Heterobicyclic amides as inhibitors of CD38

Abstract

To provide compounds, pharmaceutical compositions, and methods for inhibiting the function of CD38, the compounds being inhibitors of CD38 and useful in the treatment of cancer.SOLUTION: A compound of Formula I or a pharmaceutically acceptable salt thereof is provided, specifically exemplified by 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to heterobicyclic amides and related compounds that are inhibitors of CD38 and are useful in the treatment of cancer. [Background technology]

[0002] CD38 (cluster of differentiation 38) is widely expressed on the surface of many cell types and binds nicotinamide adenine dinucleotide (NAD + CD38 is a member of the ADP-ribosyl cyclase family responsible for the degradation of NADPH. CD38 was first characterized as a surface antigen on immune cells, as an activation marker located on the plasma membrane and on the membranes of intracellular organelles (Quarona, V., et al. Cytometry B Clin Cytom 84(4):207-217(2013)). Human CD38 contains 300 amino acid residues, including a short N-terminal fragment, a single-pass transmembrane helix, and a C-terminal catalytic domain. CD38 is generally classified as a type II membrane protein; however, it has also been reported to exist in a type III orientation (Zhao YZ et al. Biochim Biophys Acta 1853(9):2095-2103(2012)). CD38 is a cyclase that mediates the degradation of NADPH. + NAD is converted to ADP-ribose (ADPR) or cyclic ADPR (cADPR) and nicotinamide (Chini EN et al. Trends Pharmacol Sci 39(4):424-436(2018)). + is recognized as the major substrate of CD38, while nicotinamide adenine dinucleotide phosphate (NADP + ) and nicotinamide adenine dinucleotide (NMN + It is also known that CD38 has other substrates, such as ATP, ATPase, and ATPase inhibitors. Under some conditions, CD38 can also catalyze base exchange reactions with these same substrates (Preugschat, F et al. Arch Biochem Biophys, 479:114-20 (2008)). This CD38-dependent NAD +Metabolism involves extracellular and intracellular metabolites, intracellular Ca 2+ and regulates signal transduction pathways (Horenstein, AL, et al. Oncoimmunology 2(9):e26246(2013)); Chini EN et al. 2018). CD38 also functions as a receptor, and its receptor-ligand activity regulates the development, activation, and differentiation of numerous immune cell types (Quorona B et al. 2013). CD31 / PECAM-1 has been reported to be a ligand for CD38 (Deaglio S, J Immunol, 160:395-402(1998)).

[0003] CD38 exerts diverse physiological functions, and characterization of CD38 knockout (KO) mice has clarified the various roles played by this protein. CD38 KO mice are characterized by a profound reduction in endogenous cADPR levels in all tissues / organs analyzed except the brain (Partida-Sanchez S et al. Nat Med, 7:1209-16 (2001); Ceni C et al. J Biol Chem 278(42):40670-40678 (2003)). In pancreatic islets, loss of CD38 results in a significant reduction in cADPR, intracellular Ca 2+ CD38 KO also impairs acetylcholine-induced accumulation of cADPR in acinar cells, resulting in impaired glucose-induced production of insulin and insulin secretion (Kato J et al. J Biol Chem, 274:1869-72 (1999)). 2+ This leads to a significant change in signal transduction patterns (Fukushi Y et al. J Biol Chem, 276:649-55 (2001)). Similarly, in neutrophils, cADPR production increases intracellular Ca during chemotaxis. 2+ Release and extracellular Ca 2+It has been shown to regulate both influx and influx and is required for bacterial clearance in vivo (Partida-Sanchez S et al. Nat Med, 7:1209-16 (2001)). CD38 KO mice also exhibit other defects, including defective osteoclast formation and function (Sun L et al. FASEB J, 17:369-75 (2003)), altered airway responsiveness (Deshpande DA et al. Am J Respir Cell Mol Biol, 32:149-56 (2005)), impaired dendritic cell trafficking and reduced humoral immune responses (Partida-Sanchez S et al. Immunity, 20:279-91 (2004)), impaired α-adrenergic receptor-stimulated contraction in the aorta (Mitsui-Saito M et al. J Vet Med Sci, 65:1325-30 (2003)), and cardiac hypertrophy (Takahashi J et al. Biochem Biophys Res Commun, 312:434-40 (2003)). These findings underscore the diverse biological roles played by CD38.

[0004] CD38 expression is also associated with the immunosuppressive functions of regulatory T (Treg) cells, tumor-associated macrophages (TAM), and myeloid-derived suppressor cells (MDSC) (Feng X et al. Clin Cancer Res 23(15):4290-4300(2017); Krejcik J et al. Blood 128(3):384-394(2016); Chevrier S et al. Cell 169(4):736-749 e718(2017); Levy A Neuro Oncol 14(8):1037-1049(2012)). CD38 KO Treg cells are associated with the immunosuppressive functions of NAD + NAD cannot be consumed +They are highly sensitive to induced cell death (Chen J et al. J Immunol 176(8):4590-4599(2006); Hubert, SB et al. J Exp Med, 207:2561-8(2010)). Conversely, Tregs with high CD38 expression are more suppressive than other subsets with low or no CD38 expression (Krejcik et al. 2016; Patton DT et al. PLoS One 6(3):e17359(2011)). Similarly, CD38 高 MDSCs have a greater ability to suppress activated T cells. 高 MDSC activity promotes esophageal tumor growth in mice, and this effect could be inhibited by CD38 blockade (Karakasheva TA et al. Cancer Res 75(19):4074-4085(2015)). Functional CD38 + Expansion of MDSCs has been described for colorectal cancer, particularly in previously treated patients (Karakasheva TA et al. JCI Insight 3(6)(2018)). Broad systems immunology approaches have revealed an association between CD38-expressing tumor-infiltrating lymphocytes (TILs) and poor prognosis in clear cell renal cell carcinoma (ccRCC) and early-stage lung adenocarcinoma (Chevrier S et al. 2017; Lavin Y et al. Cell 169(4):750-765 e717(2017)). In ccRCC, CD38 was determined to be co-expressed with other markers of T cell exhaustion, whereas in lung adenocarcinoma, CD38 高Treg cells are enriched in the tumor microenvironment (TME) (Chevrier S et al. 2017; Lavin Y et al. 2017). High co-expression of CD38 and CD101 on TILs in tumor tissue correlated with poor survival in pancreatic cancer patients (Zhang M et al. Immunol Invest, 48:466-79 (2019)). Studies investigating exhausted T cell populations in humans with chronic infections and various cancers identified CD38 as a marker of T cell exhaustion, and the presence of such exhausted T cells was associated with more severe disease from dysfunctional TILs in HIV infection and lung cancer (Bengsch B et al. Immunity 48(5):1029-1045 e1025 (2018)). CD38 also provides guidance for T cell metabolic adaptation, and inhibition of CD38 expression on T cells reduces NADPH. + It activates T cells by upregulating ATP, promoting glutaminolysis, enhancing oxidative phosphorylation, and altering mitochondrial dynamics (Chatterjee S et al. 2018). This study further demonstrated that CD38 blockade prevented T cell exhaustion, thereby enhancing the efficacy of adoptive T cell therapy (Chatterjee S et al. Cell Metab 27(1):85-100 e108(2018)).

[0005] The role of CD38 in tumorigenesis and immunosuppression is an active area of ​​research, and numerous studies have linked CD38 to tumor progression. CD38 has been shown to promote cervical cancer cell growth by reducing reactive oxygen species levels and preventing apoptosis (Liao S et al. Mol Carcinog 56(10):2245-2257(2017)), and loss of CD38 in human lung adenocarcinoma cells inhibited cell proliferation, invasion, and xenograft growth in nude mice (Bu X et al. Carcinogenesis 39(2):242-251(2017)). CD38 knockout mice were shown to be more resistant to tumor growth and efficiently rejected B16-F10 melanoma tumors (Baruch BB et al. Oncotarget, 9:31797-811(2018)). Similarly, targeting CD38 expression or activity in the TME inhibited glioma progression and extended the lifespan of glioma-bearing mice (Blacher E et al. Int J Cancer 136(6):1422-1433(2013)). CD38 was also identified as a biomarker for aggressive localized prostate cancer (Sahoo D et al. Oncotarget,9:6550-61(2018)).

[0006] Recent research has shown that NAD + We are investigating the role of CD38 in the ectoenzyme cascade that generates immunosuppressive adenosine from ATP. In addition to CD38, this cascade includes ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) and the 5'-ectonucleotidase CD73. CD38 generates ADPR, which is further hydrolyzed by ENPP1 to produce AMP, and the subsequent conversion of AMP to adenosine is regulated by CD73 (Ferretti E et al. Immunol Lett 205:25-30(2019)). This non-canonical adenosine generation pathway, which is CD38-dependent, occurs independently of ATP, and bypasses CD39 (Horenstein AL et al. 2013), plays a major role in generating the immunosuppressive TME, where dying cells release NAD. +This ultimately leads to adenosine conversion (Haag F et al. Purinergic Signal 3(1-2):71-81(2007); Zhu Y et al. Pharmacol Ther 200:27-41(2019)).

[0007] Furthermore, recent studies have shown that cancer cells acquire resistance to immune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) or its ligand (PD-L1) through upregulation of CD38 and CD8 through adenosine receptor signaling. + It was demonstrated that CD38 blockade inhibits T cell function (Chen L et al. Cancer Discov 8(9):1156-1175(2018)). + It restored T cell proliferation, antitumor cytokine secretion, and cytotoxicity. Pathological analysis of lung cancer specimens revealed positive immunohistochemical staining for CD38 on tumor cells in 15–23% of cases, and bioinformatics analysis of datasets from patients with non-small cell lung cancer (NSCLC) and melanoma revealed a strong correlation between CD38 expression and the inflammatory TME (Chen L et al. 2018).

[0008] CD38 is a major NAD-dependent regulator of aging in mammals. + CD38 is one of the key enzymes involved in the decline of NAD (Hogan KA et al. Front Immunol 10:1187(2019)). CD38 KO mice are consistently protected from this progressive deficiency and age-related metabolic dysfunction (Camacho-Pereira J et al. Cell Metab,23:1127-39(2016)). Similarly, inhibition of CD38 prevents the age-related decline of NAD +CD38 knockout mice reversed the decline in ATP and improved several metabolic, structural, and molecular hallmarks of aging in chronologically aged and progeria mice (Camacho-Pereira J et al. 2016). CD38 knockout mice also exhibit enhanced energy expenditure and are protected from diet-induced obesity, hepatic steatosis, and glucose intolerance (Barbosa MT et al. FASEB J 21(13):3629-3639(2007)).

[0009] CD38 is a cell surface marker for multiple myeloma, and because these cells are specifically susceptible to CD38 depletion, CD38 provides a useful therapeutic target for this malignancy (Chini EN et al. 2018). Clinical trials have demonstrated that CD38-targeting antibodies are particularly effective in patients with relapsed / refractory multiple myeloma (Frerichs KA et al. Expert Rev Clin Immunol, 14:197-206 (2018); van de Donk NWCJ et al. Front Immunol, 9:2134 (2018)). The anti-CD38 antibody daratumumab has been approved by the FDA for the treatment of multiple myeloma. Several other therapeutic antibodies against CD38 are in clinical development for multiple myeloma and other cancers (van de Donk NWCJ 2018).

