some embodiments, R 5 is methyl, ethyl, cyclopropyl, imidazol-4-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, or pyrimidin-4-yl, each of which is selected from one, two, or three independently selected R 5A It is optionally substituted by a substituent.

[0057] In some embodiments, Each R 5A are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 C(O)OR a51 , N.R. c51 C(O)NR c51 R d51 , N.R. c51 S(O)2R b51 , N.R. c51 S(O)NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5B optionally substituted with substituents, Each R a51, R c51 , and R d51 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5B optionally substituted with substituents, Each R b51 are independently selected from 1, 2, 3, or 4 independently selected R 5B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4alkyl, Each R 5B are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a52 , S.R. a52 , NHOR a52 , C(O)R b52 , C(O)NR c52 R d52 , C(O)OR a52 ,OC(O)R b52 , OC(O)NR c52 R d52 , N.R. c52 R d52 , N.R. c52 C(O)R b52 , N.R. c52 C(O)OR a52 , N.R. c52 C(O)NR c52 R d52 , N.R. c52 S(O)2R b52 , N.R. c52 S(O)NR c52 R d52 , S(O)2R b52 , and S(O)NR c52 R d52 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5C optionally substituted with substituents, Each R a52 , R c52 , and R d52 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 5C optionally substituted with substituents, Each R b52 are independently selected from 1, 2, 3, or 4 independently selected R 5C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 5C are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0058] In some embodiments, Each R 5A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a51 , S.R. a51 , NHOR a51 , C(O)R b51 , C(O)NR c51 R d51 , C(O)OR a51 ,OC(O)R b51 , OC(O)NR c51 R d51 , N.R. c51 R d51 , N.R. c51 C(O)R b51 , N.R. c51 C(O)OR a51 , N.R. c51 C(O)NR c51 Rd51 , N.R. c51 S(O)2R b51 , N.R. c51 S(O)NR c51 R d51 , S(O)2R b51 , and S(O)NR c51 R d51 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 5B optionally substituted with substituents, Each R a51 , R c51 , and R d51 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4each alkyl is selected from 1, 2, or 3 independently selected R 5B optionally substituted with substituents, Each R b51 are independently selected from 1, 2, or 3 independently selected R 5B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 5B are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0059] In some embodiments, Each R 5A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 wherein C is selected from 1-6 Alkyl, the C 1-6 haloalkyl, and the C 3-4 Each cycloalkyl is selected from one or two independently selected R 5B optionally substituted with substituents, Each R a51 , R c51 , and R d51 are independently H, C 1-6 Alkyl, and C 1-6haloalkyl; Each R 5B are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0060] In some embodiments, Each R 5A are independently H, halo, CN, and C 1-3 Alkyl, C 1-3 Haloalkyl and NR c51 R d51 is selected from Each R c51 and R d51 are independently H and C 1-3 alkyl.

[0061] In some embodiments, each R 5A is independently selected from CH3 and NH2.

[0062] In some embodiments, R 2 , R 3 , and R 4 is defined as in group (a).

[0063] In some embodiments, R 3 H, halo, CN, C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0064] In some embodiments, R 3 is H, F, Cl, Br, CN, CH3, CH2CH3, CF3, CHF2, CH2F, CH2CF3, or CH2CHF2.

[0065] In some embodiments, R 3 is H, F, Cl, Br, CN, or CH3.

[0066] In some embodiments, R 3 H, halo, CN, C 1-3 Alkyl, or C 1-3 It is haloalkyl.

[0067] In some embodiments, R 3 is H, Cl, Br, CN, or CH3.

[0068] In some embodiments, R 2 H, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, Cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, or C 1-3 Alkoxy-C 1-4 It is alkyl.

[0069] In some embodiments, R 2 H, halo, C 1-4 Alkyl, or HO-C 1-4 It is alkyl.

[0070] In some embodiments, R 2 is H, Cl, methyl, or isobutyl, wherein the methyl and the isobutyl are each optionally substituted with one OH group.

[0071] In some embodiments, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, 6-10 membered aryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-10 cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-10 Cycloalkyl-C 1-4 Alkyl, the 6- to 10-membered aryl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A It is optionally substituted by a substituent.

[0072] In some embodiments, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A It is optionally substituted by a substituent.

[0073] In some embodiments, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C 3-7 Cycloalkyl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, and the C 3-7 Cycloalkyl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A It is optionally substituted with a substituent.

[0074] In some embodiments, R 4 is selected from H, methyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, isobutyl, cyclopropylmethyl, phenyl, pyridinyl, and tetrahydropyran, and the methyl, the 2,2-difluoroethyl, the 2,2,2-trifluoroethyl, the isobutyl, the cyclopropylmethyl, the phenyl, the pyridinyl, and the tetrahydropyran each have one or two R selected from F, Cl, CN, OH, CH3, CF3, CH3NHCH2, CH3C(O)NH, NH2, and CNCH2. 4A It is optionally substituted by a substituent.

[0075] In some embodiments, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-9 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C1-6 haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 9-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4A It is optionally substituted by a substituent.

[0076] In some embodiments, R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-9 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 9-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4A It is optionally substituted by a substituent.

[0077] In some embodiments, R 4 is H, C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one, and cyclopropylmethyl; 1-6 Alkyl, the C 1-6haloalkyl, the phenyl, the tetrahydropyranyl, the pyridyl, the pyrazolyl, the isobenzofuran-1(3H)-one, and the cyclopropylmethyl each represent 1, 2, or 3 independently selected R 4A It is optionally substituted by a substituent.

[0078] In some embodiments, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4B optionally substituted with substituents, Each R b41are independently selected from 1, 2, 3, or 4 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 4B are independently H, halo, CN, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , S.R. a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 ,OC(O)R b42 , OC(O)NR c42 R d42 , N.R. c42 R d42 , N.R. c42 C(O)R b42 , N.R. c42 C(O)OR a42 , N.R. c42 C(O)NR c42 R d42 , N.R. c42 S(O)2R b42, N.R. c42 S(O)NR c42 R d42 , S(O)2R b42 , and S(O)NR c42 R d42 wherein C is selected from 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4C optionally substituted with substituents, Each R b42 are independently selected from 1, 2, 3, or 4 independently selected R 4C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 4C are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0079] In some embodiments, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, ORa41 , S.R. a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R b41 are independently selected from 1, 2, or 3 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 4B are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0080] In some embodiments, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4Cycloalkyl, OR a41 , S.R. a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, and the C 3-4 Each cycloalkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, 1-6 Alkyl, and the C 1-6 Each haloalkyl is selected from one or two independently selected R 4B optionally substituted with substituents, Each R b41 are independently selected from 1, 2, or 3 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl and C 1-6 haloalkyl; Each R 4B are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0081] In some embodiments, each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , and NR c41 C(O)R b41 , N.R. c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 haloalkyl, and the C 3-4 Each cycloalkyl is selected from one or two independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R b41 independently, C 1-6 Alkyl and C 1-6 haloalkyl; Each R 4B are independently H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0082] In some embodiments, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R b41 are independently selected from 1, 2, or 3 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R 4B are independently H, D, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , S.R. a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 ,OC(O)R b42 , OC(O)NR c42 R d42 , N.R. c42 R d42 , N.R. c42 C(O)R b42 , N.R. c42 C(O)OR a42 , N.R. c42 C(O)NR c42 R d42 , N.R. c42 S(O)2R b42 , N.R. c42 S(O)NR c42 R d42 , S(O)2R b42 , and S(O)NR c42 R d42 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R b42 are independently selected from 1, 2, or 3 independently selected R 4C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 4C are independently H, D, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino.

[0083] In some embodiments, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , C(O)NR c41 R d41 , N.R. c41 R d41 , and NR c41 C(O)R b41 wherein C is selected from 1-6 Alkyl, the C 1-6 haloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H and C 1-6 alkyl, 1-6 alkyl is one, two, or three independently selected R 4B optionally substituted with substituents, Each R b41 independently, 1, 2, or 3 independently selected R 4B C optionally substituted with substituents 1-6 alkyl, Each R 4B are independently H, D, halo, CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, OR a42 , N.R. c42 R d42 , and NR c42 C(O)Rb42 wherein C is selected from 1-6 alkyl and the 4- to 7-membered heterocycloalkyl are each selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocycloalkyl, and C 3-7 Cycloalkyl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the 4- to 7-membered heterocycloalkyl, and the C 3-7 Cycloalkyl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R b42 independently, 1, 2, or 3 independently selected R 4C C optionally substituted with substituents 1-6 alkyl, Each R 4C are independently D, CN, OH and C 1-3 alkyl.

[0084] In some embodiments (Embodiment A), n is 0, 1, or 2; ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidine ring, or an azepane ring; R 1 H, halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 2 H, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, Cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, or C1-3 Alkoxy-C 1-4 is alkyl, R 3 H, halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, 3, or 4 independently selected R 4A optionally substituted with substituents, Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a41 , S.R. a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NR c41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41, N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, and the C 3-4 Each cycloalkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl, 1-6 Alkyl, and the C 1-6 Each haloalkyl is selected from one or two independently selected R 4B optionally substituted with substituents, Each R b41 are each independently selected from 1, 2, or 3 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl and C 1-6 haloalkyl; Each R 4B independently, H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; R Z is R 5 and In some embodiments, R 5 is C 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 5A optionally substituted with substituents, Each R 5A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-4 Cycloalkyl, OR a51 , and NR c51 R d51 wherein C is selected from 1-6 Alkyl, the C 1-6 haloalkyl, and the C 3-4 Each cycloalkyl is selected from one or two independently selected R 5B optionally substituted with substituents, Each R a51 , R c51 , and R d51 are independently H, C 1-6 Alkyl, and C 1-6 haloalkyl; Each R 5B independently, H, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; Each R 6 independently, C 1-3 Alkyl and C 1-3 haloalkyl; R 7 is H.

[0085] In some embodiments (Embodiment B), n is 0, Ring moiety A is a piperidine ring, R 1 is H, R 2 H, halo, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, Cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, or C 1-3 Alkoxy-C 1-4 is alkyl, R 3 is H, CN, halo, CH3, or CF3, R 4 is H, C 1-6 Alkyl, C 1-6 haloalkyl, phenyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C 3-6 Cycloalkyl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 6-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, and the C 3-6 Cycloalkyl-C 1-4 Each alkyl is selected from 1 or 2 independently selected R 4A is optionally substituted by a substituent; Each R 4A are independently H, halo, CN, and C 1-3 Alkyl, C 1-3 Haloalkyl, OR a41 , N.R.c41 R d41 , and NR c41 C(O)R b41 wherein C is selected from 1-3 Alkyl is one R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H and C 1-3 alkyl, Each R b41 independently, C 1-3 alkyl, Each R 4B are independently H, CN, amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; R Z is R 5 and R 5 is C 1-6 Alkyl, C 3-6 cycloalkyl, or 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is 5A is optionally substituted by a substituent; Each R 5A are independently H and C 1-6 alkyl, Each R 6 is H, R 7 is H.

[0086] In some embodiments (Embodiment C), n is 0 or 1, Ring moiety A is a piperidine ring, R 1 Halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 2 H, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, or HO-C 1-6 is alkyl, R3 H, halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 4 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-9 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 9-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4A is optionally substituted by a substituent; Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , S.R. a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)OR a41 ,OC(O)R b41 , OC(O)NRc41 R d41 , N.R. c41 R d41 , N.R. c41 C(O)R b41 , N.R. c41 C(O)OR a41 , N.R. c41 C(O)NR c41 R d41 , N.R. c41 S(O)2R b41 , N.R. c41 S(O)NR c41 R d41 , S(O)2R b41 , and S(O)NR c41 R d41 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 alkyl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R b41 are independently selected from 1, 2, or 3 independently selected R 4B C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl and 5-10 membered heteroaryl-C 1-4 alkyl, Each R 4B are independently H, D, halo, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, 5-6 membered heteroaryl-C 1-4 Alkyl, OR a42 , S.R. a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)OR a42 ,OC(O)R b42 , OC(O)NR c42 R d42, N.R. c42 R d42 , N.R. c42 C(O)R b42 , N.R. c42 C(O)OR a42 , N.R. c42 C(O)NR c42 R d42 , N.R. c42 S(O)2R b42 , N.R. c42 S(O)NR c42 R d42 , S(O)2R b42 , and S(O)NR c42 R d42 wherein C is selected from 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R b42 are independently selected from 1, 2, or 3 independently selected R 4C C, optionally substituted with substituents 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, Each R 4C are independently H, D, halo, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 alkyl)amino; R Z is NR 5 R 5Z or R 5 and R 5Z is H or methyl, R 5 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4Alkyl, 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 7-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 5A optionally substituted with substituents, Each R 5A are independently H, halo, CN, and C 1-3 Alkyl, C 1-3 Haloalkyl and NR c51 R d51 is selected from Each R c51 and R d51 are independently H and C 1-3 alkyl, Each R 6 independently, C 1-3 Alkyl and C 1-3 haloalkyl; R 7 is H.

[0087] In some embodiments (Embodiment D), n is 0 or 1, Ring moiety A is a piperidine ring, R 1 Halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 2 H, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, or HO-C 1-6 is alkyl, R 3H, halo, CN, C 1-3 Alkyl, or C 1-3 is haloalkyl, R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, Phenyl-C 1-4 Alkyl, 4-9 membered heterocycloalkyl-C 1-4 Alkyl and 5-6 membered heteroaryl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C 3-7 Cycloalkyl-C 1-4 Alkyl, the phenyl-C 1-4 Alkyl, the 4- to 9-membered heterocycloalkyl-C 1-4 Alkyl, and the 5- to 6-membered heteroaryl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4A is optionally substituted by a substituent; Each R 4A are independently H, halo, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, OR a41 , C(O)NR c41 R d41 , N.R. c41 R d41 , and NR c41 C(O)R b41 wherein C is selected from 1-6 Alkyl, the C 1-6 haloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, and the 5- to 10-membered heteroaryl-C 1-4each alkyl is selected from 1, 2, or 3 independently selected R 4B optionally substituted with substituents, Each R a41 , R c41 , and R d41 are independently H and C 1-6 alkyl, 1-6 alkyl is one, two, or three independently selected R 4B optionally substituted with substituents, Each R b41 independently, 1, 2, or 3 independently selected R 4B C optionally substituted with substituents 1-6 alkyl, Each R 4B are independently H, D, halo, CN, C 1-6 Alkyl, 4-7 membered heterocycloalkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, OR a42 , N.R. c42 R d42 , and NR c42 C(O)R b42 wherein C is selected from 1-6 alkyl and the 4- to 7-membered heterocycloalkyl are each selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R a42 , R c42 , and R d42 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocycloalkyl, and C 3-7 Cycloalkyl-C 1-4 alkyl, 1-6 Alkyl, the C 1-6 Haloalkyl, the C 3-7 cycloalkyl, the 4- to 7-membered heterocycloalkyl, and the C 3-7 Cycloalkyl-C 1-4 each alkyl is selected from 1, 2, or 3 independently selected R 4C optionally substituted with substituents, Each R b42 independently, 1, 2, or 3 independently selected R 4C C optionally substituted with substituents 1-6 alkyl, Each R 4C are independently D, CN, OH and C 1-3 alkyl, R Z is NR 5 R 5Z or R 5 and R 5Z is H or methyl, R 5 is C 1-6 Alkyl, C 3-7 cycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from 1, 2, or 3 independently selected R 5A optionally substituted with substituents, Each R 5A is independently selected from CH3 and NH2; Each R 6 is H, halo, or C 1-3 haloalkyl; R 7 is H.

[0088] In some embodiments, the compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound is a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, X is a bond, CH, or CHCH; Y is a bond or CH2.

[0091] In some embodiments, the compound is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound is a compound of formula (IVa): [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, X is a bond, CH, or CHCH; Y is a bond or CH2.

[0094] Formulas (I), (II), (IIa), (III), (IV), (IVa) and (V) can be combined with any of the preceding embodiments, more preferably with embodiment A or embodiment B, or most preferably with embodiment C or embodiment D.

[0095] In some embodiments, an “alkyl,” “alkenyl,” “alkynyl,” “aryl,” “phenyl,” “cycloalkyl,” “heterocycloalkyl,” or “heteroaryl” substituent or “—C 1-41, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms of the "alkyl-" and "alkylene" linking group are optionally replaced by deuterium atoms.

[0096] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0097] In various places herein, divalent linking substituents are described. Unless otherwise indicated, each divalent linking substituent is specifically intended to include both the forward and backward forms of the linking substituent. For example, -NR(CR'R'') n -NR(CR'R'') n -and-(CR'R'') n Both NR- and NR- are included. When a structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group.

[0098] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0099] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valence, that the normal valence of the specified atom is not exceeded, and that the substitution results in a stable compound.

[0100] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at each occurrence from an applicable list.

[0101] As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "at each occurrence, 'variable' is selected from."

[0102] In any component or formula of a compound, a variable (e.g., R G When a group R occurs more than one time, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, when the group R G When the group is shown to be substituted with up to four R G R G is R G is selected independently from the definition of

[0103] In some embodiments, the optional plurality of substituents is [ka] When specified in the form, it is understood that the substituent R can occur p times on the ring and R can be a different moiety at each occurrence. Each R group is a (CH) nIt is understood that any hydrogen atom bonded to a ring atom may be substituted, including one or both hydrogen atoms in the ring. Additionally, in the above example, when the variable Q is defined to include hydrogen, such as when Q is said to be CH, NH, etc., any floating substituent, such as R in the above example, can replace a hydrogen of the Q variable and a hydrogen in any other non-variable component of the ring.

[0104] Through definition, "C n-m " denotes a range inclusive of the endpoints, and n and m are integers indicating the number of carbons. Examples include C 1-3 , C 1-4 , C 1-6 Examples include:

[0105] As used herein, "C" when used alone or in combination with other terms n-m The term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0106] As used herein, "C n-m "Alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Exemplary 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.