[0010] The literature is replete with references reporting the potential therapeutic benefits of inhibiting aberrant expression or activity of CD38. For example, the following diseases are characterized by abnormal expression or activity of CD38: non-small cell lung cancer, melanoma, cancers treated with and / or resistant to checkpoint therapy, and adenosine-dependent tumors (Chen L et al. "CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1 / PD-L1 blockade." Cancer Discov. 8, 1156-1175 (2018)); lung cancer (adenocarcinoma) (Bu X et al. "CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells." Carcinogenesis 39, 242-251 (2018)); cervical cancer (Liao S et al. "CD38 enhances the proliferation and inhibits the apoptosis of cervical cancer cells by affecting the mitochondrial functions." Mol. Carcinog. 56, 2245-2257 (2017)); glioma (Blacher E et al. al.“Inhibition of glioma progression by a newly discovered CD38 inhibitor.”Int.J.Cancer 136,1422-1433(2015));Colon cancer (Karakasheva TA et al.“CD38 +M-MDSC expansion characterizes a subset of advanced colorectal cancer patients.” JCI Insight 3,1-8(2018)); esophageal cancer (Karakasheva TA et al. “CD38-expressing myeloid-derived suppressor cells promote tumor growth in a murine model of esophageal cancer.” Cancer Res. 75,4074-4085(2015)); renal clear cell carcinoma (Chevrier S et al. “An immune atlas of clear cell renal cell carcinoma.” Cell 169,736-749(2017)); prostate cancer (Sahoo D et al. “Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer.” Oncotarget 9,6550-6561(2018)); regulatory T cell-infiltrated tumors (Lavin Y et al. “Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.” Cell 169,750-757.e15(2017)); MDSC-infiltrated tumor (Karakasheva TA et al. “CD38 +M-MDSC expansion characterizes a subset of advanced colorectal cancer patients.”JCI Insight 3,1-8(2018));HIV / AIDS(Bengsch B et al.“Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted resource epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells.”Cell 48,1029-1045(2018)); Adoptive T cell therapy (Chatterjee S et al. “CD38-NAD + pancreatic cancer (Zhang M et al. “Prognostic values ​​of CD38 + CD101 + PD1 + CD8 + T cells in pancreatic cancer.”Immunol.Invest.48,466-479(2019));and multiple myeloma(Chini EN et al.“The Pharmacology of CD38 / NADase: An Emerging Target in Cancer and Diseases of Aging.”Trends Pharmacol.Sci.39,424-436(2018)).

[0011] In summary, CD38 plays a key role in cancer progression, the generation of immunosuppressive TME, metabolic adaptability of T cells, and NAD during aging and other physiological conditions. +CD38 is a multifunctional enzyme and signaling receptor that plays a key role in regulating levels of CD38. Inhibition of CD38 in a variety of disease states, including tumor growth, has already shown clinical promise, and the development of potent and selective small molecule inhibitors will generate treatment options for other disease states characterized by aberrant CD38 expression or activity. The compounds, compositions, and methods described herein will help address these and other needs. Summary of the Invention

[0012] The present invention relates to compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0013] The present invention also relates to pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0014] The present invention also relates to a method of inhibiting the function of CD38 by contacting CD38 with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0015] The present invention also relates to a method for treating a disease associated with aberrant activity or expression of CD38 by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0016] The present invention further relates to a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with abnormal activity or expression of CD38.

[0017] The present invention is further directed to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy. [Brief explanation of the drawings]

[0018] [Figure 1A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 7. [Figure 1B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 7. [Figure 2A] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 7. [Figure 2B] 1 is a graph of the concentration of ADPR in the liver at a single time point after administration of various amounts of Example 7. [Figure 3A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 115. [Figure 3B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 115. [Figure 4A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 191. [Figure 4B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 191. [Figure 5A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 195. [Figure 5B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 195. [Figure 6A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 189. [Figure 6B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 189. [Figure 7A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 193. [Figure 7B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 193. [Figure 8A] 1 is a graph of the concentration of NAD+ in the spleen at a single time point after administration of various amounts of Example 182. [Figure 8B] 1 is a graph of the concentration of NAD+ in the liver at a single time point after administration of various amounts of Example 182. [Figure 9A] 1 is a plot of the mean B16-F10 tumor volume in mice treated with Example 7. [Figure 9B] Figure 10 is a plot of the mean B16-F10 tumor volume in mice treated with Example 7 and anti-mPD-L1. [Figure 10] Figure 10 is a plot of the survival rate of B16-F10 tumor-bearing mice treated with anti-mPD-L1 (10 mg / kg) and B16-F10 tumor-bearing mice treated with Example 7 (300 mg / kg) in combination with anti-mPD-L1 (10 mg / kg). [Figure 11A] 1 is a plot of the mean MC-38 tumor volume in mice treated with Example 7. [Figure 11B] Figure 10 is a plot of the mean MC-38 tumor volume in mice treated with Example 7 and anti-mPD-L1. [Figure 12] 1 is a plot of the survival rate of MC-38 tumor-bearing mice treated with Example 7 (60 mg / kg). [Figure 13] Figure 10 is a plot of the survival rate of MC-38 tumor-bearing mice treated with anti-mPD-L1 (5 mg / kg) and MC-38 tumor-bearing mice treated with Example 7 (60 mg / kg) in combination with anti-mPD-L1 (5 mg / kg). [Figure 14A] 1 is a plot of the mean Cloudman S91 tumor volume in mice treated with Example 7. [Figure 14B] Figure 10 is a plot of the mean Cloudman S91 tumor volume in mice treated with Example 7 and anti-mPD-L1. [Figure 15] 1 is a plot of survival of Cloudman S91 tumor-bearing mice treated with Example 7 (60 mg / kg). [Figure 16] Figure 10 is a plot of the survival rate of Cloudman S91 tumor-bearing mice treated with anti-mPD-L1 (5 mg / kg) and Example 7 (60 mg / kg) in combination with anti-mPD-L1 (5 mg / kg). DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides CD38 inhibitory compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] is selected from Ring A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N is H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R N The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R A , R B , and R C H, halo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R A , R B , and R C The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NRc R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C 1-4 is an alkylene linker; n is 0 or 1; Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NRc1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 1 , CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1, and S(O)NR c1 R d1 optionally with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)Rb , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c and R d together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NRc3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and However, if V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 Rd1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It is unexpected

[0020] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] is selected from Ring A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N is H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R N The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)Rb , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R A , R B , and R C H, halo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R A , R B , and R C The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d, N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C 1-4 is an alkylene linker; n is 0 or 1; Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 optionally substituted with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 Rd2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c and R d together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NRc3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R.c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R.c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , and R e3 is H, C 1-4alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It's surprising.

[0021] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] Selected from; Ring A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N is H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R N The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 6-10 Aryl, the C 3-7 The cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each selected from Cy, Cy-C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R doptionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R A , R B , and R C H, halo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R A , R B , and R C The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c Rd , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C 1-4 is an alkylene linker; n is 0 or 1; Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1)NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)Rb , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 Rd2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 Rd3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c and R d together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3, N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3, C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e , R e1 , R e2 , and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It's surprising.

[0022] In some embodiments, [ka] The part represented by [ka] is selected from.

[0023] In some embodiments, [ka] The part represented by [ka] is.

[0024] In some embodiments, [ka] The part represented by [ka] is.

[0025] In some embodiments, each R A , R B , and R C is H and C 1-4 In some embodiments, R A is H. In some embodiments, R B is H. In some embodiments, R C is H.

[0026] In some embodiments, V is N.

[0027] In some embodiments, V is CR V In some embodiments, V is CH.

[0028] In some embodiments, W is N.

[0029] In some embodiments, W is CRW In some embodiments, W is CH.

[0030] In some embodiments, V is N and W is N. In some embodiments, V is N and W is CR W In some embodiments, V is CR V and W is N. In some embodiments, V is CR V and W is the CR W is.

[0031] In some embodiments, at least one of V and W is N.

[0032] In some embodiments, ring A is [ka] Selected from

[0033] In some embodiments, ring A is [ka] is.

[0034] In some embodiments, R 1 , R 2 , and R 3 are H and C, respectively. 1-4 In some embodiments, R 1 , R 2 , and R 3 are each H.

[0035] In some embodiments, Q is C 1-10 Alkyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein C 1-10 Alkyl, C 6-10 Aryl, C 3-14Each of cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 1 , CN, NO2, OR a1 , S.R. a1 , C(O)Rb1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally with 1, 2, or 3 substituents independently selected from:

[0036] In some embodiments, Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Each of cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0037] In some embodiments, Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein C1-10 Alkyl, C 6-10 Aryl, C 3-14 Each of cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0038] In some embodiments, Q is C 1-4 Alkyl, C1-4 Haloalkyl, phenyl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein C of Q 1-4 Alkyl, phenyl, C 3-10 Each of cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 and optionally with 1, 2, or 3 substituents independently selected from:

[0039] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-10 alkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0040] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NRc1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-10 It is alkyl.

[0041] In some embodiments, Q is C 1-10 Alkyl or C 1-10 haloalkyl, wherein C 1-10 Alkyl is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0042] In some embodiments, Q is C 1-4 It is alkyl.

[0043] In some embodiments, Q is C 1-4 Alkyl and C 1-4 haloalkyl.

[0044] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 Rd1 , S(O)2R b1 , and S(O)NR c1 R d1 and wherein C is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0045] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NRc1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0046] In some embodiments, Q is halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, and OR a1 and wherein C is phenyl optionally substituted with 1 or 2 substituents independently selected from 1-6 The alkyl is optionally substituted by CN.

[0047] In some embodiments, Q is halo, C 1-6 Haloalkyl and OR a1 and phenyl optionally substituted with 1 or 2 substituents independently selected from:

[0048] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 3-14 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0049] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 Rd1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 3-14 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0050] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NRe1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0051] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NRc1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and wherein C is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0052] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NRc1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 3-14 It is cycloalkyl.

[0053] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 Rd1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0054] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1, OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 4-7 It is cycloalkyl.

[0055] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , and NR c1 C(O)R b1 C optionally substituted with 1 or 2 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0056] In some embodiments, Q is C 1-6 Haloalkyl, OR a1 , and NR c1 R d1 C optionally substituted with 1 or 2 substituents independently selected from 4-7 It is cycloalkyl.

[0057] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 C optionally substituted with 1 or 2 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0058] In some embodiments, Q is C 1-6 Alkyl, C 1-6 Haloalkyl, OR a1 , and NR c1 R d1 C optionally substituted with 1 or 2 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)Rb1 is optionally substituted with 1 or 2 substituents independently selected from:

[0059] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 and wherein C is cyclohexyl optionally substituted with 1 or 2 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0060] In some embodiments, Q is C 1-6 Alkyl, C 1-6 Haloalkyl, OR a1 , and NR c1 R d1 and wherein C is cyclohexyl optionally substituted with 1 or 2 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1 or 2 substituents independently selected from:

[0061] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, ORa1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 C substituted with 1 or 2 substituents independently selected from 4-7 cycloalkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0062] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 and wherein C is a cyclohexyl substituted by 1 or 2 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0063] In some embodiments, Q is C 1-6 cyclohexyl substituted with alkyl, wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 Rd1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1 or 2 substituents independently selected from:

[0064] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1and wherein C is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0065] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1R d1 is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0066] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and wherein C is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl and C 2-6Alkynyl is OH, CN, C 1-6 Alkoxy, NR c1 R d1 , and NR c1 C(O)R b1 and optionally with 1, 2, or 3 substituents independently selected from:

[0067] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, or OR a1 is a 5- or 6-membered heteroaryl optionally substituted with 1-6 Alkyl is C 1-6 Optionally substituted with alkoxy.

[0068] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, or OR a1 is a 5- or 6-membered heteroaryl optionally substituted with 1-6 The alkyl is optionally substituted with methoxy.

[0069] In some embodiments, Q is OR a1 is a 5- or 6-membered heteroaryl optionally substituted with

[0070] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, or OR a1 is a 5- or 6-membered heteroaryl optionally substituted with 1-6 Alkyl and C 2-6 Alkynyl is C 1-6 Alkoxy or NR c1 R d1 is arbitrarily selected by

[0071] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and wherein C is a 4- to 14-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0072] In some embodiments, Q is Cy 1 , Cy 1 -C 1-4Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and 4-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0073] In some embodiments, Q is Cy 1 , C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 , and S(O)2R b1and a 5-10 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from: 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0074] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 , and S(O)2R b1 is a 5-10 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from:

[0075] In some embodiments, Q is Cy 1 , C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 , and S(O)2R b1 and wherein C is a 5- or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0076] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 , and S(O)2R b1 is a 5- or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from:

[0077] In some embodiments, Q is Cy 1 , C 1-6 Alkyl, C 1-6Haloalkyl, C(O)R b1 , and S(O)2R b1 is a 5- or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from:

[0078] In some embodiments, Q is C 1-6 9- or 10-membered heterocycloalkyl optionally substituted with alkyl, wherein C 1-6 Alkyl is C 1-6 Optionally substituted with alkoxy.

[0079] In some embodiments, Q is C 1-6 Alkyl or C(O)R b1 and a 9- or 10-membered heterocycloalkyl optionally substituted with 1-6 Alkyl is C 1-6 Optionally substituted with alkoxy.

[0080] In some embodiments, Q is C 1-6 9- or 10-membered heterocycloalkyl optionally substituted with alkyl, wherein C 1-6 The alkyl is optionally substituted with methoxy.

[0081] In some embodiments, each Cy 1 is independently selected from phenyl, morpholinyl, piperidinyl, and isothiazolidinyl-1,1-dione, wherein piperidinyl is optionally substituted with 4-6 membered heterocycloalkyl. 1 is independently selected from phenyl, morpholinyl, piperidinyl, and isothiazolidinyl-1,1-dione, wherein piperidinyl is optionally substituted with morpholinyl.

[0082] In some embodiments, each Cy 1are independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and isothiazolidinyl-1,1-dione, each optionally substituted with 1 or 2 substituents independently selected from halo, OH, and 4-6 membered heterocycloalkyl.

[0083] In some embodiments, each Cy 1 are independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and isothiazolidinyl-1,1-dione, each of which is selected from C 1-6 Optionally substituted with 1 or 2 substituents independently selected from alkyl, halo, OH, CN, and 4-6 membered heterocycloalkyl.

[0084] In some embodiments, each Cy 1 is independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and isothiazolidinyl-1,1-dione, each optionally substituted with 1 or 2 substituents independently selected from halo, OH, and morpholinyl.

[0085] In some embodiments, each Cy 1 are independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and isothiazolidinyl-1,1-dione, each optionally substituted with 1 or 2 substituents independently selected from methyl, F, OH, CN, and morpholinyl.

[0086] In some embodiments, L is a methylene linker.

[0087] In some embodiments, L is an ethylene linker.

[0088] In some embodiments, n is 0.

[0089] In some embodiments, n is 1.

[0090] In some embodiments, each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 C 1-6 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is CN, OR a3 , C(O)NR c3 R d3 , and NR c3 R d3 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from

[0091] In some embodiments, each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6Haloalkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 C 1-6 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is CN, OR a3 , C(O)NR c3 R d3 , and NR c3 R d3 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0092] In some embodiments, each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, and C 1-6 haloalkyl, wherein C 1-6 Alkyl and C 1-6 Haloalkyl is OH, di(C 1-6 alkyl)amino, and C 1-6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0093] In some embodiments, each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, and C 1-6 haloalkyl, wherein C 1-6 Alkyl and C 1-6 Each haloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, dimethylamino, and methoxy.

[0094] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] Selected from; Each R N is H and C 1-4 independently selected from alkyl; Each R A , R B , and R C is H and C 1-4 independently selected from alkyl; Ring A is [ka] Selected from; R 1 , R 2 , and R 3 are H and C, respectively. 1-4 independently selected from alkyl; L is methylene; n is 0 or 1; Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 6-10 Aryl, C 3-14 Each of cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl is selected from Cy 1 , Cy 1-C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 optionally substituted with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy 1 is C 6-10Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NRc2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R.c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NRe3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3, N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e1 , R e2 , and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It's surprising.

[0095] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] Selected from; Each R N is H and C 1-4 independently selected from alkyl; Each R A , R B , and R C is H and C 1-4independently selected from alkyl; Ring A is [ka] Selected from; R 1 , R 2 , and R 3 are H and C, respectively. 1-4 independently selected from alkyl; L is methylene; n is 0 or 1; Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 6-10 Aryl, C 3-14 Each of cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NRc1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 optionally substituted with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2, OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4alkyl, wherein R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3, S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R e1 , R e2 , and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It's surprising.

[0096] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; wherein at least one of V and W is N; [ka] The part represented by [ka] Selected from; Ring A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R N is H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R N The above C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, ORa , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R A , R B , and R C H, halo, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R A , R B , and R C The above C 1-4 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are Cy, Cy-C, respectively. 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C 1-4 is an alkylene linker; n is 0 or 1; Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 Rd1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 1 , CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 optionally with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C 6-10Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy 1 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. 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 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 Rd2 , S(O)2R b2 , and S(O)NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c and R d together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)Rb3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)Rb3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each Re , R e1 , R e2 , and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; and wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups.

[0097] In some embodiments, V is N or CR V where R V is H, halo, or C 1-4 is alkyl; W is N or CR W where R W is H, halo, or C 1-4 is alkyl; [ka] The part represented by [ka] Selected from; Ring A is [ka] Selected from; Each R N is H and C 1-4 independently selected from alkyl; Each R A and R B is H and C 1-4 independently selected from alkyl; R 1 , R 2 , and R 3 are H and C, respectively. 1-4 independently selected from alkyl; L is C 1-4is an alkylene linker; n is 0 or 1; Q is C 1-4 Alkyl, C 1-4 Haloalkyl, phenyl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, wherein the C 1-4 Alkyl, phenyl, C 3-10 Each of cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl is selected from Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1, and S(O)NR c1 R d1 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 optionally with 1, 2, or 3 substituents independently selected from Each Cy 1 is independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and isothiazolidinyl-1,1-dione, each optionally substituted with 1 or 2 substituents independently selected from halo, OH, and morpholinyl; Each R a1 , R b1 , R c1 , and R d1 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a1 , R b1 , R c1 , and R d1 The above C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is Cy 2 , Cy 2 -C 1-4 Alkyl, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R c1 and R d1together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy 2 is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from the group consisting of halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3, C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a3 , R b3 , R c3 , and R d3 is H, C 1-6 Alkyl, and C 1-6 haloalkyl, wherein 1-6 Alkyl and C 1-6 Haloalkyl is OH, di(C 1-6 alkyl)amino, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; Each R e1 and R e3 is H, C 1-4 alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; However, if V is CH; W is CH; [ka] The part represented by [ka] and; n is 0; and Q is Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R.c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 is cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is [ka] It's surprising.

[0098] In some embodiments, provided herein are compounds of formula IIa: [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, provided herein are compounds of formula IIb: [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, provided herein are compounds of formula IIIa: [ka] or a pharmaceutically acceptable salt thereof, wherein R Q Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1, and S(O)2R b1 wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0101] In some embodiments, provided herein are compounds of formula IIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein R Q Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 , N.R. c1 R d1 , C(O)NR c1 R d1 , N.R. c1 C(O)R b1 , and S(O)2R b1 wherein C 1-6 Alkyl is OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 , N.R. c1 R d1 , and NR c1 C(O)R b1 is optionally substituted with 1, 2, or 3 substituents independently selected from:

[0102] It is further understood that certain features of the invention, which are, for clarity, described in the context of individual 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.

[0103] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0104] At various points in this specification, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the remainder of the molecule at any ring member, valence permitting. For example, the term "pyridinyl," "pyridyl," or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0105] The term "n-membered" refers to the number of ring-forming atoms in a moiety, where n is an integer and typically the number of ring-forming atoms is "n." For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0106] In compounds of the invention where a variable appears more than one time, each variable is independently selected from the groups defining the variable and can be a different moiety. For example, when a structure is described with two R groups present in the same compound at the same time, the two R groups are independently selected from the groups defining R and can represent different moieties.

[0107] As used herein, the phrase "optionally substituted" refers to unsubstituted or substituted.

[0108] As used herein, the term "substituted" refers to the replacement of a hydrogen atom with a non-hydrogen group. It should be understood that the resulting atom substitution is limited by valence.

[0109] As used herein, the term "C i-j " where i and j are integers and are used in conjunction with a chemical group, ij defines a range to indicate the range of carbon atoms in the chemical group. For example, C 1-6 Alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0110] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that can be straight-chained or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0111] As used herein, the term "alkylene," used alone or in combination with other terms, refers to a linking alkyl group.

[0112] As used herein, "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0113] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. 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 or 2 to 4 carbon atoms.

[0114] As used herein, "halo" or "halogen," alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0115] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having a halogen atom substituent of the highest valence, which can be either the same or different. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF, C2F, CHF, CCl, CHCl, C2Cl, and the like.

[0116] As used herein, the term "alkoxy," used alone or in combination with other terms, refers to a group of formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, alkyl groups have 1 to 6 or 1 to 4 carbon atoms.

[0117] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example of a haloalkoxy group is -OCF.

[0118] As used herein, "amino," used alone or in combination with other terms, refers to NH2.

[0119] As used herein, the term "alkylamino," used alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0120] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of formula -N(alkyl). Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0121] As used herein, the term "cycloalkyl," used alone or in combination with other terms, 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, bridged, or spiro rings) ring systems. Additionally, the definition of cycloalkyl includes moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to a cycloalkyl ring, e.g., benzo derivatives such as cyclopentane, cyclohexene, cyclohexane, or derivatives of pyridocyclopentane or cyclohexane. Optionally, ring-forming carbon atoms of a cycloalkyl group can be substituted with oxo. Additionally, cycloalkyl groups include cycloalkylidene. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, e.g., adamantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused together through a single carbon atom, e.g., spiro[2.5]octane, etc.). In some embodiments, cycloalkyl groups have 3 to 10 ring members, or 3 to 7 ring members, or 3 to 6 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3-7 Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0122] As used herein, the term "cycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl moiety is monocyclic. In some embodiments, the cycloalkyl moiety is C 3-7 It is a monocyclic cycloalkyl group.

[0123] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included within the definition of heterocycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline. When a heterocycloalkyl group contains a fused aromatic ring, the heterocycloalkyl group can be attached to the main structure through either the aromatic or non-aromatic ring. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-1-yl) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused together through a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl]). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms.Carbon atoms or heteroatoms of the ring(s) of the heterocycloalkyl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized. In some embodiments, the heterocycloalkyl moiety is C. 2-7 In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a dihydropyran ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0124] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl moiety is monocyclic. In some embodiments, the heterocycloalkyl moiety is C 2-7 It is a monocyclic heterocycloalkyl group.