[0107] As used herein, "C n-m"Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Examples of 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. As used herein, the term "C" used alone or in combination with other terms means n-m "Alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0108] As used herein, the term "amino" refers to a group of formula -NH2.

[0109] 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 (e.g., having two fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has 6 to 14 or 6 to 10 carbon atoms. In some embodiments, an aryl group is phenyl or naphthyl. In some embodiments, an aryl is phenyl.

[0110] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0111] As used herein, "Cn-m "Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. Exemplary haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is exclusively fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0112] As used herein, "C" when used alone or in combination with other terms n-m The term "haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s+1 halogen atoms, which may be the same or different ("s" is the number of carbon atoms in the alkyl group), where the alkyl group has n to m carbons. In some embodiments, the haloalkyl group is exclusively fluorinated. In some embodiments, the alkyl group of the haloalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0113] As used herein, "C n-m The term "fluoroalkyl" refers to an alkyl group having from 1 fluoro atom to 2s+1 fluoro atoms, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group of the fluoroalkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary fluoroalkyl groups include CF, C2F5, CHF2, CH2F, and the like.

[0114] As used herein, the term "thio" refers to a group of formula -SH.

[0115] As used herein, "C n-m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0116] As used herein, "C n-m The term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkoxycarbonyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0117] As used herein, "C n-m The term "alkylcarbonyl" refers to a group of formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0118] As used herein, "C n-m The term "alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0119] As used herein, "C n-m The term "alkoxycarbonylamino" refers to a group of the formula -NHC(O)O(C n-m The term "alkoxycarbonylamino" refers to an alkoxycarbonylamino (alkyl) group, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkoxycarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0120] As used herein, "C n-m The term "alkylsulfonylamino" refers to a group of formula -NHS(O)2-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0121] As used herein, the term "aminosulfonyl" refers to a group of formula -S(O)2NH2.

[0122] As used herein, "C n-m The term "alkylaminosulfonyl" refers to a group of formula -S(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminosulfonyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0123] As used herein, the term "di(C n-m The term "dialkylaminosulfonyl" refers to a group of formula -S(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonyl independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0124] As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O)2NH2.

[0125] As used herein, "C n-m The term "alkylaminosulfonylamino" refers to a group of formula -NHS(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminosulfonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0126] As used herein, "di(C n-m The term "dialkylaminosulfonylamino" refers to a group of formula -NHS(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of the dialkylaminosulfonylamino independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0127] As used herein, the term "aminocarbonylamino," employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0128] As used herein, "C n-m The term "alkylaminocarbonylamino" refers to a group of formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminocarbonylamino has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0129] As used herein, "di(C n-m The term "NHC(O)N(alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group of dialkylaminocarbonylamino independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0130] As used herein, "C n-m The term "alkylcarbamyl" refers to a group of formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbamyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0131] As used herein, "C n-m The term "alkylthio" refers to a group of formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylthio has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0132] As used herein, "C n-mThe term "alkylsulfinyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfinyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0133] As used herein, "C n-m The term "alkylsulfonyl" refers to an alkyl group of formula -S(O)-, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylsulfonyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0134] As used herein, "cyano-C" n-m The term "alkyl" refers to a group of the formula -(C n-m As used herein, "cyano-C" refers to the group "cyano-C" where the alkylene group has n to m carbon atoms. 1-6 The term "alkyl" refers to a group of the formula -(C 1-6 As used herein, "cyano-C" refers to the group 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 refers to the group alkylene-CN.

[0135] As used herein, "HO-C n-m The term "alkyl" refers to a group of the formula -(C n-m As used herein, "HO-C" refers to a group of alkylene-OH, where the alkylene group has n to m carbon atoms. 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 refers to the group alkylene-OH.

[0136] As used herein, "C n-m Alkoxy-C o-p The term "alkyl" refers to a group of the formula -(C n-m alkylene)-O(C o-p As used herein, "C" refers to a group of alkylene groups, where the alkylene group has n to m carbon atoms and the alkyl group has o to p carbon atoms.1-6 Alkoxy-C 1-6 The term "alkyl" refers to a group of the formula -(C 1-6 alkylene)-O(C 1-6 As used herein, "C" refers to a group of alkyl groups. 1-3 Alkoxy-C 1-3 The term "alkyl" refers to a group of the formula -(C 1-3 alkylene)-O(C 1-3 It refers to a group of (alkyl).

[0137] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0138] As used herein, "di(C n-m The term "dialkylamino" refers to a group of formula -N(alkyl), where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group in the dialkylamino independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0139] As used herein, "di(C n-m The term "dialkyl)carbamyl" refers to a group of formula -C(O)N(alkyl), where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group in the dialkylcarbamyl independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0140] As used herein, "C n-m The term "alkylcarbonyloxy" refers to an alkyl group of formula -OC(O)-, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylcarbonyloxy has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0141] As used herein, "aminocarbonyloxy" is a group of the formula -OC(O)-NH2.

[0142] As used herein, "Cn-m The term "alkylaminocarbonyloxy" refers to a group of formula -OC(O)-NH-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group of the alkylaminocarbonyloxy has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0143] As used herein, "di(C n-m The term "dialkylaminocarbonyloxy" refers to a group of formula -OC(O)-N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group in the dialkylaminocarbonyloxy independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0144] As used herein, "C n-m The term "alkoxycarbonylamino" refers to a radical of the formula -NHC(O)-O-alkyl, wherein the alkyl radical has n to m carbon atoms.

[0145] As used herein, the term "carbamyl" refers to a group of formula -C(O)NH2.

[0146] As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a --C(O)-- group.

[0147] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings), spirocyclic, and bridged rings (e.g., bridged bicycloalkyl groups). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to (i.e., having a common bond with) a cycloalkyl ring, e.g., a benzo or thienyl derivative such as cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbon atoms (i.e., C 3-14 In some embodiments, the cycloalkyl can have C 3~14 is cycloalkyl, 3~14 One, two, three, or four ring-forming carbon atoms of a cycloalkyl can be optionally substituted by one or more oxo or sulfido. In some embodiments, a cycloalkyl is C 3-10 In some embodiments, the cycloalkyl is a monocyclic or bicyclic cycloalkyl. 3-7 In some embodiments, the cycloalkyl is C 4-7 In some embodiments, the cycloalkyl is C 4-14and spirocyclic or bridged cycloalkyl (e.g., bridged bicycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0148] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 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 5-14 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. 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, 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 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, heteroaryl contains 3 to 14, 3 to 10, 4 to 14, 4 to 10, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl groups contain 5 to 14, 5 to 10, or 5 to 6 ring-forming atoms. In some embodiments, heteroaryl groups have 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different.Exemplary heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), quinolinyl, isoquinolinyl. , indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), 1,2-dihydro-1,2-azoborinyl, and the like. In some embodiments, heteroaryl is independently selected from imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, quinoxalinyl, and quinolinyl. In some embodiments, heteroaryl is independently selected from imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridyl, quinoxalinyl, and quinolinyl.

[0149] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, S, and B; and the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl groups include monocyclic and polycyclic 4- to 14-membered, 4- to 12-membered, 3- to 10-membered, 4- to 10-membered, 3- to 7-membered, 4- to 7-membered, and 5- to 6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., 5- to 14-membered bridged biheterocycloalkyl rings having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds.

[0150] Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) a non-aromatic heterocyclic ring, e.g., a benzo or thienyl derivative, such as piperidine, morpholine, or azepine. Heterocycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. In some embodiments, heterocycloalkyl groups contain 3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, 4 to 7 ring-forming atoms, 4 to 6 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0151] In some embodiments, heterocycloalkyl is a 4-14-membered monocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein 1, 2, 3, or 4 ring-forming carbons or heteroatoms can be optionally substituted with one or more oxo or sulfido. In some embodiments, heterocycloalkyl is a 4-10-membered monocyclic, bicyclic, or tricyclic heterocycloalkyl having 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein 1, 2, 3, or 4 ring-forming carbons or heteroatoms can be optionally substituted with one or more oxo or sulfido. In some embodiments, heterocycloalkyl is a 4-7-membered monocyclic heterocycloalkyl having 1 or 2 ring-forming heteroatoms independently selected from N, O, and S, wherein 1, 2, or 3 ring-forming carbons or heteroatoms can be optionally substituted with one or more oxo or sulfido. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members.

[0152] Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, Oxo-azetidinyl, oxo-imidazolidinyl, oxopyrrolidinyl, oxo-oxazolidinyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diaza Bicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl , diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl, and the like.In some embodiments, heterocycloalkyl is independently selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, isobenzofuran-1(3H)-one, oxo-azetidinyl, oxo-imidazolidinyl, oxopyrrolidinyl, oxo-oxazolidinyl, oxopiperidinyl, azabicyclo[2.2 .2]octanyl, azabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, diazaspiro[3.4]nonanyl, hexahydropyrrolo[1,2-a]pyrazinyl, oxazabicyclo[2.2.1]heptanyl, oxazabicyclo[3.1.1]heptanyl, oxazabicyclo[3.2.1]octanyl, and oxazabicyclo[2.2.2]octanyl.

[0153] As used herein, "C o-p Cycloalkyl-C n-m "Alkyl-" refers to a group of the formula cycloalkyl-alkylene- where the cycloalkyl has from o to p carbon atoms and the alkylene linking group has from n to m carbon atoms.

[0154] As used herein, "C o-p Aryl-C n-m "Alkyl-" refers to a group of formula aryl-alkylene-, where the aryl has from o to p carbon ring members and the alkylene linking group has from n to m carbon atoms.

[0155] As used herein, "heteroaryl-C n-m "Alkyl-" refers to a group of formula heteroaryl-alkylene-, where the alkylene linking group has n to m carbon atoms.

[0156] As used herein, "heterocycloalkyl-C n-m "Alkyl-" refers to a group of the formula heterocycloalkyl-alkylene-, where the alkylene linking group has n to m carbon atoms.

[0157] As used herein, the term "alkylene" refers to a divalent straight or branched alkyl linking group. Examples of "alkylene groups" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0158] As used herein, the term "alkenylene" refers to a divalent straight-chain or branched alkenyl linking group. Examples of "alkenylene groups" include ethene-1,1-diyl, ethene-1,2-diyl, propene-1,3-diyl, 2-butene-1,4-diyl, 3-pentene-1,5-diyl, 3-hexene-1,6-diyl, 3-hexene-1,5-diyl, and the like.

[0159] As used herein, the term "alkynylene" refers to a divalent straight-chain or branched alkynyl linking group. Examples of "alkynylene groups" include propyne-1,3-diyl, 2-butyne-1,4-diyl, 3-pentyne-1,5-diyl, 3-hexyne-1,6-diyl, 3-hexyne-1,5-diyl, and the like.

[0160] As used herein, an "alkyl linking group" is a straight-chain or branched alkyl linking group (an "alkylene group"). For example, "C o-p Cycloalkyl-C n-m Alkyl-, C o-p Aryl-C n-m Alkyl-, Phenyl-C n-m Alkyl-, Heteroaryl-C n-m alkyl-, and heterocycloalkyl-C n-m "Alkyl-" includes alkyl linking groups. Examples of "alkyl linking groups" or "alkylene groups" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0161] As used herein, the term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent which, when attached to a carbon, forms a carbonyl group (e.g., C=O or C(O)), or to a nitrogen or sulfur heteroatom, forms a nitroso, sulfinyl, or sulfonyl group.

[0162] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent is independently selected at each occurrence from an applicable list.

[0163] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be bonded to any ring member, provided that the valence of the atom is not exceeded. For example, the azetidine ring can be bonded at any position on the ring, while the pyridin-3-yl ring is bonded at the 3-position.

[0164] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated herein. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R) configuration. In some embodiments, the compounds have the (S) configuration. The formulas provided herein (e.g., Formulas (I), (II), etc.) include stereoisomers of the compounds.

[0165] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional recrystallization are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, and the D- and L-forms of lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereoisomerically pure forms (e.g., S- and R-forms, or diastereomerically pure forms) of α-methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0166] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0167] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the accompanying migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidinic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0168] All compounds, and their pharmaceutically acceptable salts, may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0169] In some embodiments, preparation of compounds may involve the addition of acids or bases, for example to affect catalysis of a desired reaction or the formation of salt forms, such as acid addition salts.

[0170] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched for the compounds provided herein. Substantial separation can include compositions comprising 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 compounds provided herein, or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0171] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

[0172] As used herein, the phrase "pharmaceutically acceptable" is used to refer to those compounds, materials, compositions, and / or dosage forms that 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, commensurate with a reasonable benefit / risk ratio.

[0173] 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 in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred). Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0174] synthesis As will be appreciated by those skilled in the art, the compounds provided herein, including their salts and stereoisomers, can be prepared using known organic synthesis techniques, or can be synthesized according to any of a number of possible synthetic routes, such as those provided in the following schemes.

[0175] The reaction for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0176] As used herein, the expressions "ambient temperature" or "room temperature" or "rt" are understood in the art and generally refer to a temperature, e.g., a reaction temperature that is about the same as the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0177] Preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found in, for example, Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007), Peturssion et al., "Protective Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0178] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g.,1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0179] The following schemes provide general guidance regarding the preparation of compounds of the present invention. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention.

[0180] Compounds of formula (I) can be prepared by the general synthetic procedure illustrated in Scheme 1. In Scheme 1, a substituted 2,4-dichloropyrimidine of formula 1-1 is reacted with an appropriately substituted compound of formula 1-2 (M=e.g., a suitably functionalized boron species, i.e., a boronic acid pinacol ester, or a suitably functionalized tin species, i.e., tributylstannane) by a suitable Suzuki or Steele cross-coupling (e.g., in the presence of a palladium catalyst such as Pd(dppf)Cl, Pd(PPh)Cl, or Pd(PPh) and a base such as sodium carbonate) in a suitable solvent (e.g., CHCN / HO, 1,4-dioxane / HO, DMF) to provide a compound of formula 1-3. Appropriately substituted compounds of formula 1-3 can then be converted to compounds of formula (I) by several methods, for example, by nucleophilic aromatic substitution with an appropriate amine nucleophile in a suitable solvent (e.g., DMSO, DMF, 1,4-dioxane) with or without a suitable base (e.g., triethylamine, N,N-diisopropylethylamine, or CsCO) or acid additive (e.g., a Lewis acid such as ZnCl, or a Bronsted acid such as p-toluenesulfonic acid), or by a suitable C-N cross-coupling including Buchwald-Hartwig amination (e.g., in the presence of a palladium precatalyst such as RuPhos Pd G and a base such as CsCO) in a suitable solvent (e.g., 1,4-dioxane). [ka]

[0181] As shown in Scheme 2, the reaction sequence is 2 , R 3 , and R 4The compound of formula 2-1 can be modified for later exploration of substitution at the position. In Scheme 2, compounds of formula 2-1 are accessed via the reaction of an appropriately substituted compound of formula 1-1 with an amine of formula 1-4 in the presence of zinc(II) chloride and triethylamine in a suitable solvent (e.g., a mixture of tert-butanol and 1,2-dichloroethane). Suzuki cross-coupling (e.g., in the presence of a palladium catalyst such as Pd(dppf)Cl or Pd(PPh)Cl and a base such as sodium carbonate) or Steele cross-coupling (e.g., in the presence of a palladium catalyst such as Pd(PPh)) of an appropriately substituted compound of formula 2-1 with a compound of formula 1-2 (M = e.g., a suitably functionalized boron species, i.e., a boronic acid pinacol ester, or a suitably functionalized tin species, i.e., tributylstannane) provides compounds of formula (I). [ka]

[0182] R 4Compounds of Formula (I) with various substitutions at positions 1 and 2 can be prepared using the process illustrated in Scheme 3. In Scheme 3, Suzuki or Steele cross-coupling of a 4-chloropyrimidine of Formula 2-1 with an appropriately substituted imidazole of Formula 3-1 (M = e.g., a suitably functionalized boron species, i.e., a boronic acid pinacol ester, or a suitably functionalized tin species, i.e., tributylstannane), where PG represents a protecting group (e.g., Boc, SEM, or Tr), followed by removal of the protecting group, provides compounds of Formula 3-2. Under certain conditions, the protecting group can be removed during the Suzuki or Steele coupling to directly afford the 1H-imidazole of Formula 3-2. Alternatively, deprotection of various protecting groups can be achieved under standard conditions. Compounds of Formula 3-2 can then be converted to compounds of Formula (I) by a variety of methods. Functionalization of the imidazole nitrogen in appropriately substituted compounds of formula 3-2 can be accomplished by the reaction of R 1, where LG represents a leaving group (e.g., halide, mesylate, or triflate) under basic conditions in a suitable solvent (e.g., DMF, THF). 4 This can be achieved through the reaction of an appropriately substituted compound of formula 3-2 with a hydroxy group of formula R under Mitsunobu conditions. 4 Reaction of -OH with an alcohol gives compounds of formula (I). 4When R is aryl, appropriately substituted compounds of formula 3-2 can be converted to N-arylimidazoles of formula (I) by a variety of methods, including nucleophilic aromatic substitution with an appropriate aryl halide under basic conditions (e.g., N,N-diisopropylethylamine, sodium hydride, or CsCO) in a suitable solvent (e.g., DMSO, DMF, THF), or by a suitable copper-mediated coupling, such as the Ullmann reaction with an aryl halide in a suitable solvent (e.g., DMSO, DMF, CHCN) (e.g., in the presence of a copper catalyst such as copper(I) iodide, a ligand such as trans-N,N'-dimethylcyclohexane-1,2-diamine, phenanthroline, or 2-hydroxybenzaldehyde oxime, and a base such as CsCO), or by a Chang-Ramu coupling with an aryl halide in a suitable solvent (e.g., CHCl) (e.g., in the presence of copper(II) acetate and a copper catalyst such as pyridine). 4 A range of functionalities at positions can also be introduced by nucleophilic conjugate addition reactions with various Michael-like acceptors (e.g., acrylates, acrylonitrile, or nitroalkenes) with or without basic reaction additives (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine) in suitable solvents (e.g., CH3CN, CH2Cl2). [ka]