[0125] As used herein, the term "aryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., two fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, an aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group. In some embodiments, an aryl group is phenyl or naphthyl.

[0126] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl moiety is methylene. In some embodiments, the aryl moiety is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0127] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. Carbon atoms or heteroatoms of the ring(s) of a heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or a nitrogen atom can be quaternized, provided that the aromatic nature of the ring is maintained. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0128] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

[0129] The compounds described herein can be asymmetric (e.g., having one or more chiral centers). Unless otherwise specified, all stereoisomers, e.g., enantiomers and diastereomers, are intended. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. In addition, many geometric isomers of olefins, C=N double bonds, and the like can exist in the compounds described herein, and all such stable isomers are included in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and can be isolated as a mixture of isomers or as isolated isomeric forms.

[0130] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the interchange of adjacent double bonds with a single bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of proton-releasing tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy more than one position in a heterobicyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Appropriate substitution can bring tautomeric forms into equilibrium or sterically lock them into a single form. Tautomeric forms also include methyltropic tautomers, which result from the interchange of adjacent double bonds with a single bond along with the concomitant migration of a methyl group. Methyltropic tautomers can include, for example, 2-methyl-2H-pyrazolo[3,4-c]pyridine and 1-methyl-1H-pyrazolo[3,4-c]pyridine.

[0131] The compounds of the present invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom.

[0132] The term "compound," as used herein, unless otherwise specified, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0133] All compounds, and pharmaceutically acceptable salts thereof, can be found together with or isolated from other substances, such as water and solvents (eg, in the form of hydrates and solvates).

[0134] In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation can include, for example, compositions enriched with the compounds of the invention. Substantial isolation can include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the invention, or salts thereof. Methods for isolating compounds and salts thereof are routine in the art.

[0135] The phrase "pharmaceutically acceptable" as used herein refers to 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.

[0136] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds that are modified by converting an acidic or basic moiety present in the parent compound into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues, such as amines; alkali or organic salts of acidic residues, such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention 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 a mixture of the two. 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.

[0137] synthesis The compounds of the present invention (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0138] The reactions for preparing the compounds of the present invention can be carried out in suitable solvents that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be those that do not substantially react with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A particular reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the particular reaction step, one skilled in the art can select a suitable solvent for a particular reaction step.

[0139] The preparation of compounds of the present invention can 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, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0140] The reaction can be monitored according to any suitable method known in the art, for example, by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), product formation can be monitored by infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry, or chromatography, e.g., high performance liquid chromatography (HPLC) or thin layer chromatography.

[0141] The terms "ambient temperature," "room temperature," and "rt," as used herein, are understood in the art and generally refer to a temperature, e.g., a reaction temperature, i.e., about room temperature, at which a reaction is carried out, e.g., from about 20°C to about 30°C.

[0142] Compounds of formula I can be prepared according to many preparative routes known in the literature. The following schemes provide examples of synthetic methods for preparing compounds of the present invention. Unless otherwise specified, all substituents are as defined herein.

[0143] Scheme 1 [ka] Scheme 1 illustrates the synthesis of analogs following a general route utilizing well-established chemistry. Substituted haloaromatic esters can be coupled to five-membered heteroaromatic rings (Step 1) via several different methods known to those skilled in the art. These include coupling of aromatic tributylstannanes in the presence of a Pd catalyst such as Pd(PPh3)2Cl2 in a polar solvent such as DMF at elevated temperatures; coupling of boronic acids or boronic esters in the presence of a Pd / Cu catalyst such as Pd(dppf)Cl2 and CuI and a base such as sodium carbonate or cesium fluoride in a solvent such as DMF; and coupling of substituted imidazoles in the presence of a Pd catalyst such as Pd2dba3, a ligand such as tBuXPhos, and a base such as K3PO4 in a nonpolar solvent such as toluene at elevated temperatures. The resulting ester can be hydrolyzed with a base such as sodium hydroxide in the presence of water to afford the carboxylic acid (Step 2). This can then be converted to the amine NH2(L) using an amide coupling reagent such as HATU in the presence of a base such as diisopropylethylamine in a polar solvent such as DMF. n The desired amide analog can be converted by coupling Q (Step 3). Alternatively, the substituted ester product of Step 1 can be converted to the amine NH2 (L) in the presence of trimethylaluminum in a non-polar solvent such as toluene. n Treatment with Q allows direct conversion to the desired amide analogs (Step 4).

[0144] Scheme 2 [ka] Scheme 2 illustrates the synthesis of substituted aromatic ester intermediates following a route utilizing well-established chemistry. Aromatic dichlorides (which may be commercially available or can be made via routes known to those skilled in the art) can be converted to enol ethers by coupling to tributyl(1-ethoxyvinyl)stannane in the presence of a Pd catalyst, such as Pd(PPh3)Cl2, in a polar solvent in DMF at elevated temperature (Step 1). Five-membered heteroaromatics can be introduced using the coupling conditions described in Scheme 1, Step 1 (Step 2). Treatment of the enol ether with KMnO4, NaIO4, and water in a nonpolar solvent, such as dioxane, at room temperature provides the substituted esters (Step 3), which can then be converted to amide analogs using the conditions described in Scheme 1, Steps 2 and 3, or Step 4.

[0145] Scheme 3 [ka] Scheme 3 shows an alternative route to substituted aromatic esters, which can be prepared from aromatic dichlorides by first treating them with carbon monoxide in the presence of a Pd catalyst such as Pd(dppf)Cl2, an amine base such as triethylamine, and an alcohol such as methanol in a polar solvent such as DMF at elevated temperature (Step 1). The resulting chloroester can then be coupled with a five-membered heteroaromatic ring using the coupling conditions described in Scheme 1, Step 1.

[0146] Scheme 4 [ka] Scheme 4 illustrates a synthetic route to imidazole-substituted amide analogs. Starting from commercially available chloro-nitro heteroaromatic amines, the imidazole ring can be introduced by treatment with imidazole in the presence of a base such as KCO in a polar solvent such as DMF at elevated temperature (Step 1). The amine can then be converted to a bromide by treatment with CuBr and isopentyl nitrite in a polar solvent such as acetonitrile at elevated temperature (Step 2). Reaction with vinylmagnesium bromide in an aprotic solvent such as THF at elevated temperature (Step 3) followed by treatment with an amine in the presence of carbon monoxide, a Pd catalyst such as Pd(dppf)Cl, and an amine base such as triethylamine in a polar solvent such as DMSO at elevated temperature (Step 4) provides the imidazole-substituted amide analogs.

[0147] How to use The compounds of the present invention can inhibit the activity of CD38. For example, the compounds of the present invention can be used to inhibit the activity or function of CD38 in a cell, individual, or patient in need of enzyme inhibition by administering an inhibitory amount of a compound of the present invention to the cell, individual, or patient. As used herein, the term "intracellular" includes both within the cell membrane and on the surface of the cell membrane.

[0148] The compounds of the present invention act as CD38 inhibitors, inhibiting NAD + Thus, the present invention further provides a method for the treatment of NAD in a sample or a patient, comprising contacting the sample or administering to the patient a compound of formula I or a pharmaceutically acceptable salt thereof. + How to increase levels of NAD + The increase in the level of NAD before contact or administration + This is relative to the level of

[0149] The compounds of the present invention are useful for treating various diseases associated with abnormal expression or activity of CD38. For example, the compounds of the present invention are useful for treating cancer. In some embodiments, the cancer is characterized by abnormal expression or activity, e.g., increased expression or activity, of CD38 compared to normal cells. In some embodiments, cancers treatable by the present invention include breast, central nervous system, endometrial, kidney, colon, lung, esophagus, ovary, pancreas, prostate, head and neck (upper aerodigestive), urinary tract, colon, and others.

[0150] The compounds of the invention are useful for treating tumors driven by exhausted T cells (see, e.g., Hashimoto M, Kamphorst AO, Im SJ, et al. CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med. 2018;69:301-318. doi:10.1146 / annurev-med-012017-043208), and tumors defined as hot, altered, and cold immune tumors based on immunoscore (see, e.g., Galon J, Bruni D. Approaches to treat immune hot, altered, and cold tumors with combination immunotherapies. Nat Rev Drug Discov. 2019;18(3):197-218. doi:10.1038 / s41573-018-0007-y).

[0151] In some embodiments, cancers treatable by the present invention include hematopoietic malignancies such as leukemia and lymphoma. Examples of lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0152] In some embodiments, the cancer treatable by administration of the compounds of the invention is lung cancer.

[0153] In some embodiments, the cancer treatable by administration of the compounds of the invention is melanoma.

[0154] In some embodiments, the cancer treatable by administration of the compounds of the invention is colon cancer.

[0155] Other cancers that can be treated by administration of the compounds of the invention include cancers treated with checkpoint therapy, resistant cancers treated with checkpoint therapy, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0156] Other cancers that may be treated by administration of the compounds of the invention include bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, glioma, head and neck cancer (upper aerodigestive cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0157] In some embodiments, cancers treatable by administration of the compounds of the invention are multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0158] Other cancers that can be treated by administration of the compounds of the invention include cancers treated with checkpoint therapy, resistant cancers treated with checkpoint therapy, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0159] The compounds of the present invention may also be used to treat the following diseases or conditions: HIV / AIDS, adoptive T cell therapy, acute lung injury, acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus erythematosus, rheumatoid arthritis, ataxia telangiectasia, sleep disorders, epilepsy, exercise intolerance, hypertension, hypoxic pulmonary vasoconstriction, leprosy, tuberculosis, leishmaniasis, cardiac hypertrophy, congestive heart failure (CHF), muscular dystrophy, stroke, organ reperfusion injury, idiopathic pulmonary fibrosis, pancreatitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), irritable bowel syndrome (IBS), colitis, gout, obesity The following conditions can be treated: obesity, sarcopenia, metabolic syndrome, end-stage renal failure, dyslipidemia, hearing loss, liver disease, steatosis, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, multiple sclerosis, neurocognitive disorders, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnup disease, skin hyperpigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontal disease, chronic lymphocytic leukemia, amyotrophic lateral sclerosis, Parkinson's disease, Leber's hereditary amaurosis, insulin resistance, and type 1 diabetes.

[0160] The CD38 inhibitors of the present invention may have therapeutic utility in CD38-associated disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly diseases characterized by overexpression or increased activity of CD38.

[0161] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, e.g., a mammal. In some embodiments, an in vivo cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living within an organism, e.g., a mammal.

[0162] As used herein, the term "contacting" refers to an in vivo system or bringing the indicated moieties together in an in vivo system. For example, "contacting" CD38 with a compound of the invention or "contacting" a cell with a compound of the invention includes administering a compound of the invention to an individual or patient, e.g., a human, that has CD38, as well as introducing a compound of the invention into a sample containing, for example, a preparation or purified preparation of cells that contain CD38.

[0163] As used herein, the terms "individual" or "patient" are used interchangeably and refer to mammals, and in particular, humans. An individual or patient may be in need of treatment.

[0164] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or pharmaceutical response of a tissue, system, animal, individual or human that is desired by a researcher, veterinarian, physician or other clinician.

[0165] As used herein, the term "treat" or "treatment" refers to 1) inhibiting a disease (i.e., further suppressing the onset of the disease and / or symptoms) in an individual experiencing or exhibiting a symptom or symptom of the disease, or 2) ameliorating a disease (i.e., reversing the disease and / or symptoms) in an individual experiencing or exhibiting a symptom or symptom of the disease.

[0166] As used herein, the terms "preventing" or "prevention" refer to preventing disease in an individual who may be predisposed to the disease, but who has not yet experienced or exhibited the pathology or symptoms of the disease. In some embodiments, the present invention relates to a method of preventing disease in a patient by administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0167] Combination therapy In combination with the compounds of the present invention, one or more additional drugs or therapeutic methods can be used in combination with the compounds of the present invention, such as chemotherapeutic agents or other anti-cancer agents, immune enhancers, immune inhibitors, radiation, anti-tumor and anti-viral vaccines, cytokine therapies (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors. The compounds and the drugs can be mixed in a single dosage form, or the drugs can be administered simultaneously or sequentially as separate dosage forms.

[0168] Suitable drugs for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds of the present invention can be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors.Suitable examples include, but are not limited to, antiestrogens, including tamoxifen and toremifene; aromatase inhibitors, including but not limited to, letrozole, anastrozole, and exemestane; corticosteroids (e.g., prednisone); progestins (e.g., megastrol acetate); and estrogen receptor antagonists (e.g., fulvestrant).Other suitable antihormonal agents used in the treatment of prostate and other cancers can be mixed with the compounds of the present invention. These include, but are not limited to, antiandrogens, including flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide); and agents that suppress androgen production (e.g., abiraterone).

[0169] Suitable agents for use in combination with the compounds of the invention for the treatment of cancer further include agents that target adenosine signaling such as A2aR and A2bR, inhibitors and nodes of the adenosine production pathway such as CD39, CD73, and ENPP1 inhibitors, and agents that target the production of immunosuppressive amino acids and their products such as IDO inhibitors and AHR inhibitors.

[0170] Angiogenesis inhibitors may be effective in some tumors in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR, or VEGFR kinase inhibitors. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0171] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (including ™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0172] Other anti-cancer agent(s) include antibody therapeutics directed against checkpoint or costimulatory molecules, such as CTLA-4, PD-1, PD-L1, or 4-1BB, respectively, or antibodies directed against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Additional anti-cancer agent(s) include antibody therapeutics directed against surface molecules of hematological cancers, such as ofatumumab, rituximab, and alemtuzumab.

[0173] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art, and 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.

[0174] Pharmaceutical Formulations and Dosage Forms When used as a pharmaceutical, the compounds of the present invention can be administered in the form of a pharmaceutical composition. A pharmaceutical composition refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared by methods well known in the pharmaceutical arts, 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 oral, topical (including ocular and transmucosal administration, including intranasal, vaginal, and rectal), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including nebulizers; tracheal, intranasal, epidermal, and transdermal), ocular, or parenteral.

[0175] The present invention also includes pharmaceutical compositions containing one or more of the compounds of the present invention as an active ingredient in combination with one or more pharmaceutically acceptable carriers. To produce the compositions of the present invention, 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 the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance, and acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0176] The compositions can be prepared in unit dosage form. The term "unit dosage form" means physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0177] The active compound can be effective over a wide dosage range and is 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 according to the relevant circumstances, including the condition being treated, the selected route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0178] To prepare solid compositions, e.g., tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition, and the composition can be readily subdivided into uniformly effective unit dosage forms, e.g., tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

[0179] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action. For example, the tablets or pills can comprise an inner dose and an outer dose component, the latter coated over the former. The two components can be separated by an enteric layer that prevents disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0180] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral administration or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions, edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0181] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized by use of inert gases. Nebulized solutions can be breathed directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in the appropriate manner.

[0182] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, e.g., prophylaxis or therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the progression of the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated and the judgment of the attending clinician depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0183] The composition administered to patients can be in the form of the pharmaceutical composition described above.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solutions can be packaged for immediate use or lyophilized, and the lyophilized preparation is mixed with a sterile aqueous carrier before administration.

[0184] Therapeutic dosages of the compounds of the invention can vary depending, for example, on the particular use to be treated, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the invention 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 dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. Dosages are likely to depend on such variables as the type and extent of 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 vivo or animal model test systems.

[0185] The compounds of the present invention may also be formulated in combination with one or more additional active ingredients, including any drug, such as antiviral drugs, vaccines, antibodies, immune enhancers, immune inhibitors, anti-inflammatory drugs, etc. [Example]

[0186] The present invention will be further described in detail by 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 easily recognize various non-critical parameters that can be changed or modified to obtain essentially the same results.The compounds of the examples have been found to be inhibitors of CD38 according to one or more of the assays provided herein.

[0187] device: 1H NMR spectra were recorded at 300 or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Topspin software to assign chemical shifts and multiplicities. When two adjacent peaks of equal or unequal height were observed, these two peaks could be labeled as either multiple or doublet. In the case of doublets, coupling constants could be assigned using this software. In any given example, one or more protons may not be observed due to obscuration by water and / or solvent peaks. LCMS equipment and conditions were as follows:

[0188] 1. LC (basic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Kinetex 2.6 μm EVO C18 100A, 50*3.0 mm, 2.6 μm. Mobile phase: A: water / 5 mM NH4HCO3, B: acetonitrile. Flow rate: 1.2 mL / min at 40°C. Detector: 254 nm, 220 nm. Gradient stop time: 2.9 min. Timetable: [Table 1]

[0189] 2. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Poroshell HPH-C18 50*3.0mm, 2.7μm. Mobile phase A: 0.04% ammonium hydroxide, Mobile phase B: acetonitrile. Flow rate: 1.2mL / min at 40℃. Detector: 254nm, 220nm. Gradient stop time: 3.0min. Timetable: [Table 2]

[0190] 3. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Ascentis Express C18, 50*3.0mm, 2.7μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5mL / min at 40℃. Detector: 254nm, 220nm. Gradient stop time: 2.9min. Timetable: [Table 3]

[0191] 4. LC (acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: Accucore C18 50*2.1mm, 2.6μm. Mobile phase A: water / 0.1% FA. Mobile phase B: acetonitrile / 0.1% FA. Flow rate: 1.0mL / min at 40℃. Detector: 254nm, 220nm. Gradient stop time: 3.0min. Timetable: [Table 4]

[0192] 1.S: LCMS-2020, quadrupole LC / MS, ion source: ES-API, TIC: 90-900 m / z, fragmentor: 60, drying gas flow: 15 L / min, nebulization gas flow: 1.5 L / min, drying gas temperature: 250 °C, Vcap: 1100 V.

[0193] 2. Sample preparation: Samples were dissolved in ACN or methanol at 1-10 mg / mL and then filtered through a 0.22 μm filter membrane. Injection volume: 1-10 μL.

[0194] Definitions: ACN (acetonitrile); Ac2O (acetic anhydride); AcOH (acetic acid); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); BPO (benzoyl peroxide); conc (concentrated); CsF (cesium fluoride); CuI (copper iodide); CH3CN (acetonitrile); CDCl3 (deuterated chloroform); CD3OD (deuterated methanol); DCM (dichloromethane); DEA (diethylamine); DIPEA or DIEA (N,N-diisopropylethylamine); DMF (N,N -dimethylformamide; DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); eq (equivalent); dppf (bis(diphenylphosphino)ferrocene); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); eq (equivalent); EtOAc (EtOAc); EtOH (ethanol); g (gram); h (hour); (HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); Hex (hexane); HOAc (acetic acid); HOBt (hydroxybenzotriazole); 1H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); Hz (hertz); IPA (isopropyl alcohol); K2CO3 (potassium carbonate); KOAc (potassium acetate); L (liter); LCMS (liquid chromatography-mass spectrometry); M (mol); MeOH (methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimol); NaCl (sodium chloride); NaH (sodium hydride); n-BuOH (1-butanol); NHCl (ammonium chloride); NaN3 (sodium azide); NBS (N-bromosuccinimide); NIS (N-iodosuccinimide); NMP ( N-Methyl-2-pyrrolidone; Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Pd2(dba)3.CHCl3 (tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct); Pd(OH)2 / C (palladium hydroxide on carbon); Prep-HPLC (preparative high-performance liquid chromatography); ppm (parts per million); RT (room temperature); SEM (2-(trimethylsilyl)ethoxymethyl); SEMCl (2-(trimethylsilyl)ethoxymethyl chloride); T3P (propanephosphonic anhydride); t-BuOH (tert-butyl alcohol); t-BuOK (potassium tert-butoxide); tBuXPhos(2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl); TEA(triethylamine); THF(tetrahydrofuran); Ti(Oi-Pr)4(titanium(IV) tetraisopropoxide); TsCl(tosyl chloride); tR(retention time); TFA(trifluoroacetic acid); TLC(thin layer chromatography); v / v(volume / volume); XPhos(2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).

[0195] Synthesis of intermediates Int-A1: 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylic acid [ka]

[0196] Step 1: Methyl 6-bromo-3H-benzimidazole-4-carboxylate To a solution of methyl 2,3-diamino-5-bromobenzoate (500 mg, 2.0 mmol, 1 equiv.) in 1 M HCl (1.5 mL, 2.0 mmol, 1 equiv.), trimethoxymethane (5 mL, 2.0 mmol, 1 equiv.) was added, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: EtOAc, 1:1) to give the title compound (506 mg, 2.0 mmol, 97% yield) as a gray solid. LCMS: [M+H] + 256.9.

[0197] Step 2: Methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate To a solution of methyl 6-bromo-3H-benzimidazole-4-carboxylate (1.5 g, 5.89 mmol, 1 equiv.) in anhydrous THF (15 mL) at 0 °C under a N atmosphere, NaH (212 mg, 8.82 mmol, 1.5 equiv.) was slowly added, and the mixture was stirred at 0 °C for 1 h. SEMCl (824 mg, 7.06 mmol, 1.2 equiv.) was added, and the mixture was stirred for an additional 1.5 h. The reaction was quenched with water (30 mL), and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: EtOAc, 20:1 to 2:1) to give the title compound (800 mg, 2.1 mmol, 35% yield). LCMS: [M+H] + 385.1.

[0198] Step 3: 6-Bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid To a solution of methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate (200 mg, 0.52 mmol, 1 equiv.) in THF (3 mL) was added a solution of lithium hydroxide (65 mg, 1.6 mmol, 3 equiv.) in water (1 mL). The mixture was stirred at 25 °C overnight. The pH of the mixture was adjusted to 3-4 with 2 N HCl, diluted with water (15 mL), and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na SO and concentrated under reduced pressure to give the title compound (180 mg, 0.5 mmol, 93% yield) as a brown solid. LCMS: [M+H] + 373.1.

[0199] Int-A2: 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid [ka]

[0200] Step 1: 2-chloro-4-(1-ethoxyvinyl)-5H-pyrrolo[3,2-d]pyrimidine Under nitrogen, a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (112 g, 597 mmol, 1 equiv.), tributyl(1-ethoxyethenyl)stannane (226 g, 627 mmol, 1.1 equiv.), and Pd(PPh3)2Cl2 (42 g, 60 mmol, 0.1 equiv.) in DMF (900 mL) was stirred at 70 °C for 3 h. The resulting solution was cooled to room temperature and quenched with saturated aqueous KF. The solids were filtered, and the resulting solution was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was subjected to a silica gel column eluting with EtOAc:petroleum ether (1:5) to give the title compound (105 g, 79% yield). LCMS: [M+H] + 224.1, 226.1.