[0183] As shown in Scheme 4, substituted imidazoles of formula 4-1 can be treated with a halogenating agent (e.g., N-chlorosuccinimide, N-bromosuccinimide) in a suitable solvent (e.g., CHCN, DMF, DCM) to give compounds of formula 4-2 (X = e.g., chloro, bromo). A suitable cross-coupling reaction with the halogenated imidazole of formula 4-2 can provide compounds of formula I. [ka]

[0184] The substituted imidazoles of formula 5-1 can be prepared by reacting R 2 The R group of imidazoles of formula 5-1 can be directly functionalized at the R position. This can be achieved by palladium-mediated CH activation of imidazoles of formula 5-1 with aryl iodides in the presence of a suitable catalyst (e.g., Pd(OAc)2) in a suitable solvent (e.g., DMF) to provide compounds of formula I. Alternatively, imidazoles of formula 5-1 can be sequentially treated with an excess of lithium reagents (e.g., n-butyllithium) and various electrophiles (e.g., alkyl halides, epoxides, carbonyl-containing compounds, Michael-like acceptors) in a suitable solvent (e.g., THF, toluene) to provide compounds of formula I. 2 Functionalized imidazoles can be delivered. [ka]

[0185] As shown in Scheme 6, substituted imidazoles of formula 5-1 can be halogenated with a halogenating agent (e.g., N-chlorosuccinimide, N-bromosuccinimide) in a suitable solvent (e.g., CHCN, DMF, DCM) to give compounds of formula 6-1 (X = e.g., chloro, bromo). The halogenated imidazoles of formula 6-1 can then undergo a cross-coupling reaction to provide compounds of formula I. [ka]

[0186] How to use The compounds of the present disclosure can inhibit CDK2 and are therefore useful for treating diseases whose underlying pathology is mediated in whole or in part by CDK2. Such diseases include cancer and other diseases with proliferative disorders. In some embodiments, the present disclosure provides in vivo treatment of an individual or patient using a compound of Formula (I) or a salt thereof, such that cancerous tumor growth is inhibited. A compound of Formula (I) or any of the formulas described herein, or any of the claimed compounds and described herein, or a salt thereof, can be used to inhibit the growth of cancerous tumors with abnormalities that activate CDK2 kinase activity. These include, but are not limited to, diseases (e.g., cancers) characterized by CCNE1 amplification or overexpression, such as ovarian cancer, uterine carcinosarcoma, and breast cancer, and p27 inactivation, such as breast cancer and melanoma. Thus, in some embodiments of the method, the patient has previously been determined to have cyclin E1 (CCNE1) gene amplification and / or CCNE1 expression levels higher than control expression levels in a biological sample obtained from the human subject. Alternatively, a compound of Formula (I) or any of the formulas described herein, or a compound described in any of the claims and described herein, or a salt thereof, can be used in combination with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting tumor cell growth in vitro. The method comprises contacting tumor cells in vitro with a compound of Formula (I) or any of the formulas described herein, or a compound described in any of the claims and described herein, or a salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells having CCNE1 amplification and overexpression in an individual or patient. The method comprises administering to an individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I) or any of the formulas described herein, or a compound described in any of the claims and described herein, or a salt or stereoisomer thereof.

[0187] In some embodiments, provided herein are methods of inhibiting CDK2, comprising contacting CDK2 with a compound of Formula (I) or any of the formulas described herein, a compound described in any of the claims and described herein, or a salt thereof. In some embodiments, provided herein are methods of inhibiting CDK2 in a patient, comprising administering to the patient a compound of Formula (I) or any of the formulas described herein, a compound described in any of the claims and described herein, or a salt thereof.

[0188] In some embodiments, methods for treating cancer are provided herein. The methods include administering to a patient (in need thereof) a therapeutically effective amount of a compound of Formula (I) or any of the formulas described herein, a compound described in any of the claims and described herein, or a salt thereof. In another embodiment, the cancer is characterized by CCNE1 amplification or overexpression. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by CCNE1 amplification or overexpression.

[0189] In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any of the formulae described herein, a compound described in any of the claims and described herein, or a salt thereof. In some embodiments, the CDK2-associated disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0190] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutated lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancers with FBW7 mutations and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017.77(18):4881-4893).

[0191] In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0192] In some embodiments, the CDK2-associated disease or disorder is lung adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0193] In some embodiments, the CDK2-associated disease or disorder is adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0194] In some embodiments, the CDK2-associated disease or disorder is uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0195] In some embodiments, the CDK2-related disease or disorder is cancer.

[0196] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian or breast cancer characterized by amplification or overexpression of CCNE1.

[0197] In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0198] Examples of cancers treatable using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, and uterine cancer. Cancers of the present disclosure include, but are not limited to, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphoid lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for treating metastatic cancers.

[0199] In some embodiments, cancers treatable by the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma, urothelial carcinoma (e.g., bladder cancer), and microsatellite instability-high cancer (MSI). high Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0200] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of said cancers.

[0201] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell carcinoma, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0202] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0203] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancer, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0204] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), and multiple myeloma (MM).

[0205] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0206] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0207] Exemplary gastrointestinal cancers include cancer of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0208] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor, [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0209] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0210] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0211] Exemplary nervous system cancers include cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, non-epithelial malignant tumors), as well as neuroblastoma and Lhermitte-Dacros disease.

[0212] Exemplary gynecological cancers include cancer of the uterus (endometrial cancer), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), and fallopian tube (epithelial carcinoma).

[0213] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, biliary tract cancer, esophageal cancer, and urothelial cancer.

[0214] It is believed that compounds of formula (I), or any of its embodiments, may have a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicity profile, metabolic and pharmacokinetic properties, solubility, and permeability. It will be understood that determining appropriate biopharmaceutical properties, such as determining cytotoxicity in cells or inhibition of a particular target or channel to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0215] The terms "individual," "patient," and "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0216] The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0217] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptomology), and (2) ameliorating a disease, condition, or disorder in an individual experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), e.g., reducing the severity of the disease.

[0218] 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, condition, or disorder in individuals who may be predisposed to the disease, condition, or disorder but who do not yet experience or display the pathology or symptomology of the disease.

[0219] Combination therapy I. Cancer Therapy Cancer cell growth and survival may be affected by the dysfunction of multiple signal transduction pathways.Therefore, to treat such conditions, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different preferences in the targets that regulate their activity.Targeting two or more signal transduction pathways (or two or more biological molecules involved in a given signal transduction pathway) can reduce the possibility of drug resistance occurring in cell populations and / or reduce the toxicity of treatment.

[0220] For example, one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immuno-oncological agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4 / 6 kinase inhibitors, such as those described in WO 2006 / 056399, may be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, may be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. The one or more additional pharmaceutical agents may be administered to a patient simultaneously or sequentially.

[0221] In some embodiments, a CDK2 inhibitor is administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0222] The compounds disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitor therapies for the treatment of diseases such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapy include those described herein. Examples of cancer include solid tumors and non-solid tumors such as liquid tumors and blood cancers. Examples of infectious diseases include viral, bacterial, fungal, or parasitic infections. For example, the compounds disclosed herein can be combined with inhibitors of one or more of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK- 1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), 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 may be combined with one or more of the following inhibitors for the treatment of cancer or infectious diseases. Non-limiting examples of inhibitors that may be combined with the compounds of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1, e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib,cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., GSK29979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-delta inhibitors (e.g., palsaclisib (INCB50465) or INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INC B53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer, e.g., INCB081776), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDACs) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo- and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0223] In some embodiments, the compounds or salts described herein are administered together with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor. In some embodiments, the compounds or salts described herein are administered together with a JAK1 inhibitor that is more selective than JAK2.

[0224] Examples of antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (Avastin™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (e.g., anti-CD20), and antibodies against c-MET.

[0225] One or more of the following agents may be used in combination with the compounds of the present disclosure, and are presented as a non-limiting list: cytostatic agents, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, Intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, teniposide 17 alpha.Ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, Avastin, HERCEPTIN™ (trastuzumab) , BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestra Cetuximab, C225 (cetuximab), Cambus (alemtuzumab), clofarabine, cladribine, aphidicolon, Rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0226] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapies include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like. The compounds can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents. Examples of chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitonin, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate. , eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosilate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,Mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptomycin, Examples include tozocine, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0227] Additional examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0228] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0229] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0230] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds such as those disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0231] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds such as those disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0232] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharmaceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include those compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharmaceutically acceptable salts thereof.

[0233] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds such as those disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0234] In some embodiments, compounds of the present disclosure may be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0235] In some embodiments, compounds of the present disclosure may be used in combination with chemotherapeutic agents in the treatment of cancer, and may improve therapeutic response compared to the response to the chemotherapeutic agent alone without exacerbating its toxic effects. In some embodiments, compounds of the present disclosure may be used in combination with the chemotherapeutic agents provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma may include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). An additive or synergistic effect is a desired outcome of combining a CDK2 inhibitor of the present disclosure with an additional agent.

[0236] The agents may be combined with the compound in a single or continuous dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0237] The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies to treat infectious diseases. Examples of infectious diseases include viral, bacterial, fungal, or parasitic infections.

[0238] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the present disclosure, and the dexamethasone is administered intermittently rather than continuously.

[0239] A compound of Formula (I) or any of the formulae described herein, or any of the claims and described herein, or a salt thereof, can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0240] Compounds of Formula (I) or any of the formulas described herein, compounds listed in any of the claims and described herein, or salts thereof, can be used in combination with vaccination protocols 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 implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. Compounds of Formula (I) or any of the formulas described herein, compounds listed in any of the claims and described herein, or salts thereof, can be combined with dendritic cell immunity to activate potent anti-tumor responses.

[0241] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effector cells to tumor cells. The compounds of the present disclosure can also be used in combination with macrocyclic peptides that activate host immune responsiveness.

[0242] In some further embodiments, the combination of the disclosed compounds and other therapeutic agents may be administered to patients before, during, and / or after bone marrow or stem cell transplantation. The disclosed compounds may be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0243] A compound of Formula (I) or any of the formulae described herein, or any of the compounds described in the claims and described herein, or a salt thereof, can be used in combination with a vaccine to stimulate an immune response to pathogens, toxins, and autoantigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which there is currently no effective vaccine, or for which conventional vaccines are not completely effective. These include, but are not limited to, HIV, hepatitis (types A, B, and C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

[0244] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, infectious disease virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0245] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme burgdorferi.

[0246] Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (e.g., albicans, krusei, glabrata, tropicalis), Cryptococcus neoformans, Aspergillus (e.g., fumigatus, niger), Genus Mucorales (e.g., mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0247] Pathogenic parasites that cause infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0248] When two or more pharmaceutical agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for three or more agents).

[0249] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Moreover, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0250] II. Immune checkpoint therapy The compounds of the present disclosure may be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRβ inhibitor.

[0251] In some embodiments, the compounds provided herein may 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).

[0252] 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.

[0253] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, e.g., an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AB122 (GLS-010), AMP-224, AMP-51 4 / MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, the PD-1 or PD-L1 inhibitor is one disclosed in U.S. Pat. Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference in its entirety.

[0254] In some embodiments, the antibody is an anti-PD-1 antibody, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (also known as MPDL3280A, 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.

[0255] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound selected from among those described in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US Ser. No. 16 / 369,654 (filed March 29, 2019), and US Ser. No. 62 / 688,164, each of which is incorporated by reference in its entirety.

[0256] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0257] In some embodiments, the inhibitor is MCLA-145.

[0258] In some embodiments, the inhibitor of an 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.

[0259] In some embodiments, the inhibitor of an 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 eftiragimode alpha (IMP321).

[0260] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0261] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0262] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA, hi some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0263] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0264] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of a KIR. In some embodiments, the inhibitor of a KIR is lirilumab or IPH4102.

[0265] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR, hi some embodiments, the inhibitor of A2aR is CPI-444.

[0266] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta, hi some embodiments, the inhibitor of TGF-beta is travedersen, galcertinib, or M7824.

[0267] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0268] 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.

[0269] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0270] 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.

[0271] In some embodiments, the inhibitor of an 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.

[0272] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0273] 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).

[0274] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomilumab.

[0275] 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, e.g., an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0276] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of CD40, hi some embodiments, the CD40 agonist is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0277] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS, hi some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0278] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28, hi some embodiments, the agonist of CD28 is celalizumab.

[0279] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27, hi some embodiments, the agonist of CD27 is valilumab.

[0280] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8, hi some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0281] The compounds of the present disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or a TGFβ 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.

[0282] 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.

[0283] As provided throughout, the additional compounds, inhibitors, drugs, etc. may be combined with the compounds of the present invention in a single or continuous dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0284] Pharmaceutical Preparations and Dosage Forms When used as a formulation, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared using techniques well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucosal, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or filling of powders or aerosols, including by nebulizer), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion, or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0285] The present disclosure also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid vehicles), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0286] When preparing formulation, before being combined with other components, active compound can be pulverized to obtain suitable particle size.If active compound is substantially insoluble, it can be pulverized to particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by pulverization to provide substantially uniform distribution in formulation, for example, about 40 mesh.

[0287] The compound of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tableting and other types of formulations.The finely divided (nanoparticulate) preparation of the compound of the present disclosure can be prepared by the process known in the art.See, for example, International Application No. WO2002 / 000196.

[0288] Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.The compositions of the present disclosure can be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients by adopting procedures known in the art.

[0289] The compositions may be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), or more, of the active ingredient, such as from about 100 to about 500 mg. 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 the active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0290] In some embodiments, compositions of the present disclosure contain about 5 to about 50 mg of the active ingredient. One of skill 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 the active ingredient.

[0291] In some embodiments, the compositions of the present disclosure contain about 50 to about 500 mg of the active ingredient. One of skill in the art will appreciate that specific compositions include 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 the active ingredient.

[0292] In some embodiments, compositions of the present disclosure contain about 500 to about 1000 mg of the active ingredient. One of skill 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 the active ingredient.

[0293] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0294] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0295] To prepare solid compositions such as tablets, the active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout 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.

[0296] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which resists disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0297] Liquid forms into which the compounds and compositions of the present disclosure may be incorporated for oral administration or by injection include aqueous solutions, suitably 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.

[0298] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, obturator, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0299] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions may be based on a combination of water with glycerol and one or more other components, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water, suitably combined with other components, such as glycerol, hydroxyethylcellulose, etc. In some embodiments, topical formulations include at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of a compound of the present disclosure. Topical formulations may be suitably packaged, for example, in 100g tubes, optionally with instructions for treating a selected indication, such as psoriasis or other skin conditions.

[0300] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated, as well as the judgment of the attending clinician, based on factors such as the severity of the disease, the age, weight, and general health of the patient, etc.

[0301] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions may be packaged or lyophilized for immediate use, although lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of some of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0302] Therapeutic dosages of compounds of the present disclosure can vary depending, for example, on the particular application for which the treatment is given, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0303] The compositions of the present disclosure may further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0304] Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds (radiolabeled, fluorescently labeled, etc.) of the present disclosure that may be useful in both in vitro and in vivo assays, as well as imaging techniques, to locate and quantify CDK2 in tissue samples, including humans, and to identify CDK2 activators through the inhibitory binding of the labeled compounds. Substitution of one or more atoms of the compounds of the present disclosure may also be useful for generating differentiated ADME (adsorption, distribution, metabolism, and excretion). Thus, the present disclosure includes CDK2 binding assays comprising such labeled or substituted compounds.

[0305] The present disclosure also includes isotopically labeled compounds of the present disclosure. An "isotope" 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 that is different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present disclosure include: 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. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced with a deuterium atom (e.g., C of formula (I) 1~6 One or more hydrogen atoms of an alkyl group can be optionally replaced with a deuterium atom, such as -CD3 substituted for -CH3.) In some embodiments, the alkyl groups of the disclosed formulas (e.g., Formula (I)) can be perdeuterated.

[0306] One or more constituent atoms of the compounds presented herein may be replaced or substituted with an isotope of the atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be replaced with a deuterium atom (C in formula (I)). 1~6 One or more hydrogen atoms of the alkyl group may be optionally replaced with a deuterium atom, such as -CD3 substituted for -CH3. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0307] In some embodiments, an "alkyl," "alkenyl," "alkynyl," "aryl," "phenyl," "cycloalkyl," "heterocycloalkyl," or "heteroaryl" substituent or "-C 1-4 In the "alkyl-," "alkylene," "alkenylene," and "alkynylene" linking groups, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms bonded to carbon atoms are optionally replaced by deuterium atoms.

[0308] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas, New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0309] Substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some situations. (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 can provide one or more therapeutic benefits.

[0310] The radionuclide that is incorporated into the radiolabeled compound will depend on the particular application of that radiolabeled compound. For example, for in vitro CDK2 labeling and competition assays: 3 H, 14 C. 82 Br, 125 I, 131 I, or 35 Compounds incorporating S may be useful. For radioimaging applications, 11 C. 18 F, 125 I,123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br may be useful.

[0311] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0312] The present disclosure can further include synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known to those of skill in the art, and those of skill in the art will readily recognize methods applicable to the compounds of the present disclosure.

[0313] The labeled compounds of the present disclosure can be used in screening assays to identify / evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to and activate CDK2 by monitoring its concentration fluctuations upon contact with CDK2 through label tracking. For example, a labeled test compound can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to inhibit CDK2. Thus, the ability of a test compound to compete with a standard compound for binding to CDK2 is directly correlated with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and the test compound is unlabeled. Therefore, to evaluate competition between the standard compound and the test compound, the concentration of the labeled standard compound is monitored, thereby ascertaining the relative binding affinity of the test compound.