[0201] Step 2: 4-(1-ethoxyvinyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine Under nitrogen, a solution of 2-chloro-4-(1-ethoxyethenyl)-5H-pyrrolo[3,2-d]pyrimidine (55.8 g, 249.3 mmol, 1.0 equiv.), 1H-imidazole (84.9 g, 1.25 mol, 5.00 equiv.), Pd(dba)CHCl (38.7 g, 37.39 mmol, 0.15 equiv.), tBuXphos (26.5 g, 62.32 mmol, 0.25 equiv.), and KPO (105.8 g, 498.53 mmol, 2.00 equiv.) in toluene (1 L) was stirred at 110 °C for 2 h. The resulting solution was quenched with water (500 mL) and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The crude product was subjected to a silica gel column eluting with EtOAc:petroleum ether (1:1) to give the title compound (54 g, 85% yield). LCMS: [M+H] + 256.1.

[0202] Step 3: Ethyl 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate A solution of 4-(1-ethoxyvinyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (54.0 g, 211.5 mmol, 1.0 equiv.), KMnO (13.4 g, 84.61 mmol, 0.40 equiv.), and NaIO (180.9 g, 846.13 mmol, 4.00 equiv.) in dioxane (1.1 L) and water (1.1 L) was stirred at 0 °C for 2 h. The reaction was quenched with water. The resulting solution was extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure to give the title compound (41.0 g, 76% yield) as a white solid. LCMS: [M+H] + 258.1.

[0203] Step 4: 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid A solution of ethyl 2-(imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (39 g, 152 mmol, 1.0 equiv.) and NaOH (12.1 g, 303 mmol, 2.00 equiv.) in HO (350 mL) and EtOH (350 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 5 with concentrated HCl. The solid was collected by filtration. The solid was further purified by slurrying in CHCN and filtering to give the title compound (30.0 g, 86% yield) as a white solid. [M+H] + 230.1.

[0204] Int-A3: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka]

[0205] Step 1: Ethyl 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate A solution of NaIO (20.2 g, 94.44 mmol, 4.0 equiv.) in HO (80 mL) was added to a solution of 2-chloro-4-(1-ethoxyethenyl)-5H-pyrrolo[3,2-d]pyrimidine (5.3 g, 23.47 mmol, 1.0 equiv.) in dioxane (100 mL). To this mixture was added a solution of KMnO (1.48 g, 9.37 mmol, 0.40 equiv.) in HO (20 mL), and the resulting mixture was stirred at 25 °C for 1 h. The solid was filtered. The resulting solution was extracted with 4 × 100 mL of dichloromethane, and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound (5 g, 94% yield) as a yellow solid. LCMS: [M+H] + 226.03.

[0206] Step 2: 2-Chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid A mixture of ethyl 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (4.5 g, 19.94 mmol, 1.0 equiv.), lithium hydroxide hydrate (1.68 g, 40.04 mmol, 2.0 equiv.) in THF (30 mL), and HO (10 mL) was stirred at 25° C. for 2 hours. The resulting mixture was concentrated to remove THF, and the pH value was adjusted to 3 with 2 M HCl. The solid was collected by filtration to give the title compound (2.3 g, 58% yield) as a yellow solid. LCMS: [M+H] + 198.00.

[0207] Step 3: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (2.3 g, 11.64 mmol, 1.0 equiv.), DIPEA (4.49 g, 34.74 mmol, 2.9 equiv.), HATU (5.30 g, 13.94 mmol, 1.2 equiv.), and Int B1 (2.40 g, 13.85 mmol, 1.2 equiv.) in DMF (20 mL) was stirred at 25 °C for 2 h. The reaction was quenched with water and extracted with 3 x 100 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by recrystallization from MeOH to give the title compound (2.4 g, 58% yield) as a yellow solid. LCMS: [M+H] + 353.13.

[0208] Int-A4: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid [ka]

[0209] Step 1: Methyl 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxylate A solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 g, 584.4 mmol, 1 equiv.), K2CO3 (185.8 g, 1.34 mmol, 2.3 equiv.), and 1-(chloromethyl)-4-methoxy-benzene (111.7 g, 713.0 mmol, 1.2 equiv.) in DMF (1.10 L) was stirred at 50 °C for 4 h. Upon completion, the reaction was quenched with HO (1.5 L) and extracted with ethyl acetate (3 × 1.2 L). The organic layers were combined and washed with 3 × 300 ml of brine. The mixture was dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude product was purified on a silica gel column eluting with ethyl acetate / petroleum ether (1:3) to give the title compound (170.0 g, 99%) as a yellow oil. LCMS: [M+H] + 292.15

[0210] Step 2: 1-(4-Methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxamide A solution of methyl 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxylate (170 g, 584.19 mmol, 1.0 equiv) in NH3 / MeOH (7 M, 800 mL) was stirred at room temperature for 16 h. After concentration in vacuo, the crude product was slurried in HO, then filtered and rinsed to give the title compound (149.0 g, 92.2%) as a white solid. LCMS: [M+H] + 277.10.

[0211] Step 3: 4-amino-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide A solution of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxamide (80 g, 289.8 mmol, 1 equiv.), Pd / C (20.0 g) in DCM (1.2 L), and EtOH (1.6 L) was stirred at room temperature for 2 hours under an H atmosphere. The solid was filtered. The resulting mixture was concentrated in vacuo to give the title compound (79.2 g, % yield) as a pink solid. LCMS: [M+H] + 247.15.

[0212] Step 4: 5-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one To a solution of 4-amino-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide (260 g, 1.06 mol, 1 eq.) in 1,4-dioxane (5.0 L) was slowly added thiophosgene (265.4 g, 2.32 mol, 2.2 eq.) at room temperature. The mixture was stirred at 95° C. for 4 hours. After concentration in vacuo, the crude product was slurried in petroleum ether / EtOAc (2:1, 800 ml), filtered, and rinsed to give the title compound (257 g, 83%) as a yellow solid. LCMS [M+H] + :291.10.

[0213] Step 5: 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one Under a N atmosphere, a solution of 5-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (257 g, 886.2 mmol, 1 equiv.), imidazole (211 g, 3.1 mol, 3.5 equiv.), Pd(dba)CHCl (55 g, 53.14 mmol, 0.06 equiv.), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (34 g, 80.1 mmol, 0.09 equiv.) in toluene (4500 mL) was stirred at 110° C. for 2 h. Upon completion, the solid was collected by filtration and slurried in 600 mL of MeOH, then filtered and rinsed to give the title compound (200 g, 70%) as a brown solid.

[0214] Step 6: 7-chloro-5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine A solution of 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (63 g, 195.4 mmol, 1 equiv.), SOCl (500 mL, 6.89 mol, 35.26 equiv.), and DMF (20 mL) was stirred at 90° C. for 2.5 h. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 1000 mL of DCM and 200 mL of H O. The pH value of the solution was adjusted to 8.0 with saturated aqueous Na CO . The resulting solution was extracted with 3×500 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (58.3 g, 88%) as a yellow solid. LCMS: [M+H] + 341.20.

[0215] Step 7: 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine-7-carbonitrile A solution of 7-chloro-5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine (41.2 g, 120.90 mmol, 1 equiv.), XantPhos (3.5 g, 6.04 mmol, 0.05 equiv.), zinc cyanide (14.9 g, 126.72 mmol, 1.05 equiv.), DMF (350 mL), and Pd(allyl)Cl (2.2 g, 6.06 mmol, 0.05 equiv.) was stirred at 80 °C for 2.0 h under a N atmosphere. The resulting solution was diluted with 500 mL of HO. The solid was filtered, and the residue was loaded onto a silica gel column eluted with DCM / MeOH (97:3). This afforded the title compound (16.0 g) as a brown solid. This was carried on without further purification.

[0216] Step 8: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid A solution of 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine-7-carbonitrile (16.0 g, 48.2 mmol, 1 equiv.) and HCl (37% w / w, 150 mL) was stirred at 70° C. for 12 h. The resulting mixture was concentrated in vacuo and then diluted with 10 mL of HO. The pH value of the solution was adjusted to 5.0 with aqueous NaOH (2.0 M). The solid was filtered, slurried in CHCN (25 ml), and filtered to give the title compound (4.0 g, 36%) as a brown solid. LCMS: [M+H] + 231.00.

[0217] Int-B1: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine [ka]

[0218] Step 1: (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol A mixture of (1r,4r)-4-aminocyclohexan-1-ol (30.0 g, 260.5 mmol, 1.0 equiv.), benzyl bromide (133 g, 777.6 mmol, 3 equiv.), and K2CO3 (72.0 g, 520.9 mmol, 2 equiv.) in ACN (300 mL) was stirred at 75 °C for 2 h. The reaction was quenched with water. The solid was collected by filtration to give the title compound (65 g, 85%) as a white solid. LCMS: [M+H] + 296.2.

[0219] Step 2: (1r,4r)-N,N-Dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine A mixture of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (59 g, 199.7 mmol, 1 equiv.), 1-bromo-2-methoxyethane (82.6 g, 594.3 mmol, 3 equiv.), and t-BuOK (33.6 g, 299.2 mmol, 1.5 equiv.) in DCM (1 L) was stirred at room temperature for 4 h. The reaction was quenched with water and extracted with 3 x 500 mL of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluting with 5:95 EtOAc:petroleum ether to give the title compound (48 g, 68%) as a red oil. LCMS: [M+H] + 354.2.

[0220] Step 3: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine A mixture of (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine (60.0 g, 169.7 mmol, 1 equiv.) and Pd(OH)2 / carbon (10.0 g, 71.2 mmol, 0.42 equiv.) in EtOH (600 mL) under hydrogen was stirred at room temperature for 14 hours. The solid was filtered off. The filtrate was concentrated in vacuo to give the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H] + 174.1.

[0221] Int-B2: (1r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexan-1-amine [ka]

[0222] Step 1: tert-Butyl 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)acetate A solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (8.85 g, 30 mmol, 1 equiv.), tert-butyl 2-bromoacetate (11.69 g, 60 mmol, 2 equiv.), and t-BuOK (6.72 g, 60 mmol, 2 equiv.) in DCM (120 mL) was stirred at room temperature for 2 h. Then, tert-butyl 2-bromoacetate (11.69 g, 60 mmol, 2 equiv.) and t-BuOK (6.72 g, 60 mmol, 2 equiv.) were added to the resulting solution. The mixture was stirred for an additional 2 h. The mixture was diluted with water (150 mL) and extracted with DCM (120 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography eluting with petroleum ether / EtOAc (10:1) to give the title compound (5.6 g, 46%) as a white solid. LCMS: [M+H] + 410.30.

[0223] Step 2: 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol LiAlH4 (1.14 g, 30 mmol, 3 equiv) was added to a solution of tert-butyl 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)acetate (4.10 g, 10 mmol, 1 equiv) in THF (40 mL) at 0 °C. The resulting solution was stirred for 2 h. Upon completion, the resulting solution was quenched by the addition of water (1.2 mL), 15% aqueous NaOH (1.2 mL), and water (3.6 mL) at 0 °C. The resulting solution was diluted with 30 mL THF and stirred at room temperature for 1 h. The solids were filtered and the filtrate was concentrated to give 2.5 g of the title compound as a yellow oil. LCMS: [M+H] + 340.25.