[0314] kit The present disclosure also includes pharmaceutical kits useful, for example, for treating or preventing a CDK2-related disease or disorder (e.g., cancer, inflammatory disease, cardiovascular disease, or neurodegenerative disease, etc.), which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can optionally further include one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as would be readily apparent to one of skill in the art. Instructions, either as an insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0315] Biomarkers and Pharmacodynamic Markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, such as gene copy number, gene sequence, expression level, or phosphorylation level) for identifying human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder who are likely to benefit from the administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof). The present disclosure also provides pharmacodynamic markers (e.g., phosphorylation levels) for identifying human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder who are responsive to a CDK2 inhibitor.

[0316] The present methods are based, at least in part, on the discovery that the functional status of cyclin-dependent kinase inhibitor 2A ("CDKN2A," also referred to as "p16") is a biomarker for predicting sensitivity to CDK2-targeted therapy in G1 / S-specific cyclin-E1- ("CCNE1-") amplified cells, suitable for use in patient stratification. Furthermore, the present invention is based, at least in part, on the discovery that the level of human retinoblastoma-associated protein ("Rb") phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in CCNE1-amplified cell lines is a pharmacodynamic marker of CDK2 activity, suitable for use in measuring CDK2 enzyme activity in cellular assays or in preclinical and clinical applications, such as, for example, monitoring progression or responsiveness to treatment with CDK2 inhibitors.

[0317] CCNE1 and p16 CCNE1 and p16 are identified in the Examples as genes that, in combination, are useful for predicting responsiveness (e.g., disease improvement as evidenced by disease remission / resolution) to CDK2 inhibitors in subjects with a CDK2-related disease or disorder.

[0318] p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a) acts as a negative regulator of normal cell growth by interacting with CDK4 and CDK6. p16 is encoded by the cyclin-dependent kinase inhibitor 2A ("CDKN2A") gene (GenBank accession number NM_000077). The cellular location of the CDKN2A gene is 9p21.3, which is the short (p) arm of chromosome 9 at position 21.3. The molecular location of the CDKN2A gene is from base pairs 21,967,752 to 21,995,043 on chromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Genetic and epigenetic abnormalities in the gene encoding p16 are thought to lead to escape from aging and carcinogenesis (Okamoto et al., 1994, PNAS91(23):11045-9). Non-limiting examples of genetic abnormalities in the gene encoding p16 are listed in Table 1 below. The amino acid sequence of human p16 is provided below (GenBank Accession No. NP_000068 / UniProtKB Accession No. P42771): [ka] (SEQ ID NO: 1).

[0319] CCNE1 is a cell cycle factor essential for cell cycle control at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2 and interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 is provided below (GenBank accession number NP_001229 / UniProtKB accession number P24864): [ka] (SEQ ID NO: 2).

[0320] The Examples demonstrate that CDK2 knockdown inhibits the proliferation of CCNE1-amplified cell lines, but not CCNE1-non-amplified cell lines. Conversely, the Examples show that CDK4 / 6 inhibition inhibits the proliferation of CCNE1-non-amplified cell lines, but not CCNE1-amplified cell lines. The Examples further demonstrate that the inhibition of cell proliferation observed in CCNE1-amplified cells treated with CDK2 inhibitors requires the presence of a normal (e.g., non-mutated or non-deleted) p16 gene. Thus, CCNE1 and p16 together are combined biomarkers. Cells that respond to treatment with a CDK2 inhibitor exhibit amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, have a nucleotide sequence (e.g., a gene or mRNA) encoding a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), and / or have the presence of p16 protein, while control cells that do not respond to treatment with a CDK2 inhibitor do not exhibit amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and have a mutation or deletion in the gene encoding the p16 protein and / or lack expression of the p16 protein.

[0321] Accordingly, the present disclosure provides methods of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, comprising administering a CDK2 inhibitor to the human subject, wherein the human subject has previously been determined to (i) (a) have a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) have a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) express a p16 protein, and (ii) (a) have an amplification of the CCNE1 gene, and / or (b) have an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. In certain embodiments, the predictive methods described herein predict that the subject will respond to treatment with a CDK2 inhibitor with at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or 100% accuracy. For example, in some embodiments, if the prediction methods described herein are applied to 10 subjects who have, are suspected of having, or are at risk of developing a disease or disorder associated with CDK2, and 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor based on the prediction methods described herein, and 7 of those 8 subjects actually respond to treatment with the CDK2 inhibitor, then the prediction method has an accuracy of 87.5% (7 divided by 8). A subject is considered to be responsive to a CDK2 inhibitor if the subject shows any improvement in disease status as evidenced, for example, by a reduction or alleviation of symptoms, remission / resolution of the disease, etc.

[0322] In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the human subject (i) has (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, and / or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) has previously been determined to have amplification of the CCNE1 gene in a biological sample obtained from the human subject. In some embodiments, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO:1. In certain embodiments, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO:1.

[0323] In certain embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Table 1. In certain embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999, Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated herein by reference in its entirety. [Table 1-1] [Table 1-2] [Table 1-3]

[0324] The present disclosure also features a method of treating a human subject having, suspected of having, or at risk of developing a CDK2-associated disease or disorder, comprising: (i) identifying, in a biological sample obtained from the human subject, the presence of (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions, and / or (c) a p16 protein; (ii) identifying, in a biological sample obtained from the human subject, (a) amplification of the CCNE1 gene and / or (b) an expression level of CCNE1 higher than a control expression level of CCNE1; and (iii) administering a CDK2 inhibitor to the human subject. In some embodiments, the subject has a CDK2-associated disease or disorder. In some embodiments, the subject is suspected of having or is at risk of developing a CDK2-associated disease or disorder. In some embodiments, the method includes: (i) identifying, in a biological sample obtained from the human subject, the presence of (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) a p16 protein; (ii) identifying, in the biological sample obtained from the human subject, (a) amplification of the CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject.

[0325] The disclosure also features a method for predicting the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, comprising: (i) determining, from a biological sample obtained from the human subject, (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of p16 protein; and (ii) determining, from the biological sample obtained from the human subject, (a) the nucleotide sequence of the CCNE1 gene. and (b) determining the number of copies of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of a p16 protein, and (2) (a) amplification of the CCNE1 gene and / or (b) an expression level of CCNE1 higher than a control expression level of CCNE1 predicts that the human subject will respond to a CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method includes (i) determining from a biological sample obtained from the human subject (a) the nucleotide sequence of the CDKN2A gene, and / or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) determining from the biological sample obtained from the human subject (a) the copy number of the CCNE1 gene, wherein (1) the presence of (a) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (2) amplification of (a) the CCNE1 gene predicts that the human subject will respond to a CDK2 inhibitor.

[0326] In certain embodiments, (i) determining (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of p16 protein is performed prior to administering a CDK2 inhibitor to the human subject (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or 6 hours to 16 hours, 6 hours to 20 hours, or 6 hours to 24 hours, 2 days to 3 days, 2 days to 4 days, 2 days to 5 days, 2 days to 6 days, 2 days to 7 days, 1 week to 2 weeks, 1 week to 3 weeks, or 1 week to 4 weeks). In certain embodiments, (ii) determining (a) the copy number of the CCNE1 gene and / or (b) the expression level of CCNE1 is performed prior to administering a CDK2 inhibitor to the human subject (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or 6 hours to 16 hours, 6 hours to 20 hours, or 6 hours to 24 hours, 2 days to 3 days, 2 days to 4 days, 2 days to 5 days, 2 days to 6 days, 2 days to 7 days, 1 week to 2 weeks, 1 week to 3 weeks, or 1 week to 4 weeks before).

[0327] Amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1, in combination with the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), indicates / predicts that a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder will respond to a CDK2 inhibitor.

[0328] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21.

[0329] In certain embodiments, the expression level of CCNE1 is the level of CCNE1 mRNA. In certain embodiments, the expression level of CCNE1 is the level of CCNE1 protein.

[0330] In some embodiments of the aforementioned method, the control expression level of CCNE1 is a pre-established cut-off value. In some embodiments of the aforementioned method, the control expression level of CCNE1 is the expression level of CCNE1 in a sample(s) obtained from one or more subjects who are not responding to treatment with a CDK2 inhibitor.

[0331] In some embodiments of the aforementioned method, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the aforementioned method, the expression level of CCNE1 is the expression level of CCNE1 protein. In some embodiments where the expression level of CCNE1 is the expression level of CCNE1 mRNA, the expression level of CCNE1 is measured by RNA sequencing, quantitative polymerase chain reaction (PCR), in situ hybridization, nucleic acid array, or RNA sequencing. In some embodiments where the expression level of CCNE1 is the expression level of CCNE1 protein, the expression level of CCNE1 is measured by Western blot, enzyme-linked immunosorbent assay, or immunohistochemical staining.

[0332] Rb S780 The disclosure also features a method for evaluating the CDKN2A gene and the CCNE1 gene, including determining (i) the presence of (a) the nucleotide sequence of the CDKN2A gene, or (b) the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) the copy number of the CCNE1 gene, from a biological sample(s) obtained from a human subject having a disease or disorder associated with CDK2.

[0333] The present disclosure also features a method for assessing the response of a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject, wherein the human subject has previously been determined to have CCNE1 gene amplification and / or a CCNE1 expression level higher than a control expression level; and (b) measuring the level of retinoblastoma (Rb) protein phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 in a biological sample obtained from the subject after administration of step (a), wherein a decrease in the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 compared to the control level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 indicates that the human subject is responsive to the CDK2 inhibitor. In some embodiments, the subject has a CDK2-related disease or disorder. In some embodiments, the subject is suspected of having or at risk of developing a CDK2-related disease or disorder. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample.

[0334] Phosphorylation of Rb at serine corresponding to amino acid position 780 of SEQ ID NO: 3 (referred to herein as "Ser780" or "S780") has been identified in the Examples as a useful pharmacodynamic marker for assessing the responsiveness (e.g., inhibition by CDK2) of human subjects with a disease or disorder having CCNE1 amplification to CDK2 inhibitors.

[0335] Rb is a cell cycle regulator and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and by cyclin E / CDK2 at Ser807 and Ser811. Rb is encoded by the RB transcriptional repressor complement 1 ("RB1") gene (GenBank accession number NM_000321). The amino acid sequence of human Rb is provided below (GenBank accession number NP_000312 / UniProtKB accession number P06400) (S780 is bold and underlined): [ka] (SEQ ID NO: 3).

[0336] As described above, the examples demonstrate that CDK2 knockdown inhibits the growth of CCNE1-amplified cell lines but not CCNE1-non-amplified cell lines. The examples further demonstrate that CDK2 knockdown or inhibition blocks Rb phosphorylation at S780 in CCNE1-amplified cell lines but not in CCNE1-non-amplified cell lines. Thus, Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 is a pharmacodynamic marker for assessing the response to CDK2 inhibition in CCNE1-amplified cancer cells or patients with diseases or disorders associated with CCNE1 amplification. Thus, provided herein is a method for using the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 in a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder as a marker for indicating the response of the human subject to a CDK2 inhibitor, wherein the human subject has an increased expression level of CCNE1.

[0337] Accordingly, the disclosure features a method for measuring the amount of a protein in a sample, comprising: (a) providing a biological sample obtained from a human subject having a disease or disorder associated with CDK2; and (b) measuring in the biological sample the level of Rb protein phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. In certain embodiments, provided herein is a method for assessing the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject, wherein the human subject has previously been determined to have CCNE1 gene amplification and / or a CCNE1 expression level higher than a control expression level of CCNE1; and (b) measuring the level of Rb protein phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the human subject after administration of step (a), wherein a decrease in the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the human subject is responsive to the CDK2 inhibitor. In certain embodiments, the human subject has a disease or disorder associated with CDK2.

[0338] A decrease in the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 compared to the control level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3, combined with amplification of the CCNE1 gene and / or a CCNE1 expression level higher than the control expression level of CCNE1, indicates that a human subject having, suspected of having, or at risk of developing a CDK2-related disease or disorder will respond to a CDK2 inhibitor. For example, in a subject with amplification of the CCNE1 gene and / or a CCNE1 expression level higher than the control expression level of CCNE1, a biological sample obtained from the subject after treatment with a CDK2 inhibitor having a low (e.g., reduced compared to the control) or undetectable level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 indicates that the subject will respond to a CDK2 inhibitor.

[0339] A biological sample obtained from a subject after administration of a CDK2 inhibitor to the subject, which has a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3, in combination with (i) amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and (ii) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), indicates that the human subject has, is suspected of having, or is at risk of developing a disease or disorder associated with CDK2, will respond to the CDK2 inhibitor. For example, in a human subject having (i) amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and (ii) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), a biological sample obtained from the human subject after administration of a CDK2 inhibitor to the subject and having a low (e.g., reduced compared to a control) or undetectable level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the human subject will respond to the CDK2 inhibitor.

[0340] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In certain embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21. In certain embodiments, the expression level of CCNE1 is the level of CCNE1 mRNA. In certain embodiments, the expression level of CCNE1 is the level of CCNE1 protein.

[0341] Control As described above, methods related to biomarkers and pharmacodynamic markers can include measuring one or more markers (e.g., biomarkers or pharmacodynamic markers, e.g., amplification of the CCNE1 gene, expression levels of CCNE1, the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1), and Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3) in a biological sample from a human subject having, suspected of having, or at risk of developing a CDK2-associated disease or disorder. In certain embodiments, the human subject has a CDK2-associated disease or disorder. In certain embodiments, the human subject is suspected of having a CDK2-associated disease or disorder, or is at risk of developing a CDK2-associated disease or disorder. are at risk of developing it. In certain aspects, the level of one or more biomarkers (e.g., amplification (e.g., for the CCNE1 gene), expression level (e.g., for CCNE1 or p16 protein), or phosphorylation level (e.g., for Rb)), compared to a control level of the one or more biomarkers, predicts / indicates a human subject's response to a treatment comprising a CDK2 inhibitor. In certain embodiments, a human subject is identified as likely to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present.In other embodiments, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) in a biological sample from the human subject after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In yet another embodiment, a human subject is identified as responding to a CDK2 inhibitor if: (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than a control expression level of CCNE1; (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present; and (iii) in a biological sample from the human subject after the human subject has been administered a CDK2 inhibitor, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In this context, the term "control" includes a sample (from the same tissue type) obtained from a human subject known to be unresponsive to CDK2 inhibitors. The term "control" also includes a sample (from the same tissue type) previously obtained from a human subject known not to respond to CDK2 inhibitors, and is used as a reference for future comparison with a test sample collected from a human subject predicting therapeutic response. The "control" level (e.g., gene copy number, expression level, or phosphorylation level) of a particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in a particular cell type or tissue can be previously established by analyzing the biomarker level (e.g., expression level, or phosphorylation level) in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 or more) human subjects who did not respond to treatment with a CDK2 inhibitor.This pre-established reference value (which may be an average or median value (e.g., gene copy number, expression level, or phosphorylation level) obtained from multiple human subjects who did not respond to therapy) can then be used as a "control" level of the biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in comparison with the test sample. In such a comparison, a human subject is predicted to respond to a CDK2 inhibitor if the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the pre-established reference, and a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present. In another such comparison, if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a pre-established reference, and (ii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a pre-established reference, the human subject is predicted to be responsive to the CDK2 inhibitor. In yet another such comparison, if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a pre-established reference, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present, and (iii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a pre-established reference, the human subject is indicated to be responsive to a CDK2 inhibitor.

[0342] Alternatively, the "control" level of a particular biomarker in a particular cell type or tissue can be established in advance by analyzing the biomarker level in one or more human subjects who have responded to treatment with a CDK2 inhibitor. This pre-established reference value (which can be the average or median value (e.g., expression level or phosphorylation level) obtained from multiple human subjects who have responded to the therapy) can then be used as the "control" level (e.g., expression level or phosphorylation level) in comparison with the test sample. In such a comparison, if the level of the analyzed biomarker (e.g., the copy number of the CCNE1 gene, the expression level of CCNE1, the expression level of p16, or the phosphorylation level of Rb at serine corresponding to amino acid position 780 of SEQ ID NO: 3) is equal to or corresponds to (e.g., at least 85% but less than 115%) the pre-established reference, the human subject is indicated to be responsive to the CDK2 inhibitor.

[0343] In certain embodiments, the "control" is a pre-established cutoff value. The cutoff value is typically a biomarker level (e.g., copy number, expression level, or phosphorylation level) above or below which a human subject is thought to be responsive to a therapy of interest. Thus, according to the methods and compositions described herein, a reference level (e.g., CCNE1 gene copy number, CCNE1 expression, p16 expression, or Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3) is identified as a cutoff value above or below which a subject will be responsive to a CDK2 inhibitor. The cutoff value determined for use in the methods described herein can be compared, for example, to a published concentration range, but can be individualized to the methodology and patient population used.

[0344] In some embodiments, the expression level of CCNE1 is increased compared to the expression level of CCNE1 in a control. For example, the expression level of CCNE1 analyzed is at least 1.5, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 25, at least 50, at least 75, or at least 100 times higher than the expression level of CCNE1 in a control, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 75, or at least 100 times higher than the expression level of CCNE1 in a control. The affinity may be 0%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000%, at least 1,500%, at least 2,000%, at least 2,500%, at least 3,000%, at least 3,500%, at least 4,000%, at least 4,500%, or at least 5,000% higher.

[0345] p16 protein is present if the protein is detectable by any assay known in the art or described herein, such as, for example, Western blot, immunohistochemistry, fluorescence-activated cell sorting, and enzyme-linked immunoassay. In some embodiments, p16 protein is present at an expression level within at least 5%, at least 10%, at least 20%, or at least 30% of the p16 expression level in healthy controls.

[0346] In some embodiments, the analyzed level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is reduced compared to the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. For example, the analyzed level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 can be at least 1.5, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 25, at least 50, at least 75, or at least 100 times lower, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% lower than the control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3.

[0347] biological samples Suitable biological samples for the methods described herein include any sample containing blood or tumor cells obtained or derived from a human subject in need of treatment.For example, biological samples can include tumor cells from a biopsy from a patient suffering from a solid tumor.Tumor biopsies can be obtained by various means known in the art.Alternatively, blood samples can be obtained from patients suffering from blood cancer.

[0348] The biological sample can be obtained from a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the disease or disorder associated with CDK2 is cancer (such as those described above).

[0349] Methods for obtaining and / or storing samples that maintain the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those of skill in the art. For example, a biological sample can be further contacted with one or more additional agents, such as buffers and / or inhibitors, including one or more of nuclease inhibitors, protease inhibitors, and phosphatase inhibitors, that maintain or minimize alteration of the molecules in the sample.

[0350] Evaluation of biomarkers and pharmacodynamic markers The expression level of CCNE1 or p16 can be detected, for example, as the RNA expression of the target gene (i.e., the gene encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and / or measuring the mRNA expression level of the gene encoding CCNE1. Alternatively, the expression level of CCNE1 or p16 can be detected, for example, as the protein expression of the target gene (i.e., the gene encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and / or measuring the protein expression level of the gene encoding CCNE1 or p16.

[0351] In some embodiments, the expression level of CCNE1 or p16 is determined by measuring RNA levels. Various suitable methods can be used to detect and / or measure the mRNA expression level of a gene. For example, mRNA expression can be determined using Northern blot or dot blot analysis, reverse transcriptase-PCR (RT-PCR, e.g., quantitative RT-PCR), in situ hybridization (e.g., quantitative in situ hybridization), nucleic acid arrays (e.g., oligonucleotide arrays or gene chips), and RNA sequencing analysis. Details of such methods are described below and in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual Second Edition, vol. 1, 2 and 3. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, USA, November 1989; Gibson et al. (1999) Genome Res., 6(10):995-1001; and Zhang et al. (2005) Environ. Sci. Technol., 39(8):2777-2785; U.S. Publication No. 2004086915; European Patent No. 0543942; and U.S. Patent No. 7,101,663; Kukurba et al. (2015) Cold Spring Harbor Protocols., 2015(11):951-69, the disclosures of each of which are incorporated herein by reference in their entirety.

[0352] In one example, the presence or amount of one or more distinct mRNA populations in a biological sample can be determined by isolating total mRNA from the biological sample (see, e.g., Sambrook et al., supra, and U.S. Pat. No. 6,812,341) and subjecting the isolated mRNA to agarose gel electrophoresis to separate the mRNA by size. The size-separated mRNA is then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more mRNA populations in the biological sample can then be determined using one or more detectably labeled polynucleotide probes complementary to the mRNA sequences of interest, which bind to their corresponding mRNA populations, thus rendering them detectable. Detectable labels include, for example, fluorescent labels (e.g., umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, allophycocyanin, or phycoerythrin), luminescent labels (e.g., europium, terbium, Qdot™ nanoparticles supplied by Quantum Dot Corporation, Palo Alto, CA), radiolabels (e.g., 125I, 131I, 35S, 32P, 33P, or 3H), and enzyme labels (horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase).

[0353] In some embodiments, the expression level of CCNE1 or p16 is determined by measuring protein levels. A variety of suitable methods can be used to detect and / or measure the protein expression level of a target gene. For example, CCNE1 or p16 protein expression can be determined using Western blot, enzyme-linked immunosorbent assay ("ELISA"), fluorescence-activated cell sorting, or immunohistochemical analysis (e.g., using CCNE1-specific or p16-specific antibodies, respectively). Details of such methods are described below and, for example, in Sambrook et al., supra.

[0354] In one example, the presence or amount of one or more distinct protein populations (e.g., CCNE1 or p16) in a biological sample can be determined by Western blot analysis, for example, by isolating total protein from the biological sample (see, e.g., Sambrook et al., supra) and subjecting the isolated proteins to agarose gel electrophoresis to separate the proteins by size. The size-separated proteins are then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more protein populations in the biological sample can then be determined using one or more antibody probes, for example, a first antibody specific for the protein of interest (e.g., CCNE1 or p16) and a detectably labeled second antibody specific to the first antibody, which binds to the corresponding protein population and thus makes it detectable. Detectable labels suitable for use in Western blot analysis are known in the art.

[0355] Methods for detecting or measuring gene expression (e.g., mRNA or protein expression) can optionally be performed in a format that allows for the rapid preparation, processing, and analysis of multiple samples. This can be, for example, in multiwell assay plates (e.g., 96-well or 386-well) or arrays (e.g., nucleic acid or protein chips). Stock solutions of various reagents can be provided manually or robotically, and subsequent sample preparation (e.g., RT-PCR, labeling, or cell fixation), pipetting, dilution, mixing, dispensing, washing, incubation (e.g., hybridization), sample readout, data collection (optical data), and / or analysis (computer-assisted image analysis) can be performed robotically using commercially available analysis software, robotics, and detection instruments capable of detecting signals generated from the assay. Examples of such detectors include, but are not limited to, spectrophotometers, luminometers, fluorometers, and devices that measure the decay of radioactive isotopes. Exemplary high-throughput cell-based assays (e.g., detecting the presence or levels of a target protein in cells) can utilize ArrayScan® VTI HCS Reader or KineticScan® HCS Reader technology (Cellomics Inc., Pittsburg, PA).

[0356] In some embodiments, the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 and / or the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is determined by assessing the DNA sequence of the CDKN2A gene (e.g., genomic DNA or cDNA) or assessing the RNA sequence of the CDKN2A gene (e.g., RNA, e.g., mRNA). Methods for performing nucleic acid sequencing analysis are known in the art and described above. Non-limiting examples of inactivating nucleic acid substitutions and / or deletions that prevent the CDKN2A gene from encoding a protein comprising the amino acid sequence of SEQ ID NO: 1 are listed in Table 1 above. In certain embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999; Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998; and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated herein by reference in its entirety.

[0357] In some embodiments, the expression level of a gene or the presence of a gene lacking one or more inactivating nucleic acid substitutions or deletions is determined by evaluating the copy number variation (CNV) of the gene. The CNV of a gene (e.g., the CCNE1 gene and / or the CDKN2A gene) can be determined / identified by various suitable methods. For example, the CNV can be determined using fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) arrays, and next-generation sequencing (NGS) technologies.

[0358] In one example, copy number variation of one or more distinct genes in a biological sample can be determined by MLPA, for example, by extracting a DNA sample from the biological sample (see, e.g., Sambrook et al., supra, and U.S. Pat. No. 6,812,341) and amplifying a DNA sequence of interest (e.g., CCNE1 or CDKN2A) using a mixture of MLPA probes. Each MLPA probe consists of two oligonucleotides that hybridize to immediately adjacent target DNA sequences (e.g., CCNE1 or CDKN2A) to be ligated into a single probe. The ligated probe is amplified via PCR with a fluorescently labeled PCR primer, which allows visualization of the amplification product during fragment separation by capillary electrophoresis. The presence, absence, or amplification of one or more genes of interest in the biological sample is calculated by measuring the fluorescence from the PCR, quantifying the amount of PCR product after normalization, and comparing it to a control DNA sample.

[0359] The level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 can be detected by various suitable methods. For example, the phosphorylation status can be determined using Western blot, ELISA, fluorescence-activated cell sorting, or immunohistochemical analysis. Details of such methods are described below and, for example, in Sambrook et al., supra.

[0360] Similar to the methods for detecting or measuring gene expression (described above), the methods for detecting or measuring the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3 can optionally be performed in a format that allows for rapid preparation, processing, and analysis of multiple samples.

[0361] The present invention will be described in more detail using specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. [Example]

[0362] The experimental procedures for the compounds of the present invention are provided below. Preparative LC-MS purification of some of the prepared compounds was carried out on a Waters mass-directed fractionation system. The basic instrument setup, protocols, and control software for the operation of these systems are described in detail in the literature. See, for example, "Two-Pump at-Column Dilution Configuration for Preparative LC-MS," K. Blom, J. Combi. Chem., 4, 295 (2002), "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification," K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003), and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity checks under the following conditions: Instrument: Agilent 1100 series, LC / MSD, Column: Waters Sunfire™ C 18 5 μm particle size, 2.1 × 5.0 mm, buffer: Mobile phase A: 0.025% TFA in water and Mobile phase B: acetonitrile, gradient 2% to 80% of B in 3 min at a flow rate of 2.0 mL / min.

[0363] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel), as shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows: pH=2 purification: Waters Sunfire(TM) C 18 The 5 μm particle size, 19 × 100 mm column, elution with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile, flow rate 30 mL / min, separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol described in the literature (see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with the 30 × 100 mm column was 60 mL / min.

[0364] pH=10 purification: Waters XBridge (trademark) C 18 The 5 μm particle size, 19 × 100 mm column was eluted with mobile phase A: 0.15% NH OH in water and mobile phase B: acetonitrile at a flow rate of 30 mL / min. The separation gradient was optimized for each compound using a Compound Specific Method Optimization protocol described in the literature (see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with a 30 × 100 mm column was 60 mL / min.

[0365] Intermediate 1. 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (9.18 g, 42.3 mmol) in tert-butanol (81 mL) and 1,2-dichloroethane (81 mL) was cooled to 0 °C in an ice bath in a flask equipped with a stir bar. A 1 molar (M) solution of zinc chloride (60 mL, 60 mmol) in diethyl ether was then added, and the resulting mixture was stirred at 0 °C for 1 hour. To the reaction mixture was then added 1-(methylsulfonyl)piperidin-4-amine (7.18 g, 40.3 mmol), followed by the dropwise addition of a solution of triethylamine (6.74 mL, 48.3 mmol) in a 1:1 mixture of 1,2-dichloroethane / tert-butanol (7 mL). The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature and then heated to 60 °C overnight. The reaction mixture was then concentrated to approximately one-third volume and diluted with water. An off-white precipitate formed, and the mixture was slurried for 2 hours. The precipitate was then collected by filtration, washed with water and dried under air. The crude product obtained was used directly without further purification. LCMS C 11 H 15 ClF3N4O2S(M+H) + Calculated for: m / z = 359.1; Found: 359.0.

[0366] Intermediate 2. 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] To a vial containing 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 1, 0.30 g, 0.836 mmol), tetrakis(triphenylphosphine)palladium(0) (0.048 g, 0.042 mmol), and 4-(tributylstannyl)-1-trityl-1H-imidazole (0.501 g, 0.836 mmol) was added DMF (3.4 mL). The vial was flushed with nitrogen and a fresh cap was applied, then the reaction was heated to 100° C. for 18 h.

[0367] After cooling to room temperature, the solution was filtered and washed with MeOH (3.4 mL). Aqueous HCl (1 M aqueous solution, 3.4 mL) was added and the solution was heated to 80° C. for 1 h. The reaction was cooled to room temperature and the MeOH was evaporated on a rotovap. Additional aqueous HCl (1 M, 3.4 mL) was added. The aqueous layer was extracted with EtOAc (3×) to remove unwanted organic by-products. The aqueous layer was basified by adding NaOH to pH 13. This was extracted with DCM (5×). The combined organics were dried over sodium sulfate and evaporated to deliver the desired product, which was used without further purification. LCMS C 14 H 18 F3N6O2S(M+H) + Calculated for: m / z = 391.1; Found: 391.2.

[0368] Intermediate 3. tert-Butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ka] A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (11.4 g, 52.5 mmol) in tert-butanol (100 mL) and 1,2-dichloroethane (100 mL) was cooled to 0 °C in an ice bath, followed by the addition of a 1 M solution of zinc chloride (75 mL, 75 mmol) in diethyl ether. The resulting mixture was purged with nitrogen and stirred at 0 °C for 1 hour. tert-Butyl 4-aminopiperidine-1-carboxylate (10.0 g, 49.9 mmol) was then added to the reaction mixture, followed by the dropwise addition of a solution of triethylamine (8.35 mL, 59.9 mmol) in a 1:1 mixture of 1,2-dichloroethane / tert-butanol (15 mL). The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature before being heated to 60 °C overnight. After cooling to room temperature, the reaction mixture was concentrated to approximately one-third volume and diluted with water. Upon stirring, an off-white precipitate formed and the mixture was slurried for 1 hour. The precipitate was then collected by filtration, washed with water and hexane, and dried under air. The resulting crude product was used directly without further purification. LCMS C 11 H 13 ClF3N4O2(M-C4H8+H) + Calculated for: m / z = 325.1; found 325.0.

[0369] Intermediate 4. 4-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] A mixture of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Intermediate 3, 3.00 g, 7.88 mmol) in THF (39.4 mL) was purged with nitrogen and stirred at 80 °C for 10 min. After that, a 4 M solution of HCl in 1,4-dioxane (7.88 mL, 31.5 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was sparged with nitrogen for 5 min, after which 1-methyl-1H-imidazole-4-sulfonyl chloride (1.71 g, 9.47 mmol) was added, followed by the dropwise addition of triethylamine (6.59 mL, 47.3 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with water and extracted with EtOAc and CHCl. The combined organic phases were then dried over MgSO and concentrated. The crude material obtained was used directly without further purification. 14 H 17 ClF3N6O2S(M+H) + Calculated for: m / z = 425.1; found 425.1.

[0370] Intermediate 5. 4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] Step 1: N,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide [ka] A mixture of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 250 mg, 0.588 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (177 mg, 0.588 mmol), Pd(dppf)Cl.CHCl (96.0 mg, 0.118 mmol), sodium carbonate (187 mg, 1.77 mmol), acetonitrile (8 mL), and water (1.6 mL) was sparged with nitrogen in a microwave vial equipped with a stir bar and heated at 80 °C for 16 h. After cooling to room temperature, the solution was filtered through a pad of SiliaMetS Thiol® and concentrated. The residue was purified by flash column chromatography (Agela Flash Column Silica-CS (24 g)) eluting with a gradient of 0-20% CHCl / methanol to give N,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide, which was used in the next reaction without further purification. LCMS: C 19 H 25 F3N9O4S2(M+H) + Calculated for: m / z = 564.1; found 564.2.

[0371] Step 2: 4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] N,N-Dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamide from step 1 was dissolved in EtOH (10 mL) and 12 M aqueous HCl (1 mL). The solution was irradiated in a microwave reactor at 80 °C for 1 h. After cooling to room temperature, the solution was washed with EtO (10 mL). The resulting aqueous solution was then basified with 1 M aqueous NaOH. The solution was extracted with CHCl (3 x 10 mL) and washed with brine (10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (226 mg, 0.470 mmol, 80% yield over two steps). LCMS C 17 H 20 F3N8O2S(M+H) + Calculated for: m / z = 457.1; found 457.4.

[0372] Intermediate 6. tert-Butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate [ka] A mixture of 2,4-dichloropyrimidine-5-carbonitrile (23.89 g, 137 mmol) in tert-butanol (156 mL) and 1,2-dichloroethane (156 mL) was cooled to 0 °C in an ice bath, followed by the addition of a 1 M solution of zinc chloride (25.5 g, 187 mmol) in diethyl ether. The resulting mixture was purged with nitrogen and stirred at 0 °C for 1 hour. To the reaction mixture was then added tert-butyl 4-aminopiperidine-1-carboxylate (25 g, 125 mmol), followed by the slow addition of a solution of Hunig's base (32.7 mL, 187 mmol) in a 1:1 mixture of 1,2-dichloroethane / tert-butanol (15 mL). The ice bath was then removed, and the reaction mixture was allowed to warm to room temperature before being heated to 60 °C overnight. After cooling to room temperature, the reaction mixture was concentrated to approximately one-third volume and poured into rapidly stirred water. Upon stirring, a precipitate formed and the mixture was slurried for 1 hour. The precipitate was then collected by filtration, washed with water and hexane, and dried under air. The crude product obtained was used directly without further purification. LCMS C 11 H 13 ClN5O2(M-C4H8+H) + Calculated for: m / z = 282.1; found 282.0.

[0373] Intermediate 7. tert-Butyl 4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1-carboxylate [ka] This compound was prepared according to the procedure described in Intermediate 6, using 2,4,5-trichloropyrimidine instead of 2,4-dichloropyrimidine-5-carbonitrile as the starting material. 10 H 13 Cl2N4O2(M-C4H8+H) + Calculated for: m / z = 291.0; Found: 291.0.

[0374] Intermediate 8: N-(4-chloro-3-methylpyridin-2-yl)acetamide [ka] A mixture of 4-chloro-3-methylpyridin-2-amine (62.5 mg, 0.438 mmol), acetic anhydride (0.50 mL, 5.3 mmol), and triethylamine (1.0 mL, 7.2 mmol) was stirred in a vial equipped with a stir bar at room temperature for 12 hours. The resulting solution was concentrated. The crude product was used directly without further purification. LCMS: CH 10 ClNO(M+H) + Calculated for: m / z = 185.0; found 185.2.

[0375] Intermediate 9. 4-Chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile [ka] This compound was prepared according to the procedure described in Intermediate 4, using tert-butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate (Intermediate 6) and methanesulfonyl chloride as starting materials instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride. LCMS C 11 H 15 ClNOS(M+H) + Calculated for: m / z = 316.1; Found: 316.0.

[0376] Intermediate 10. 4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile [ka] This compound was prepared according to the procedure described in Intermediate 2, using 4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (Intermediate 6) as the starting material instead of 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 14 H 18 N7O2S(M+H) + Calculated for: m / z = 348.1; Found: 348.1.

[0377] Intermediate 11. 4-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 4, using cyclopropanesulfonyl chloride instead of 1-methyl-1H-imidazole-4-sulfonyl chloride as the starting material. 13 H 17 ClF3N4O2S(M+H) + Calculated for: m / z = 385.1; Found: 385.1.