[0224] Step 3: 2-(2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-N,N-dimethylacetamide To a solution of 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol (3.40 g, 10 mmol, 1 equiv) in DMF (50 mL) was added 60% NaH (1.20 g, 30 mmol, 3 equiv). The resulting solution was stirred for 10 min, and 2-bromo-N,N-dimethylacetamide (5 g, 30 mmol, 3 equiv) was added. The resulting solution was stirred at room temperature for an additional 12 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (120 mL × 3). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH, 10:1) to give the title compound (3.4 g, 75%) as a colorless oil. LCMS: [M+H] + 425.35.

[0225] Step 4: (1r,4r)-N,N-Dibenzyl-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexan-1-amine To a solution of 2-(2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-N,N-dimethylacetamide (3.10 g, 7.3 mmol, 1 equiv) in THF (35 mL) was added LiAlH4 (0.83 g, 22 mmol, 3.00 equiv). The resulting solution was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (1 mL), 15% aqueous NaOH (1 mL), and water (3 mL) at 0 °C. The resulting solution was diluted with THF (30 mL) and stirred at room temperature for 1 h. The solids were filtered and the filtrate was concentrated under reduced pressure to give 2.5 g of the title compound as a colorless oil. LCMS: [M+H] + 411.30.

[0226] Step 5: (1r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexan-1-amine A mixture of (1r,4r)-N,N-dibenzyl-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexan-1-amine (2.50 g, 6.1 mmol, 1 equiv.) and Pd(OH)2 / C (1.2 g) in EtOH (30 mL) under hydrogen was stirred at room temperature for 4 h. The solid was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified on a reverse-phase column eluted with MeCN / H2O to give the title compound (0.4 g, 25%) as a colorless oil. LCMS: [M+H] + 231.25.

[0227] Int-B3: 1-(4-aminopiperidin-1-yl)-2-morpholinoethan-1-one hydrochloride [ka]

[0228] Step 1: tert-butyl (1-(2-morpholinoacetyl)piperidin-4-yl)carbamate A solution of tert-butyl piperidin-4-ylcarbamate (1.68 g, 8.4 mmol, 1.2 equiv.), 2-morpholinoacetic acid (1.02 g, 7 mmol, 1.00 equiv.), HATU (3.99 g, 10.5 mmol, 1.5 equiv.), and DIEA (3.62 g, 28 mmol, 4 equiv.) in DMF (15 mL) was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude product was slurried in MeOH (10 mL), filtered, and rinsed with MeOH to give the title compound (1 g, 43%) as a white solid. LCMS: [M+H] + 328.20.

[0229] Step 2: 1-(4-aminopiperidin-1-yl)-2-morpholinoethan-1-one hydrogen chloride A solution of tert-butyl (1-(2-morpholinoacetyl)piperidin-4-yl)carbamate (0.95 g, 2.91 mmol, 1.00 equiv) in HCl / 1,4-dioxane (4 M, 30.00 mL) was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to give 0.96 g of the title compound as a crude white solid. LCMS: [M+H] + 228.25.

[0230] Int-B4: 5-chloro-6-(2-morpholinoethoxy)pyridin-3-amine [ka]

[0231] Step 1: 4-(2-((3-chloro-5-nitropyridin-2-yl)oxy)ethyl)morpholine To a solution of 2-morpholinoethan-1-ol (1.60 g, 12.20 mmol, 1.23 equiv) in DMF (20 mL) was added NaH 60% (0.80 g, 20.002 mmol, 2.01 equiv) at 0 °C. The resulting solution was stirred for 10 min. 2,3-Dichloro-5-nitropyridine (1.92 g, 9.95 mmol, 1.00 equiv) was added, and the resulting solution was stirred at room temperature for 2 h. The reaction was quenched with HO and extracted with DCM (3 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (4 / 5) to give the title compound (0.99 g, 35%) as a yellow oil. LCMS: [M+H] + 288.05.

[0232] Step 2: 5-chloro-6-(2-morpholinoethoxy)pyridin-3-amine. A solution of 4-(2-((3-chloro-5-nitropyridin-2-yl)oxy)ethyl)morpholine (0.90 g, 3.27 mmol, 1.00 equiv), zinc (1.35 g, 20.78 mmol, 6.60 equiv), and acetic acid (2.08 g, 34.62 mmol, 11.00 equiv) in EtOH (20 mL) was stirred at 60 °C for 36 h. The reaction was quenched with water and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The crude product was purified on a reverse-phase column eluted with HO / ACN (1 / 3) to give the title compound (132 mg, 16%) as a brown oil. LCMS: [M+H] + 258.15.

[0233] Int-B5: 3-(2-methoxyethoxy)cyclohexan-1-amine hydrochloride [ka]

[0234] Step 1: tert-butyl (3-(2-methoxyethoxy)cyclohexyl)carbamate To a solution of tert-butyl (3-hydroxycyclohexyl)carbamate (2.50 g, 11.612 mmol, 1.00 equiv) in DMF (15 mL) was added NaH (0.70 g, 17.418 mmol, 1.5 equiv, 60%) at 0 °C. The resulting solution was stirred for 20 min. 1-Bromo-2-methoxyethane (3.23 g, 23.224 mmol, 2 equiv) was added, and the mixture was stirred at 25 °C for 24 h. The reaction was quenched with water / ice (15 mL). The resulting solution was extracted with DCM (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (20:80) to give the title compound (1.12 g, 18%) as a yellow oil. LCMS: [M+H] + 274.00.

[0235] Step 2: 3-(2-Methoxyethoxy)cyclohexan-1-amine Hydrochloride A solution of tert-butyl (3-(2-methoxyethoxy)cyclohexyl)carbamate (740 mg, 2.71 mmol, 1.00 equiv) in dioxane (5 mL) in HCl / 1,4-dioxane (5 mL, 4 M) was stirred at 25° C. for 1 h. The resulting mixture was concentrated to give the title compound (615 mg, 65.57%) as a yellow solid. LCMS: [M+H] + 174.00.

[0236] Int-B6: 6-(4-morpholinopiperidin-1-yl)pyridin-3-amine [ka]

[0237] Step 1: 4-(1-(5-nitropyridin-2-yl)piperidin-4-yl)morpholine To a solution of 4-(piperidin-4-yl)morpholine (851 mg, 5.00 mmol, 1.00 equiv.), K2CO3 (1381 mg, 9.99 mmol, 2.00 equiv.) in ACN (15 mL) was added 2-fluoro-5-nitropyridine (710 mg, 5.00 mmol, 1.00 equiv.) and the mixture was stirred at 70 °C for 1 h. The resulting solution was quenched with water (50 mL). The solid was collected by filtration and washed with water to give the title compound (1.15 g, 79%) as a yellow solid. LCMS: [M+H] + 293.15.

[0238] Step 2: 6-(4-morpholinopiperidin-1-yl)pyridin-3-amine A mixture of 4-(1-(5-nitropyridin-2-yl)piperidin-4-yl)morpholine (1110 mg, 3.80 mmol, 1.00 equiv.) and Pd / C (2020 mg, 18.99 mmol, 5.00 equiv.), DCM (5.00 mL), and EtOH (10 mL) was stirred at room temperature for 1 hour under an H atmosphere. The solid was filtered, and the filtrate was concentrated in vacuo to give the title compound (985 mg, 99%) as a black solid. LCMS: [M+H] + 263.20.

[0239] Int-B7: 1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine [ka]

[0240] Step 1: tert-butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate A solution of tert-butyl (4-amino-1-methylcyclohexyl)carbamate (630 mg, 2.76 mmol, 1 equiv.), K2CO3 (952 mg, 6.89 mmol, 2.5 equiv.), and (bromomethyl)benzene (1081 mg, 6.32 mmol, 2.29 equiv.) in MeCN (5 mL) was stirred at 80 °C for 2 h. The solid was filtered. The filtrate was concentrated and applied to a silica gel column eluted with petroleum ether: EtOAc (13:87) to give the title compound (80 mg, 71%) as a white solid. LCMS: [M+H] + 409.30.

[0241] Step 2: N1,N1-Dibenzyl-4-methylcyclohexane-1,4-diamine A solution of tert-butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate (3.3 g, 8.08 mmol, 1 equiv.) in HCl in 1,4-dioxane (60 mL, 4 M) was stirred at room temperature for 1 h. The solid was collected by filtration to give the title compound (2.1 g, 84%) as a white solid. LCMS: [M+H] + 309.20.

[0242] Step 3: N4,N4-Dibenzyl-1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine A solution of N1,N1-dibenzyl-4-methylcyclohexane-1,4-diamine (1 g, 3.24 mmol, 1 equiv.), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 6.46 mmol, 2 equiv.), and K2CO3 (1.34 g, 9.73 mmol, 3 equiv.) in ACN (50 mL) was stirred at 80 °C for 5 h. The solid was filtered. The filtrate was concentrated and applied to a silica gel column eluted with ethyl acetate / petroleum ether (20:80) to give the title compound (850 mg, 67%) as a yellow oil. LCMS: [M+H] + 391.20.

[0243] Step 4: 1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine A mixture of N4,N4-dibenzyl-1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (820 mg, 2.1 mmol, 1 equiv.) and Pd(OH)2 / C (29.5 mg, 0.21 mmol, 0.1 equiv.) in EtOH (30 mL) was stirred under hydrogen at room temperature for 2 h. The solid was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (365 mg, 82%) as a yellow oil. LCMS: [M+H] + 211.10.

[0244] Int-B8: 4-(3,3,3-trifluoropropoxy)cyclohexan-1-amine [ka]

[0245] Step 1: 1-Nitro-4-(3,3,3-trifluoropropoxy)benzene To a solution of 3,3,3-trifluoropropan-1-ol (1348 mg, 11.82 mmol, 3.3 equiv) in THF (20 mL) was added NaH (60% w / w) (170 mg, 7.09 mmol, 2 equiv) at 0 °C. The mixture was stirred for 15 min. Then, 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol, 1 equiv) was added to the solution at 0 °C. The resulting solution was stirred at room temperature for 1 h. Upon completion, the reaction was quenched by the addition of water and extracted with 3 × 100 mL EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (16:84) to give the title compound (320 mg, 38%).

[0246] Step 2: 4-(3,3,3-trifluoropropoxy)cyclohexan-1-amine In a pressure tank reactor purged and maintained with an inert atmosphere of nitrogen, a solution of 1-nitro-4-(3,3,3-trifluoropropoxy)benzene (250 mg, 1.06 mmol, 1 equiv.), isopropanol (20 mL), and Rh / AlO (1.1 g, 10.52 mmol, 10 equiv.) was stirred at 80 °C for 3 h. Upon completion, the solid was filtered. The resulting mixture was concentrated under vacuum to afford the title compound (183 mg, 82%) as a yellow oil. LCMS: [M+H] + 212.30.

[0247] Int-B9: (1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexan-1-amine hydrochloride [ka]

[0248] Step 1: tert-butyl ((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)carbamate A solution of tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate (2 g, 8.79 mmol, 1 equiv.), Ti(Oi-Pr) (2.5 g, 8.79 mmol, 1 equiv.), 2,2,2-trifluoroethylamine hydrochloride (1.43 g, 10.55 mmol, 1.2 equiv.), and HOAc (527 mg, 8.79 mmol, 1 equiv.) in EtOH (20 mL) was stirred at room temperature for 1 h. NaBHCN (828 mg, 13.19 mmol, 1.5 equiv.) was then added and stirred at room temperature for 1 h. The resulting solution was extracted with 3 × 100 mL of EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to give the title compound (1 g, 37% yield) as an off-white oil. LCMS: [M+H] + 311.10.