[0378] Intermediate 12. N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 2, using 4-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 11) as the starting material instead of 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 16 H 20 F3N6O2S(M+H)+ Calculated for: m / z=417.1; Found: 417.2.

[0379] Intermediate 13. 4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 5, using tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Intermediate 3) as the starting material in Step 1 instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS: C 13 H 16 F3N6(M+H) + Calculated for: m / z = 313.1; found 313.2.

[0380] Intermediate 14. tert-Butyl 4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ka] To a vial containing 4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 13, 1.079 g, 3.46 mmol) and di-tert-butyl dicarbonate (0.795 mL, 3.46 mmol) was added DCM (34.6 mL). The mixture was stirred vigorously until completely dissolved (approximately 10 min), and then triethylamine (1.441 mL, 10.37 mmol) was added dropwise at room temperature. The reaction was stirred for 30 min, at which point LCMS showed completion. The crude reaction mixture was concentrated and purified by flash column chromatography (Agela Flash Column Silica-CS (24 g) eluting with a gradient of 0-20% CH2Cl2 / methanol) to give tert-butyl 4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate, which was used in the next reaction without further purification. LCMS C 18 H 24 F3N6O2(M+H) + Calculated for: m / z = 413.2; found 413.3.

[0381] Intermediate 15. tert-Butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate [ka] This compound was prepared according to the procedure described in Intermediate 3, using tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate instead of tert-butyl 4-aminopiperidine-1-carboxylate as the starting material. 15 H 20 ClF4N4O2(M+H) + Calculated for: m / z = 399.1; found 399.2.

[0382] Intermediate 16. 4-Chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 4, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate (Intermediate 15) and methanesulfonyl chloride as starting materials instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride. LCMS C 11 H 14 ClF4N4O2S(M+H) + Calculated for: m / z = 377.1; found 376.9.

[0383] Intermediate 17. N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 5, using 4-chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 16) as the starting material instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 14 H 17 F4N6O2S(M+H) + Calculated for: m / z = 409.1; found 409.2.

[0384] Intermediate 18. N-((3R,4S)-3-fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 5, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate (Intermediate 15) as the starting material instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS: C 13 H 15 F4N6(M+H) + Calculated for: m / z = 331.1; found 331.0.

[0385] Intermediate 19. tert-Butyl (3R,4S)-4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1-carboxylate [ka] This compound was prepared according to the procedure described in Intermediate 4, using N-((3R,4S)-3-fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 18) as the starting material instead of 4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 18 H 23 F4N6O2(M+H) + Calculated for: m / z = 431.2; found 431.1.

[0386] Intermediate 20. tert-Butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate [ka] This compound was prepared according to the procedure described in Intermediate 3, using tert-butyl (3R,4S)-4-amino-3-methylpiperidine-1-carboxylate instead of tert-butyl 4-aminopiperidine-1-carboxylate as the starting material. 16 H 23 ClF3N4O2(M+H) + Calculated for: m / z = 395.2; found 395.2.

[0387] Intermediate 21. 4-Chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 4, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 20) and methanesulfonyl chloride as starting materials instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride. LCMS C 12 H 17 ClF3N4O2S(M+H) + Calculated for: m / z = 373.1; found 373.1.

[0388] Intermediate 22. 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 5, using 4-chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 21) as the starting material instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 15 H 20 F3N6O2S(M+H) + Calculated for: m / z = 405.1; found 405.2.

[0389] Intermediate 23. 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine [ka] This compound was prepared according to the procedure described in Intermediate 5, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 20) as the starting material instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS: C 14 H 18 F3N6(M+H) + Calculated for: m / z = 327.2; found 327.3.

[0390] Intermediate 24. tert-Butyl (3R,4S)-4-((4-(1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate [ka] This compound was prepared according to the procedure described in Intermediate 4, using 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 23) as the starting material instead of 4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS C 19 H...

Claims

1. A compound of formula (I), 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4; ring moiety A is a 4- to 14-membered heterocycloalkyl, said ring moiety A being attached to the —NH— group of formula (I) at a ring member of the saturated or partially saturated ring of said 4- to 14-membered heterocycloalkyl; R １ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; R ２ , R ３ , and R ４ is defined as shown in group (a), group (b), or group (c), Group (a): R ２ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－４ Alkoxy, C １－４ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; R ３ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; R ４ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)NR ｃ４ (OR ａ４ ), C(O)OR ａ４ , C(=NR ｅ４ ) R ｂ４ , C(=NR ｅ４ ) NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ NR ｃ４ R ｄ４ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ａ is optionally substituted by a substituent; Group (b): R ２ H, D, Halo, NO ２ , C.N., C. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ２ , S.R. ａ２ , NHOR ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)NR ｃ２ (OR ａ２ ), C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ NR ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) R ｂ２ , N.R. ｃ２ S(O)NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S(O) (=NR ｅ２ ) R ｂ２ , N.R. 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 , OS(O) ２ R ｂ２ , S(O)(=NR ｅ２ ) R ｂ２ , SF ５ , P(O)R ｆ２ R ｇ２ , OP(O)(OR ｈ２ ) (OR ｉ２ ), P(O)(OR ｈ２ ) (OR ｉ２ ), and B.R. ｊ２ R ｋ２ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ａ is optionally substituted by a substituent; R ３ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; R ４ is H, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; Group (c): R ２ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; R ３ and R ４ together with the atoms to which they are attached, may be one, two, three, or four independently selected R ４Ａ forming a 5- to 7-membered heterocycloalkyl ring optionally substituted by substituents; Each R ａ２ , R ｃ２ , and R ｄ２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ａ optionally substituted with substituents, Or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, form one, two, three, or four independently selected R ２Ａ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with substituents; Each R ｂ２ are independently selected from 1, 2, 3, or 4 independently selected R ２Ａ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｅ２ are independently 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ２ and R ｇ２ are independently H, 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ２ and R ｉ２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ２ and R ｋ２ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ２ and R ｋ２ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ２Ａ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ２１ , S.R. ａ２１ , NHOR ａ２１ , C(O)R ｂ２１ , C(O)NR ｃ２１ R ｄ２１ , C(O)NR ｃ２１ (OR ａ２１ ), C(O)OR ａ２１ , O.C.(O.)R ｂ２１ , OC(O)NR ｃ２１ R ｄ２１ , N.R. ｃ２１ R ｄ２１ , N.R. ｃ２１ NR ｃ２１ R ｄ２１ , N.R. ｃ２１ C(O)R ｂ２１ , N.R. ｃ２１ C(O)OR ａ２１ , N.R. ｃ２１ C(O)NR ｃ２１ R ｄ２１ , C(=NR ｅ２１ ) R ｂ２１ , C(=NR ｅ２１ ) NR ｃ２１ R ｄ２１ , N.R. ｃ２１ C (=NR ｅ２１ ) NR ｃ２１ R ｄ２１ , N.R. ｃ２１ C (=NR ｅ２１ ) R ｂ２１ , N.R. ｃ２１ S(O)NR ｃ２１ R ｄ２１ , N.R. ｃ２１ S(O)R ｂ２１ , N.R. ｃ２１ S (O) ２ R ｂ２１ , N.R. ｃ２１ S(O) (=NR ｅ２１ ) R ｂ２１ , N.R. 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 , OS(O) ２ R ｂ２１ , S(O)(=NR ｅ２１ ) R ｂ２１ , S.F. ５ , P(O)R ｆ２１ R ｇ２１ , OP(O)(OR ｈ２１ ) (OR ｉ２１ ), P(O)(OR ｈ２１ ) (OR ｉ２１ ), and B.R. ｊ２１ R ｋ２１ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ｂ optionally substituted with substituents, Each R ａ２１ , R ｃ２１ , and R ｄ２１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ｂ optionally substituted with substituents, Or any R bonded to the same N atom ｃ２１ and R ｄ２１ together with the N atom to which they are attached, form one, two, three, or four independently selected R ２Ｂ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ２１ are independently selected from 1, 2, 3, or 4 independently selected R ２Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｅ２１ are independently 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ２１ and R ｇ２１ are independently H, 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ２１ and R ｉ２１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ２１ and R ｋ２１ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ２１ and R ｋ２１ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ２Ｂ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ２２ , S.R. ａ２２ , NHOR ａ２２ , C(O)R ｂ２２ , C(O)NR ｃ２２ R ｄ２２ , C(O)NR ｃ２２ (OR ａ２２ ), C(O)OR ａ２２ , O.C.(O.)R ｂ２２ , OC(O)NR ｃ２２ R ｄ２２ , N.R. ｃ２２ R ｄ２２ , N.R. ｃ２２ NR ｃ２２ R ｄ２２ , N.R. ｃ２２ C(O)R ｂ２２ , N.R. ｃ２２ C(O)OR ａ２２ , N.R. ｃ２２ C(O)NR ｃ２２ R ｄ２２ , C(=NR ｅ２２ ) R ｂ２２ , C(=NR ｅ２２ ) NR ｃ２２ R ｄ２２ , N.R. ｃ２２ C (=NR ｅ２２ ) NR ｃ２２ R ｄ２２ , N.R. ｃ２２ C (=NR ｅ２２ ) R ｂ２２ , N.R. ｃ２２ S(O)NR ｃ２２ R ｄ２２ , N.R. ｃ２２ S(O)R ｂ２２ , N.R. ｃ２２ S (O) ２ R ｂ２２ , N.R. ｃ２２ S(O) (=NR ｅ２２ ) R ｂ２２ , N.R. ｃ２２ S (O) ２ NR ｃ２２ R ｄ２２ , S(O)R ｂ２２ , S(O)NR ｃ２２ R ｄ２２ , S(O) ２ R ｂ２２ , S(O) ２ NR ｃ２２ R ｄ２２ , OS(O)(=NR ｅ２２ ) R ｂ２２ , OS(O) ２ R ｂ２２ , S(O)(=NR ｅ２２ ) R ｂ２２ , SF ５ , P(O)R ｆ２２ R ｇ２２ , OP(O)(OR ｈ２２ ) (OR ｉ２２ ), P(O)(OR ｈ２２ ) (OR ｉ２２ ), and B.R. ｊ２２ R ｋ２２ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ｃ optionally substituted with substituents, Each R ａ２２ , R ｃ２２ , and R ｄ２２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ２Ｃ optionally substituted with substituents, Or any R bonded to the same N atom ｃ２２ and R ｄ２２ together with the N atom to which they are attached, form one, two, three, or four independently selected R ２Ｃ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ２２ are independently selected from 1, 2, 3, or 4 independently selected R ２Ｃ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ２２ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ２２ and R ｇ２２ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ２２ and R ｉ２２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ２２ and R ｋ２２ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ２２ and R ｋ２２ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ２Ｃ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ２３ , S.R. ａ２３ , NHOR ａ２３ , C(O)R ｂ２３ , C(O)NR ｃ２３ R ｄ２３ , C(O)NR ｃ２３ (OR ａ２３ ), C(O)OR ａ２３ , O.C.(O.)R ｂ２３ , OC(O)NR ｃ２３ R ｄ２３ , N.R. ｃ２３ R ｄ２３ , N.R. ｃ２３ NR ｃ２３ R ｄ２３ , N.R. ｃ２３ C(O)R ｂ２３ , N.R. ｃ２３ C(O)OR ａ２３ , N.R. ｃ２３ C(O)NR ｃ２３ R ｄ２３ , C(=NR ｅ２３ ) R ｂ２３ , C(=NR ｅ２３ ) NR ｃ２３ R ｄ２３ , N.R. ｃ２３ C (=NR ｅ２３ ) NR ｃ２３ R ｄ２３ , N.R. ｃ２３ C (=NR ｅ２３ ) R ｂ２３ , N.R. ｃ２３ S(O)NR ｃ２３ R ｄ２３ , N.R. ｃ２３ S(O)R ｂ２３ , N.R. ｃ２３ S (O) ２ R ｂ２３ , N.R. ｃ２３ S(O) (=NR ｅ２３ ) R ｂ２３ , N.R. ｃ２３ S (O) ２ NR ｃ２３ R ｄ２３ , S(O)R ｂ２３ , S(O)NR ｃ２３ R ｄ２３ , S(O) ２ R ｂ２３ , S(O) ２ NR ｃ２３ R ｄ２３ , OS(O)(=NR ｅ２３ ) R ｂ２３ , OS(O) ２ R ｂ２３ , S(O)(=NR ｅ２３ ) R ｂ２３ , SF ５ , P(O)R ｆ２３ R ｇ２３ , OP(O)(OR ｈ２３ ) (OR ｉ２３ ), P(O)(OR ｈ２３ ) (OR ｉ２３ ), and B.R. ｊ２３ R ｋ２３ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Each R ａ２３ , R ｃ２３ , and R ｄ２３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Or any R bonded to the same N atom ｃ２３ and R ｄ２３ together with the N atom to which they are attached, form one, two, three, or four independently selected R Ｇ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ２３ are independently selected from 1, 2, 3, or 4 independently selected R Ｇ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ２３ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ２３ and R ｇ２３ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ２３ and R ｉ２３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ２３ and R ｋ２３ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ２３ and R ｋ２３ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ａ４ , R ｃ４ , and R ｄ４ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ａ optionally substituted with substituents, Or any R bonded to the same N atom ｃ４ and R ｄ４ together with the N atom to which they are attached, form one, two, three, or four independently selected R ４Ａ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with substituents; Each R ｂ４ are independently selected from 1, 2, 3, or 4 independently selected R ４Ａ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｅ４ are independently 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ４Ａ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , S.R. ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)NR ｃ４１ (OR ａ４１ ), C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , C(=NR ｅ４１ ) R ｂ４１ , C(=NR ｅ４１ ) NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C (=NR ｅ４１ ) NR ｃ４１ R ｄ４１ , N.R. ｃ４１ C (=NR ｅ４１ ) R ｂ４１ , N.R. ｃ４１ S(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S(O)R ｂ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S(O) (=NR ｅ４１ ) R ｂ４１ , N.R. 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 , OS(O) ２ R ｂ４１ , S(O)(=NR ｅ４１ ) R ｂ４１ , SF ５ , P(O)R ｆ４１ R ｇ４１ , OP(O)(OR ｈ４１ ) (OR ｉ４１ ), P(O)(OR ｈ４１ ) (OR ｉ４１ ), and B.R. ｊ４１ R ｋ４１ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ｂ optionally substituted with substituents, Or any R bonded to the same N atom ｃ４１ and R ｄ４１ together with the N atom to which they are attached, form one, two, three, or four independently selected R ４Ｂ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ４１ are independently selected from 1, 2, 3, or 4 independently selected R ４Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｅ４１ are independently 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ４１ and R ｇ４１ are independently H, 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ４１ and R ｉ４１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ４１ and R ｋ４１ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ４１ and R ｋ４１ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ４Ｂ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ４２ , S.R. ａ４２ , NHOR ａ４２ , C(O)R ｂ４２ , C(O)NR ｃ４２ R ｄ４２ , C(O)NR ｃ４２ (OR ａ４２ ), C(O)OR ａ４２ , O.C.(O.)R ｂ４２ , OC(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ R ｄ４２ , N.R. ｃ４２ NR ｃ４２ R ｄ４２ , N.R. ｃ４２ C(O)R ｂ４２ , N.R. ｃ４２ C(O)OR ａ４２ , N.R. ｃ４２ C(O)NR ｃ４２ R ｄ４２ , C(=NR ｅ４２ ) R ｂ４２ , C(=NR ｅ４２ ) NR ｃ４２ R ｄ４２ , N.R. ｃ４２ C (=NR ｅ４２ ) NR ｃ４２ R ｄ４２ , N.R. ｃ４２ C (=NR ｅ４２ ) R ｂ４２ , N.R. ｃ４２ S(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ S(O)R ｂ４２ , N.R. ｃ４２ S (O) ２ R ｂ４２ , N.R. ｃ４２ S(O) (=NR ｅ４２ ) R ｂ４２ , N.R. ｃ４２ S (O) ２ NR ｃ４２ R ｄ４２ , S(O)R ｂ４２ , S(O)NR ｃ４２ R ｄ４２ , S(O) ２ R ｂ４２ , S(O) ２ NR ｃ４２ R ｄ４２ , OS(O)(=NR ｅ４２ ) R ｂ４２ , OS(O) ２ R ｂ４２ , S(O)(=NR ｅ４２ ) R ｂ４２ , SF ５ , P(O)R ｆ４２ R ｇ４２ , OP(O)(OR ｈ４２ ) (OR ｉ４２ ), P(O)(OR ｈ４２ ) (OR ｉ４２ ), and B.R. ｊ４２ R ｋ４２ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ｃ optionally substituted with substituents, Each R ａ４２ , R ｃ４２ , and R ｄ４２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ｃ optionally substituted with substituents, Or any R bonded to the same N atom ｃ４２ and R ｄ４２ together with the N atom to which they are attached, form one, two, three, or four independently selected R ４Ｃ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ４２ are independently selected from 1, 2, 3, or 4 independently selected R ４Ｃ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ４２ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ４２ and R ｇ４２ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ４２ and R ｉ４２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ４２ and R ｋ４２ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ４２ and R ｋ４２ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ４Ｃ are independently D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ４３ , S.R. ａ４３ , NHOR ａ４３ , C(O)R ｂ４３ , C(O)NR ｃ４３ R ｄ４３ , C(O)NR ｃ４３ (OR ａ４３ ), C(O)OR ａ４３ , O.C.(O.)R ｂ４３ , OC(O)NR ｃ４３ R ｄ４３ , N.R. ｃ４３ R ｄ４３ , N.R. ｃ４３ NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C(O)R ｂ４３ , N.R. ｃ４３ C(O)OR ａ４３ , N.R. ｃ４３ C(O)NR ｃ４３ R ｄ４３ , C(=NR ｅ４３ ) R ｂ４３ , C(=NR ｅ４３ ) NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C (=NR ｅ４３ ) NR ｃ４３ R ｄ４３ , N.R. ｃ４３ C (=NR ｅ４３ ) R ｂ４３ , N.R. ｃ４３ S(O)NR ｃ４３ R ｄ４３ , N.R. ｃ４３ S(O)R ｂ４３ , N.R. ｃ４３ S (O) ２ R ｂ４３ , N.R. ｃ４３ S(O) (=NR ｅ４３ ) R ｂ４３ , N.R. ｃ４３ S (O) ２ NR ｃ４３ R ｄ４３ , S(O)R ｂ４３ , S(O)NR ｃ４３ R ｄ４３ , S(O) ２ R ｂ４３ , S(O) ２ NR ｃ４３ R ｄ４３ , OS(O)(=NR ｅ４３ ) R ｂ４３ , OS(O) ２ R ｂ４３ , S(O)(=NR ｅ４３ ) R ｂ４３ , SF ５ , P(O)R ｆ４３ R ｇ４３ , OP(O)(OR ｈ４３ ) (OR ｉ４３ ), P(O)(OR ｈ４３ ) (OR ｉ４３ ), and B.R. ｊ４３ R ｋ４３ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Each R ａ４３ , R ｃ４３ , and R ｄ４３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Or any R bonded to the same N atom ｃ４３ and R ｄ４３ together with the N atom to which they are attached, form one, two, three, or four independently selected R Ｇ forming a 4- to 7-membered heterocycloalkyl group optionally substituted with substituents, Each R ｂ４３ are independently selected from 1, 2, 3, or 4 independently selected R Ｇ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ４３ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ４３ and R ｇ４３ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ４３ and R ｉ４３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ４３ and R ｋ４３ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ４３ and R ｋ４３ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; R Ｚ is R ５ and NR ５ R ５Ｚ is selected from R ５ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ５Ａ is optionally substituted by a substituent; R ５Ｚ is H, C １－６ Alkyl, and C １－６ haloalkyl; Or, alternatively, R ５ and R ５Ｚ together with the nitrogen atom to which they are attached, represent one, two, three, or four independently selected R ５Ａ forming a 4- to 7-membered heterocycloalkyl ring optionally substituted with substituents; Each R ５Ａ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ５１ , S.R. ａ５１ , NHOR ａ５１ , C(O)R ｂ５１ , C(O)NR ｃ５１ R ｄ５１ , C(O)NR ｃ５１ (OR ａ５１ ), C(O)OR ａ５１ , O.C.(O.)R ｂ５１ , OC(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ R ｄ５１ , N.R. ｃ５１ NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C(O)R ｂ５１ , N.R. ｃ５１ C(O)OR ａ５１ , N.R. ｃ５１ C(O)NR ｃ５１ R ｄ５１ , C(=NR ｅ５１ ) R ｂ５１ , C(=NR ｅ５１ ) NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C (=NR ｅ５１ ) NR ｃ５１ R ｄ５１ , N.R. ｃ５１ C (=NR ｅ５１ ) R ｂ５１ , N.R. ｃ５１ S(O)NR ｃ５１ R ｄ５１ , N.R. ｃ５１ S(O)R ｂ５１ , N.R. ｃ５１ S (O) ２ R ｂ５１ , N.R. ｃ５１ S(O) (=NR ｅ５１ ) R ｂ５１ , N.R. 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 , OS(O) ２ R ｂ５１ , S(O)(=NR ｅ５１ ) R ｂ５１ , SF ５ , P(O)R ｆ５１ R ｇ５１ , OP(O)(OR ｈ５１ ) (OR ｉ５１ ), P(O)(OR ｈ５１ ) (OR ｉ５１ ), and B.R. ｊ５１ R ｋ５１ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ５Ｂ optionally substituted with substituents, Each R ａ５１ , R ｃ５１ , and R ｄ５１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ５Ｂ optionally substituted with substituents, Or any R bonded to the same N atom ｃ５１ and R ｄ５１ together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, and the 4- to 10-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R ５Ｂ optionally substituted with substituents, Each R ｂ５１ are independently selected from 1, 2, 3, or 4 independently selected R ５Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｅ５１ are independently 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 ３－７ Cycloalkyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｆ５１ and R ｇ５１ are independently H, 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 ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｈ５１ and R ｉ５１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ｊ５１ and R ｋ５１ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ５１ and R ｋ５１ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５Ｂ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ５２ , S.R. ａ５２ , NHOR ａ５２ , C(O)R ｂ５２ , C(O)NR ｃ５２ R ｄ５２ , C(O)NR ｃ５２ (OR ａ５２ ), C(O)OR ａ５２ , O.C.(O.)R ｂ５２ , OC(O)NR ｃ５２ R ｄ５２ , N.R. ｃ５２ R ｄ５２ , N.R. ｃ５２ NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C(O)R ｂ５２ , N.R. ｃ５２ C(O)OR ａ５２ , N.R. ｃ５２ C(O)NR ｃ５２ R ｄ５２ , C(=NR ｅ５２ ) R ｂ５２ , C(=NR ｅ５２ ) NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C (=NR ｅ５２ ) NR ｃ５２ R ｄ５２ , N.R. ｃ５２ C (=NR ｅ５２ ) R ｂ５２ , N.R. ｃ５２ S(O)NR ｃ５２ R ｄ５２ , N.R. ｃ５２ S(O)R ｂ５２ , N.R. ｃ５２ S (O) ２ R ｂ５２ , N.R. ｃ５２ S(O) (=NR ｅ５２ ) R ｂ５２ , N.R. ｃ５２ S (O) ２ NR ｃ５２ R ｄ５２ , S(O)R ｂ５２ , S(O)NR ｃ５２ R ｄ５２ , S(O) ２ R ｂ５２ , S(O) ２ NR ｃ５２ R ｄ５２ , OS(O)(=NR ｅ５２ ) R ｂ５２ , OS(O) ２ R ｂ５２ , S(O)(=NR ｅ５２ ) R ｂ５２ , S.F. ５ , P(O)R ｆ５２ R ｇ５２ , OP(O)(OR ｈ５２ ) (OR ｉ５２ ), P(O)(OR ｈ５２ ) (OR ｉ５２ ), and B.R. ｊ５２ R ｋ５２ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ５Ｃ optionally substituted with substituents, Each R ａ５２ , R ｃ５２ , and R ｄ５２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ５Ｃ optionally substituted with substituents, Or any R bonded to the same N atom ｃ５２ and R ｄ５２ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R ５Ｃ optionally substituted with substituents, Each R ｂ５２ are independently selected from 1, 2, 3, or 4 independently selected R ５Ｃ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ５２ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ５２ and R ｇ５２ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ５２ and R ｉ５２ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ５２ and R ｋ５２ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ５２ and R ｋ５２ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ５Ｃ are independently H, D, halo, CN, NO ２ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ５３ , S.R. ａ５３ , NHOR ａ５３ , C(O)R ｂ５３ , C(O)NR ｃ５３ R ｄ５３ , C(O)NR ｃ５３ (OR ａ５３ ), C(O)OR ａ５３ , O.C.(O.)R ｂ５３ , OC(O)NR ｃ５３ R ｄ５３ , N.R. ｃ５３ R ｄ５３ , N.R. ｃ５３ NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C(O)R ｂ５３ , N.R. ｃ５３ C(O)OR ａ５３ , N.R. ｃ５３ C(O)NR ｃ５３ R ｄ５３ , C(=NR ｅ５３ ) R ｂ５３ , C(=NR ｅ５３ ) NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C (=NR ｅ５３ ) NR ｃ５３ R ｄ５３ , N.R. ｃ５３ C (=NR ｅ５３ ) R ｂ５３ , N.R. ｃ５３ S(O)NR ｃ５３ R ｄ５３ , N.R. ｃ５３ S(O)R ｂ５３ , N.R. ｃ５３ S (O) ２ R ｂ５３ , N.R. ｃ５３ S(O) (=NR ｅ５３ ) R ｂ５３ , N.R. ｃ５３ S (O) ２ NR ｃ５３ R ｄ５３ , S(O)R ｂ５３ , S(O)NR ｃ５３ R ｄ５３ , S(O) ２ R ｂ５３ , S(O) ２ NR ｃ５３ R ｄ５３ , OS(O)(=NR ｅ５３ ) R ｂ５３ , OS(O) ２ R ｂ５３ , S(O)(=NR ｅ５３ ) R ｂ５３ , S.F. ５ , P(O)R ｆ５３ R ｇ５３ , OP(O)(OR ｈ５３ ) (OR ｉ５３ ), P(O)(OR ｈ５３ ) (OR ｉ５３ ), and B.R. ｊ５３ R ｋ５３ and C is selected from １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Each R ａ５３ , R ｃ５３ , and R ｄ５３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Or any R bonded to the same N atom ｃ５３ and R ｄ５３ together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, and the 4- to 7-membered heterocycloalkyl group is selected from 1, 2, 3, or 4 independently selected R Ｇ optionally substituted with substituents, Each R ｂ５３ are independently selected from 1, 2, 3, or 4 independently selected R Ｇ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｅ５３ are independently 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｆ５３ and R ｇ５３ are independently H, 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 ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｈ５３ and R ｉ５３ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ｊ５３ and R ｋ５３ are independently OH, C １－６ Alkoxy, and C １－６ haloalkoxy; Or any R bonded to the same B atom ｊ５３ and R ｋ５３ together with the B atoms to which they are attached, １－６ Alkyl and C １－６ forming a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from haloalkyl; Each R ６ are independently H, D, halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl R ７ H, D, Halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, OH, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl)amino, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, C １－３ Alkoxy-C １－４ Alkyl, and C ３－４ cycloalkyl; Each R Ｇ are independently OH, NO ２ , CN, Halo, C １－３ Alkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, C １－３ Haloalkyl, cyano-C １－３ Alkyl, HO-C １－３ Alkyl, C １－３ Alkoxy-C １－３ Alkyl, C ３－７ Cycloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, di(C １－３ alkyl) amino, thio, C １－３ Alkylthio, C １－３ Alkylsulfinyl, C １－３ Alkyl sulfonyl, carbamyl, C １－３ Alkylcarbamyl, di(C １－３ alkyl) carbamyl, carboxy, C １－３ Alkylcarbonyl, C １－３ Alkoxycarbonyl, C １－３ Alkylcarbonyloxy, C １－３ Alkylcarbonylamino, C １－３ Alkoxycarbonylamino, C １－３ Alkylaminocarbonyloxy, C １－３ Alkyl sulfonyl amino, amino sulfonyl, C １－３ Alkylaminosulfonyl, di(C １－３ alkyl)aminosulfonyl, aminosulfonylamino, C １－３ Alkylaminosulfonylamino, di(C １－３ alkyl)aminosulfonylamino, aminocarbonylamino, C １－３ Alkylaminocarbonylamino, and di(C １－３ The compound of formula (I) above, wherein the compound is selected from the group consisting of: (a) (alkyl) aminocarbonyl amino; and (b) (alkyl) aminocarbonyl amino; or a pharmaceutically acceptable salt thereof.

2. R １ But halo, CN, or C １－３ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

3. R ７ 3. The compound of claim 1 or 2, wherein is H, or a pharmaceutically acceptable salt thereof.

4. 6. The compound according to any one of claims 1 to 5, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

5. R ５ But C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ５Ａ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally substituted with a substituent.

6. Each R ５Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５１ , and N.R. ｃ５１ R ｄ５１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, and the C ３－４ Each cycloalkyl is selected from one or two independently selected R ５Ｂ optionally substituted with substituents, Each R ａ５１ , R ｃ５１ , and R ｄ５１ However, independently, H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ５Ｂ are independently H, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino and di(C １－３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from:

7. Each R ５Ａ Independently, H, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl and NR ｃ５１ R ｄ５１ is selected from Each R ｃ５１ and R ｄ５１ independently H and C １－３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein:

8. R ２ , R ３ , and R ４ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein: is defined as group (a).

9. R ２ But, H, halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, or C １－３ Alkoxy-C １－４ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

10. R ４ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－１０ cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－１０ Cycloalkyl-C １－４ Alkyl, 6- to 10-membered aryl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ３－１０ cycloalkyl, the 6- to 10-membered aryl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－１０ Cycloalkyl-C １－４ alkyl, the 6- to 10-membered aryl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ａ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted by a substituent.

11. R ４ But H, C １－６ Alkyl, C １－６ haloalkyl, phenyl, 4- to 9-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 9-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 9-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ａ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted by a substituent.

12. R ４ But H, C １－６ Alkyl, C １－６ haloalkyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one, and cyclopropylmethyl; １－６ alkyl, the C １－６ haloalkyl, the phenyl, the tetrahydropyranyl, the pyridyl, the pyrazolyl, the isobenzofuran-1(3H)-one, and the cyclopropylmethyl each represent 1, 2, or 3 independently selected R ４Ａ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted by a substituent.

13. Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , S.R. ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, and 5-10 membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ are each independently selected from 1, 2, or 3 independently selected R ４Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ４Ｂ However, independently, H, D, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ４２ , S.R. ａ４２ , NHOR ａ４２ , C(O)R ｂ４２ , C(O)NR ｃ４２ R ｄ４２ , C(O)OR ａ４２ , O.C.(O.)R ｂ４２ , OC(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ R ｄ４２ , N.R. ｃ４２ C(O)R ｂ４２ , N.R. ｃ４２ C(O)OR ａ４２ , N.R. ｃ４２ C(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ S (O) ２ R ｂ４２ , N.R. ｃ４２ S (O) ２ NR ｃ４２ R ｄ４２ , S(O) ２ R ｂ４２ , and S(O) ２ NR ｃ４２ R ｄ４２ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ａ４２ , R ｃ４２ , and R ｄ４２ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ｂ４２ are each independently selected from 1, 2, or 3 independently selected R ４Ｃ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ４Ｃ are independently H, D, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, and di(C １－３ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from: (a) (alkyl) amino;

14. Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ haloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , and N.R. ｃ４１ C(O)R ｂ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ independently H and C １－６ alkyl, wherein C １－６ alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ is independently 1, 2, or 3 independently selected R ４Ｂ C optionally substituted with a substituent １－６ alkyl, Each R ４Ｂ However, independently, H, D, halo, CN, C １－６ Alkyl, 4- to 7-membered heterocycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, OR ａ４２ , N.R. ｃ４２ R ｄ４２ , and N.R. ｃ４２ C(O)R ｂ４２ and C is selected from １－６ alkyl and said 4- to 7-membered heterocycloalkyl each represent one, two, or three independently selected R ４Ｃ optionally substituted with substituents, Each R ａ４２ , R ｃ４２ , and R ｄ４２ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 4- to 7-membered heterocycloalkyl, and C ３－７ Cycloalkyl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the 4- to 7-membered heterocycloalkyl, and the C ３－７ Cycloalkyl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ｂ４２ is independently 1, 2, or 3 independently selected R ４Ｃ C optionally substituted with a substituent １－６ alkyl, Each R ４Ｃ are independently D, CN, OH and C １－３ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

15. Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , S.R. ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ are each independently selected from 1, 2, or 3 independently selected R ４Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ４Ｂ are independently H, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino and di(C １－３ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from: (a) (alkyl) amino;

16. n is 0, 1, or 2; Ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidine ring, or an azepane ring; R １ But, H, halo, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ２ But, H, halo, CN, C １－４ Alkyl, C １－４ Haloalkyl, cyano-C １－４ Alkyl, HO-C １－４ Alkyl, or C １－３ Alkoxy-C １－４ is alkyl, R ３ But, H, halo, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ４ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, 3, or 4 independently selected R ４Ａ optionally substituted with substituents, Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ４１ , S.R. ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, and the C ３－４ Each cycloalkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ However, independently, H, C １－６ Alkyl, and C １－６ haloalkyl, wherein C １－６ Alkyl, and the C １－６ Each haloalkyl is selected from one or two independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ are each independently one or two independently selected R ４Ｂ C optionally substituted with a substituent; １－６ Alkyl and C １－６ haloalkyl; Each R ４Ｂ are independently H, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, and di(C １－３ alkyl)amino; R Ｚ But, R ５ and R ５ But C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ５Ａ optionally substituted with substituents, Each R ５Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－４ Cycloalkyl, OR ａ５１ , and N.R. ｃ５１ R ｄ５１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, and the C ３－４ Each cycloalkyl is selected from one or two independently selected R ５Ｂ optionally substituted with substituents, Each R ａ５１ , R ｃ５１ , and R ｄ５１ However, independently, H, C １－６ Alkyl, and C １－６ haloalkyl; Each R ５Ｂ are independently H, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, and di(C １－３ alkyl)amino; Each R ６ But independently, H, halo, C １－３ Alkyl and C １－３ haloalkyl; R ７ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

17. n is 0 or 1; Ring moiety A is a piperidine ring, R １ But, Haro, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ２ But, H, halo, C １－６ Alkyl, C １－６ Haloalkyl, or HO—C １－６ is alkyl, R ３ But, H, halo, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ４ But H, C １－６ Alkyl, C １－６ haloalkyl, phenyl, 4- to 9-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 9-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 9-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ａ is optionally substituted by a substituent; Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , S.R. ａ４１ , NHOR ａ４１ , C(O)R ｂ４１ , C(O)NR ｃ４１ R ｄ４１ , C(O)OR ａ４１ , O.C.(O.)R ｂ４１ , OC(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , N.R. ｃ４１ C(O)R ｂ４１ , N.R. ｃ４１ C(O)OR ａ４１ , N.R. ｃ４１ C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ S (O) ２ R ｂ４１ , N.R. ｃ４１ S (O) ２ NR ｃ４１ R ｄ４１ , S(O) ２ R ｂ４１ , and S(O) ２ NR ｃ４１ R ｄ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, and 5-10 membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ are each independently selected from 1, 2, or 3 independently selected R ４Ｂ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl and 5- to 10-membered heteroaryl-C １－４ alkyl, Each R ４Ｂ However, independently, H, D, halo, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, 5- to 6-membered heteroaryl-C １－４ Alkyl, OR ａ４２ , S.R. ａ４２ , NHOR ａ４２ , C(O)R ｂ４２ , C(O)NR ｃ４２ R ｄ４２ , C(O)OR ａ４２ , O.C.(O.)R ｂ４２ , OC(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ R ｄ４２ , N.R. ｃ４２ C(O)R ｂ４２ , N.R. ｃ４２ C(O)OR ａ４２ , N.R. ｃ４２ C(O)NR ｃ４２ R ｄ４２ , N.R. ｃ４２ S (O) ２ R ｂ４２ , N.R. ｃ４２ S (O) ２ NR ｃ４２ R ｄ４２ , S(O) ２ R ｂ４２ , and S(O) ２ NR ｃ４２ R ｄ４２ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ａ４２ , R ｃ４２ , and R ｄ４２ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ｂ４２ are each independently selected from 1, 2, or 3 independently selected R ４Ｃ C optionally substituted with a substituent; １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, Each R ４Ｃ are independently H, D, halo, CN, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, Amino, C １－３ Alkylamino, and di(C １－３ alkyl)amino; R Ｚ But NR ５ R ５Ｚ or R ５ and R ５Ｚ is H or methyl, R ５ But C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 7-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 7-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ５Ａ optionally substituted with substituents, Each R ５Ａ Independently, H, halo, CN, C １－３ Alkyl, C １－３ Haloalkyl and NR ｃ５１ R ｄ５１ is selected from Each R ｃ５１ and R ｄ５１ independently H and C １－３ alkyl, Each R ６ But independently, H, halo, C １－３ Alkyl and C １－３ haloalkyl; R ７ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

18. n is 0 or 1; Ring moiety A is a piperidine ring, R １ But, Haro, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ２ But, H, halo, C １－６ Alkyl, C １－６ Haloalkyl, or HO—C １－６ is alkyl, R ３ But, H, halo, CN, C １－３ Alkyl, or C １－３ is haloalkyl, R ４ But C １－６ Alkyl, C １－６ haloalkyl, phenyl, 4- to 9-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－７ Cycloalkyl-C １－４ Alkyl, phenyl-C １－４ Alkyl, 4- to 9-membered heterocycloalkyl-C １－４ Alkyl, and 5- to 6-membered heteroaryl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the phenyl, the 4- to 9-membered heterocycloalkyl, the 5- to 6-membered heteroaryl, the C ３－７ Cycloalkyl-C １－４ alkyl, the phenyl-C １－４ alkyl, the 4- to 9-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 6-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ａ is optionally substituted by a substituent; Each R ４Ａ Independently, H, halo, CN, C １－６ Alkyl, C １－６ haloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl-C １－４ Alkyl, 5- to 10-membered heteroaryl-C １－４ Alkyl, OR ａ４１ , C(O)NR ｃ４１ R ｄ４１ , N.R. ｃ４１ R ｄ４１ , and N.R. ｃ４１ C(O)R ｂ４１ and C is selected from １－６ alkyl, the C １－６ haloalkyl, the 4- to 10-membered heterocycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl-C １－４ alkyl, and the 5- to 10-membered heteroaryl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ａ４１ , R ｃ４１ , and R ｄ４１ independently H and C １－６ alkyl, wherein C １－６ alkyl is selected from 1, 2, or 3 independently selected R ４Ｂ optionally substituted with substituents, Each R ｂ４１ is independently 1, 2, or 3 independently selected R ４Ｂ C optionally substituted with a substituent １－６ alkyl, Each R ４Ｂ However, independently, H, D, halo, CN, C １－６ Alkyl, 4- to 7-membered heterocycloalkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, OR ａ４２ , N.R. ｃ４２ R ｄ４２ , and N.R. ｃ４２ C(O)R ｂ４２ and C is selected from １－６ alkyl and said 4- to 7-membered heterocycloalkyl each represent one, two, or three independently selected R ４Ｃ optionally substituted with substituents, Each R ａ４２ , R ｃ４２ , and R ｄ４２ However, independently, H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 4- to 7-membered heterocycloalkyl, and C ３－７ Cycloalkyl-C １－４ alkyl, wherein C １－６ alkyl, the C １－６ haloalkyl, the C ３－７ cycloalkyl, the 4- to 7-membered heterocycloalkyl, and the C ３－７ Cycloalkyl-C １－４ each alkyl is selected from 1, 2, or 3 independently selected R ４Ｃ optionally substituted with substituents, Each R ｂ４２ is independently 1, 2, or 3 independently selected R ４Ｃ C optionally substituted with a substituent １－６ alkyl, Each R ４Ｃ are independently D, CN, OH and C １－３ alkyl, R Ｚ But NR ５ R ５Ｚ or R ５ and R ５Ｚ is H or methyl, R ５ But C １－６ Alkyl, C ３－７ cycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from 1, 2, or 3 independently selected R ５Ａ optionally substituted with substituents, Each R ５Ａ But independently, CH ３ and N.H. ２ is selected from Each R ６ is H, halo, or C １－３ haloalkyl; R ７ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

19. R Ｚ But NR ５ R ５Ｚ 19. The compound according to any one of claims 1 to 15 and 17 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. R Ｚ But N(CH ３ ) ２ , NH(CH ３ 20. The compound according to any one of claims 1 to 15 and 17 to 18, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 5

21. R Ｚ But, R ５ 19. The compound according to any one of claims 1 to 18, wherein:

22. Formula (II) 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

23. portion 【Chemistry 3】 but, 【Chemistry 4】 The compound according to any one of claims 1 to 18, selected from:

24. R ５ But C １－３ Alkyl, C ３－６ cycloalkyl, and 5- to 6-membered heteroaryl, １－３ alkyl, the C ３－７ cycloalkyl, and the 5- to 6-membered heteroaryl each represent one or two independently selected R ５Ａ 24. The compound according to any one of claims 1 to 18 and 21 to 23, or a pharmaceutically acceptable salt thereof, optionally substituted by a substituent.

25. R ５ is methyl, ethyl, cyclopropyl, imidazolyl, pyrazolyl, pyridinyl, and pyrimidinyl, each of which is selected from one, two, or three independently selected R ５Ａ 24. The compound according to any one of claims 1 to 18 and 21 to 23, or a pharmaceutically acceptable salt thereof, optionally substituted with a substituent.

26. Each R ５Ａ But independently, CH ３ and N.H. ２ 26. The compound according to any one of claims 1 to 18 and 21 to 25, or a pharmaceutically acceptable salt thereof, selected from:

27. R １ is Cl, CN, or CF ３ 27. The compound according to any one of claims 1 to 26, wherein:

28. 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein ring moiety A is piperidin-4-yl.

29. R ３ is H, F, Cl, Br, CN, or CH ３ 29. The compound according to any one of claims 1 to 28, wherein:

30. R ３ is H, Cl, Br, CN, or CH ３ 29. The compound according to any one of claims 1 to 28, wherein:

31. R ２ But, H, halo, C １－４ Alkyl, or HO—C １－４ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, which is alkyl.

32. 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-chloro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-chloro-2-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(2-amino-5-fluoropyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, N-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2-yl)acetamide, 4-(1-(2-amino-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(2,5-dichloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(5-chloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1,5-dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5-carbonitrile, (1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)methanol, 2-methyl-1-(1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-2-ol, 4-(1,2-dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(5-chloro-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol, N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-cyclopropyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propanenitrile, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 4-(1-(2-hydroxy-2-methylpropyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 4-(1-(2-chloro-4-cyanophenyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(4-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine, 6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, and 3-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

33. 6-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile, 6-methoxy-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 6-(2-(dimethylamino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 6-ethyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylbenzonitrile, 2-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(6-methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(6-methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine, 5-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methoxypicolinonitrile, 6-(2-(dimethylamino)ethoxy)-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 4-(1-(2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-fluoro-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-fluoro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)isophthalonitrile, 4-(1-(2,3-dichlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-methyl-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-chloro-3-methyl-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-bromo-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)picolinonitrile, 4-(1-(2-chloro-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(4-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine, 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)isonicotinonitrile, 2-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile, 4-(1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-methyl-4-((5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)butan-2-ol, 4-(1-(6-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-((1-(dimethylamino)propan-2-yl)oxy)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-((5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)propanenitrile, 4-(1-(2-(difluoromethyl)-6-methoxypyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 6-(2-(ethyl(methyl)amino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 4-(1-(2-chloro-3-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(((4-methyltetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol, (2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)propan-1-ol, (2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)(cyclopropyl)methanol, 3-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-(4-(2-((1-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine, 3-(4-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile, 5-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-propylpicolinonitrile, 4-(1-(6-ethyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-(2-aminopyridin-4-yl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(pyridin-3-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)picolinonitrile, 6-(difluoromethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 4-(1-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (S)-4-(1-(4-(3-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(4-(methylamino)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-1-methylpiperazin-2-one, (R)-4-(1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (S)-4-(1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-((3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)(methyl)amino)ethan-1-ol, 4-(1-(2-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-4-(1-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (S)-1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol, (R)-4-(1-(2-fluoro-4-((1-methylpiperidin-3-yl)amino)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1,4-dimethyl-1H-imidazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(difluoromethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide, 6-methyl-N-(methyl-d ３ )-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide, N,6-dimethyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide, N-isopropyl-6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide, N-ethyl-6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide, 3-chloro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide, 3-chloro-2-fluoro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide, 2,3-dichloro-N-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide, (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol, (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol, (S)-4-(1-(2-chloro-4-(3-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-4-(1-(2-chloro-4-(3-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-1-methylpiperazin-2-one, 4-(1-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((2-methoxyethyl)amino)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3-methylimidazolidin-2-one, 4-(1-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-N1,N2,N2-trimethylethane-1,2-diamine, 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperazin-2-one, 4-(1-(2-chloro-4-methoxyphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 6-methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-(4-(2-(((3R,4S)-1-((2-aminopyrimidin-5-yl)sulfonyl)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile, 6-methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 2-chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(2-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-1-methylpiperazin-2-one, 4-(1-(4-(azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(8-bromoquinolin-7-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(5-bromoquinolin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(8-chloroquinolin-7-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(5-methylquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)quinoxaline-5-carbonitrile, 4-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 4-(1-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-chloro-4-(5-chloro-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-chloro-4-(4-(5-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, N-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-N-methylacetamide, 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)acetamide, 4-(1-(2-chloro-4-(((2,2-difluoroethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-((3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)amino)acetonitrile, 4-(1-(2-chloro-4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(((cyclopropylmethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((ethyl(methyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol, 4-(1-(2-chloro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((3-fluoro-3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidine-3-carbonitrile, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol, 4-(1-(2-chloro-4-((3,3-dimethylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-2-methylazetidin-2-yl)methanol, 2-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-2-azaspiro[3.3]heptan-6-ol, 2-(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-yl)propan-2-ol, (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol, (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol, (R)-4-(1-(2-chloro-4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(piperidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-1-methylpiperazin-2-one, 4-(1-(2-chloro-4-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2-oxa-5-azabicyclo[2.2.2]octan-5-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-((3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)amino)acetonitrile, 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 5-chloro-4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-cyclopropylpiperidine-1-sulfonamide, (3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol, 2-(hydroxymethyl)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)isobenzofuran-1(3H)-one, (3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol, 3-(hydroxymethyl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 6-(hydroxymethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, (2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol, 4-(1-(4-((1H-imidazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((4H-1,2,4-triazol-4-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((1H-1,2,4-triazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2H-1,2,3-triazol-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((1H-1,2,3-triazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((2H-tetrazol-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((1H-tetrazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-(difluoromethyl)-6-((methylamino)methyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-((dimethylamino)methyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol, 5-((methylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(4-((dimethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-(azetidin-1-ylmethyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((dimethylamino)methyl)-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((methylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((cyclopropylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethyl(methyl)amino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((diethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)azetidin-3-ol, (S)-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)pyrrolidin-3-ol, (S)-3-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)pyrrolidin-3-ol, 4-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)piperidin-4-ol, 4-(1-(6-((dimethylamino)methyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-methyl-6-((3-methylazetidin-1-yl)methyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(6-((3,3-dimethylazetidin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-fluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((dimethylamino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-methyl-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(1-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((bis(methyl-d ３ )amino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-(1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-yl)propan-2-ol, 4-(1-(2-fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-methylphenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 4-(1-(4-cyano-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile, 2-methoxy-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile, 3-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 2-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile, 3-fluoro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 4-(1-(3-chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methoxynicotinonitrile, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoropyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile, 4-(1-(3-chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-methylpicolinonitrile, 3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-fluoro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile, 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)-2-methylbenzonitrile, 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile, 3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)picolinonitrile, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro-2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-methoxy-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro-2-methylpyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-fluoro-2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-(4-ethylpiperazin-1-yl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile, 2-(4-methylpiperazin-1-yl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile, 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-morpholinonicotinonitrile, 4-(1-(3-chloro-2-(4-ethylpiperazin-1-yl)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-morpholinopyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-(dimethylamino)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-chloro-2-(methylamino)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(4-(2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 1-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 1-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 1-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 2-methyl-1-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(4-(2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 1-(4-(2-(((3R,4R)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(4-(2-(((3R,4R)-3-fluoro-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 1-(4-(2-(((3R,4R)-3-fluoro-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol, 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-methyl-1-(4-(2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol, 5-((4-ethylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-((isopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-((ethylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, (R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-((cyclopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-((4-methylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(piperidin-1-ylmethyl)benzonitrile, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(pyrrolidin-1-ylmethyl)benzonitrile, 4-(1-(4-((cyclopropylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol, 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol, 4-(1-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((diethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethyl(methyl)amino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol, (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol, (S)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol, 4-(1-(3-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-morpholinoethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-(cyclopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-3-methylazetidin-3-ol, 4-(1-(3-(2-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-3-methylpyrrolidin-3-ol, 4-(1-(2-chloro-3-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(1-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-((methylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-methyl-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)azetidin-3-ol, 4-(1-(3-(azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-3-methyl-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)pyrrolidin-3-ol, 4-(1-(2-methyl-6-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 2-chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile, 4-(1-(2-fluoro-4-((isopropylamino)methyl)-6-methylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((isopropylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((ethylamino)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-6-fluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-1-(3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-1-(3-chloro-5-fluoro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-6-fluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-((ethylamino)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(3,5-difluoro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-1-methylpiperazin-2-one, (S)-1-(3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, (R)-1-(3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, (S)-1-(3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol, 4-(1-(4-(4-(diethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(4-methyl-4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(2-(azetidin-1-yl)ethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(1-methylazetidin-3-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(1-ethylazetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (S)-1-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol, 2-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)ethan-1-ol, (R)-1-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol, 1-((3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)methyl)cyclopropan-1-ol, 4-(1-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (S)-4-(1-(2-fluoro-4-((1-methylpyrrolidin-2-yl)methoxy)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, (R)-4-(1-(2-fluoro-4-((1-methylpyrrolidin-2-yl)methoxy)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 5-(1-isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(1-methylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(1-ethylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(4-methylpiperazin-1-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(methyl(2-(methylamino)ethyl)amino)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-((2-(dimethylamino)ethyl)amino)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-(2-(dimethylamino)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(2-(pyrrolidin-1-yl)ethyl)benzonitrile, 5-(2-(dimethylamino)ethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 5-ethoxy-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(2-(pyrrolidin-1-yl)ethoxy)benzonitrile, 4-(1-(2-chloro-4-(1-ethylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-4-(1-methylazetidin-3-yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)oxazolidin-2-one, 4-(1-(2-bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzyl)-4-methylpiperidin-4-ol, 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(((2,2-difluoroethyl)amino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 3-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)azetidin-3-ol, 4-(1-(4-(((2,2-difluoroethyl)amino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-4-methylpiperazin-2-one, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-2-one, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylimidazolidin-2-one, 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-2-one, 1-(1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperidin-4-yl)pyrrolidin-3-ol, 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3-methylazetidin-3-ol, 5-(2-(4-methylpiperazin-1-yl)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile, 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(2-(piperidin-1-yl)ethyl)benzonitrile, 4-(1-(4-(3-(azetidin-1-yl)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(4-(3-(ethyl(methyl)amino)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(2-bromo-1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(((methyl-d3)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidine-3-carbonitrile, 4-(1-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-(isopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(2-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(2-chloro-3-(1-(isopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 4-(1-(3-(1-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine, 1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)azetidine-3-carbonitrile, (S)-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-3-carbonitrile, and 2-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. 34. A method of inhibiting CDK2, comprising contacting said CDK2 with a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

36. 34. A method of inhibiting CDK2 in a patient, comprising administering to the patient a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

37. 34. A method for treating a disease or disorder associated with CDK2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

38. 34. A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

39. 34. A method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising administering to the human subject a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein the human subject: (i) (a) having a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1; and / or (b) having a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and / or deletions; (ii) (a) have an amplification of the cyclin E1 (CCNE1) gene, and / or (b) the biological sample obtained from the human subject has previously been determined to have an expression level of CCNE1 that is higher than a control expression level of CCNE1.

40. 1. A method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising: (i) in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1, and / or (b) identifying a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions; and (ii) in a biological sample obtained from the human subject, (a) amplification of the cyclin E1 (CCNE1) gene, and / or (b) identifying an expression level of CCNE1 that is higher than a control expression level of CCNE1; (iii) administering to the human subject a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

41. (i) in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1; and / or (b) identifying a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and (ii) in a biological sample obtained from the human subject, (a) identifying amplification of the CCNE1 gene; (iii) administering said compound or said salt to said human subject.

42. 34. A method for assessing the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) to a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, comprising: (a) administering the compound or salt to the human subject, wherein the human subject has previously been determined to have amplification of the cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 that is higher than a control expression level of CCNE1; (b) measuring in a biological sample obtained from the subject after the administering of step (a) the level of retinoblastoma (Rb) protein phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3; The method, wherein a decrease in the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 indicates that the human subject is responsive to the compound or salt.

43. The method of any one of claims 37 to 42, wherein the disease or disorder is cancer.

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