[0249] Step 2: (1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexan-1-amine A solution of tert-butyl ((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)carbamate (1 g, 3.22 mmol, 1 equiv.) in HCl (gas) in 1,4-dioxane (20 mL, 548.53 mmol, 204.3 equiv.) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to afford the title compound (505 mg, 75%) as a white solid. LCMS: [M+H] + 211.05.

[0250] Int-B10: 4-(2,2,2-trifluoroethoxy)cyclohexan-1-amine [ka]

[0251] Step 1: 1-Nitro-4-(2,2,2-trifluoroethoxy)benzene To a solution of 2,2,2-trifluoroethan-1-ol (1.7 g, 0.017 mmol, 1.2 equiv) in THF (20 mL) was added NaH (60% w / w) (0.85 g, 0.035 mmol, 2.5 equiv) in portions at 0 °C. After stirring for 30 min, to this was added 1-fluoro-4-nitrobenzene (2 g, 14.17 mmol, 1 equiv) at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The reaction was then quenched by the addition of water and extracted with 3 × 100 mL EtOAc. The organic layers were combined and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluting with ethyl acetate / petroleum ether (1:9) to afford the title compound (1.2 g, 38%) as a yellow solid.

[0252] Step 2: 4-(2,2,2-trifluoroethoxy)cyclohexan-1-amine Under a hydrogen atmosphere, a solution of 1-nitro-4-(2,2,2-trifluoroethoxy)benzene (1.1 g, 4.97 mmol, 1 equiv.) and Rh / AlO (0.39 g, 3.83 mmol, 0.77 equiv.) in i-PrOH (10 mL) was stirred at 80° C. under 10 atmospheres for 3 hours. Upon completion, the solid was filtered. The resulting mixture was concentrated under vacuum to give the title compound (450 mg, 46%) as a colorless oil. LCMS: [M+H] + 198.10.

[0253] Int-B11: N1-(1,1-difluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride [ka]

[0254] Step 1: tert-butyl (4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate A solution of tert-butyl(4-oxocyclohexyl)carbamate (938.2 mg, 4.4 mmol, 1.2 equiv.), 1,1-difluoro-2-methylpropan-2-amine (400 mg, 3.67 mmol, 1 equiv.), and Ti(Oi-Pr) (1250 mg, 4.4 mmol, 1.2 equiv.) in THF (20 mL) was stirred at room temperature for 1 hour, after which NH-BH (136.4 mg, 4.4 mmol, 1.2 equiv.) was added to the mixture, and the solution was stirred at room temperature for 1.5 hours. After completion, the reaction was then quenched by the addition of 30 mL of MeOH before being concentrated. The crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (3:1) to afford the title compound (350 mg, 31%) as a yellow solid. LCMS: [M+H] + 307.10.

[0255] Step 2: N1-(1,1-difluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride A solution of tert-butyl (4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate (300 mg, 0.98 mmol, 1 equiv) in HCl / dioxane (6.0 mL, 4 M) was stirred at room temperature for 1 hour. After completion, the resulting mixture was concentrated to give the title compound (329 mg) as a white solid. LCMS: [M+H] + 207.10.

[0256] Int-B12:N 1 -(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride. [ka]

[0257] Step 1: tert-butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate A solution of 1,1,1-trifluoro-2-methylpropan-2-amine (2.7 g, 21.241 mmol, 1.0 equiv.), tert-butyl(4-oxocyclohexyl)carbamate (5.44 g, 0.025 mmol, 1.2 equiv.), and Ti(Oi-Pr) (7.24 g, 0.025 mmol, 1.2 equiv.) in THF (100 mL) was stirred at 25 °C for 1 h, after which NH-BH (0.79 g, 0.025 mmol, 1.20 equiv.) was added, and the resulting solution was stirred at 25 °C for 3 h. After completion, the reaction was then quenched by the addition of 200 mL of MeOH. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate / petroleum ether (1:4) to afford the title compound (1.7 g, 25% yield) as a pale yellow oil. LCMS: [M+H] + 325.

[0258] Step 2:N 1 -(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride A solution of tert-butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate (300 mg, 0.93 mmol, 1 equiv) and TFA (0.2 mL) in DCM (4 mL) was stirred at 25° C. for 1 h. After completion, the resulting mixture was concentrated in vacuo to afford the title compound (180 mg, 87% yield) as a colorless oil. LCMS: [M+H] + 225.15.

[0259] Example 1: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide [ka]

[0260] Step 1: 6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid A mixture of methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate (700 mg, 1.82 mmol, 1 equiv.), imidazole (148 mg, 2.18 mmol, 1.2 equiv.), CsCO (888 mg, 2.72 mmol, 1.5 equiv.), and CuI (35 mg, 0.18 mmol, 0.1 equiv.) in NMP (10 mL) was heated at 150 °C overnight. After cooling to room temperature, the mixture was diluted with water (20 mL). The resulting precipitate was filtered. The filtrate was purified by reverse-phase chromatography (5% ACN / water) to give the title compound (200 mg, 0.56 mmol, 31% yield) as a pale yellow solid. LCMS: [M+H] + 359.2.

[0261] Step 2: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide A mixture of 6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid (200 mg, 0.56 mmol, 1 equiv.), Int-B1 (97 mg, 0.56 mmol, 1 equiv.), HATU (318 mg, 0.84 mmol, 1.5 equiv.), and DIPEA (108 mg, 0.84 mmol, 1.5 equiv.) in DMF (5 mL) was stirred at room temperature for 3 h. After dilution with EtOAc (20 mL), the organic phase was washed with brine (5 mL × 3). After concentration, the mixture was purified by silica gel chromatography (DCM:MeOH, 20:1) to give the title compound (75 mg, 0.15 mmol, 26% yield). LCMS: [M+H] + 514.4.

[0262] Step 3: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide A mixture of 6-imidazol-1-yl-N-[4-(2-methoxyethoxy)cyclohexyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide (75 mg, 0.15 mmol, 1.0 equiv.) in TFA (1 mL, 0.15 mmol, 1 equiv.) and DCM (2 mL) was stirred at room temperature for 4 h. After concentration, the residue was purified by silica gel chromatography (DCM:MeOH, 20:1) to give the title compound (35 mg, 0.09 mmol, 63% yield) as a white solid. LCMS: [M+H] + 384.1, 1 H NMR(400MHz,DMSO-d6)δ:13.23(s,1H),9.83(d,J=6Hz,1H),8.57(s,1H),8.25(s,1H),7.95(d,J=8.8Hz,2H),7.74(s,1H),7.13(s ,1H),3.90(m,1H),3.55-3.53(m,2H),3.45-3.43(m,2H),m,3.63-3.55(m,1H),3.26(s,3H),2.11-1.92(m,4H),1.58-1.43(m,4H).

[0263] Example 2: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-7-carboxamide [ka]

[0264] Step 1: 6-bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide To a solution of Int-A1 (160 mg, 0.43 mmol, 1 equiv.) in DMF (10 mL) at room temperature under a N atmosphere, [2-fluoro-6-(trifluoromethyl)phenyl]methanamine (92 mg, 0.47 mmol, 1.1 equiv.), DIPEA (84 mg, 0.65 mmol, 1.5 equiv.), and HATU (197 mg, 0.52 mmol, 1.2 equiv.) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water (20 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 3:1) to give the title compound (180 mg, 0.33 mmol, 76% yield). LCMS: [M+H] + 548.1.

[0265] Step 2: N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide The title compound (20 mg, 0.038 mmol, 11% yield) was isolated as a solid following the procedure of Example 1, Step 1 using 6-bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide. LCMS: [M+H] + 534.4.

[0266] Step 3: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-7-carboxamide The title compound (8 mg, 0.019 mmol, 51% yield) was prepared as a solid according to the procedure of Example 1, Step 3 using N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide. LCMS: [M+H] + 404.0, 1HNMR(400MHz,DMSO-d6)δ 13.3(s,1H),10.2(s,1H),8.52(s,1H),8.27(s,1H),7.98(d,J=21.6Hz,2H),7.79(s,1H),7.66-7.64(m,3H),7.13(m,1H),4.88(m,2H).

[0267] Example 3: N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide [ka]

[0268] Step 1: N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide To a solution of 6-bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide (120 mg, 0.22 mmol, 1 equiv.) prepared in Example 1, Step 1, in DMF (5 mL) was added PdCl(dppf)-CHCl (51 mg, 0.04 mmol, 0.2 equiv.), CuI (8 mg, 0.04 mmol, 0.2 equiv.), and KCO (61 mg, 0.44 mmol, 2 equiv.). Tributyl(thiazol-5-yl)stannane (99 mg, 0.26 mmol, 1.2 equiv.) was added, and the mixture was heated to 100 °C overnight. The residue was diluted with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 30:1) to give the title compound (50 mg, 0.09 mmol, 41% yield). LCMS: [M+H] + 551.2.

[0269] Step 2: N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide The title compound (30 mg, 0.069 mmol, 76% yield) was prepared as a solid according to the procedure of Example 1, Step 3 using N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide. LCMS: [M+H] + 421.0; 1 HNMR(400MHz,DMSO-d6)δ 13.1(s,1H),10.1(s,1H),9.10(s,1H),8.49(s,1H),8.36(s,1H),8.08(d,J=28.0Hz,2H),7.67-7.63(m,3H),4.88(s,2H).

[0270] Example 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide [ka]

[0271] Step 1: 5-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide To a solution of Int-A1 (100 mg, 0.27 mmol, 1 equiv.), HOBt (44 mg, 0.32 mmol, 1.2 equiv.), and EDC (50 mg, 0.32 mmol, 1.2 equiv.) in DMF (2 mL) was added Int-B1 (51 mg, 0.30 mmol, 1.1 equiv.), and the mixture was stirred at 25 °C overnight. The mixture was diluted with water (25 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 1:1) to give the title compound (50 mg, 0.095 mmol, 35% yield) as a brown oil. LCMS: [M+H] + 528.2.

[0272] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide The title compound was prepared as an oil (25 mg, 0.047 mmol, 50% yield) according to the procedure in Example 3, Step 1 using 5-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide. LCMS: [M+H] + 531.3.

[0273] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide The title compound was isolated as a yellow solid (10 mg, 0.025 mmol, 53% yield) following the procedure of Example 1, Step 3 using N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide. LCMS: [M+H] + 401.1; 1HNMR(400MHz,DMSO-d6)δ 13.10(s,1H),9.79(d,J=7.6Hz,1H),9.09(s,1H),8.53(s,1H),8.35(s,1H),8.08(s,1H),8.03(s,1H),3.90(s,1 H),3.53-3.56(m,2H),3.43-3.45(m,2H),3.29-3.35(m,1H),3.26(s,3H),1.98-2.02(m,4H),1.29-1.44(m,4H).

[0274] Example 5: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxamide [ka]

[0275] Step 1: Methyl 5-iodoindoline-7-carboxylate To a stirred solution of 1-iodopyrrolidine-2,5-dione (21.2 g, 94.3 mmol, 3 equiv.) in ACN (100 mL) was added methyl indoline-7-carboxylate (5570 mg, 31.4 mmol, 1 equiv.) in portions at -20 °C. After quenching with saturated NaSO (20 mL), the aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc, 20:1, v / v) to give the title compound (1500 mg, 4.95 mmol, 16% yield) as a pale yellow solid. LCMS: [M+H] + 304.0.

[0276] Step 2: Methyl 5-iodo-1H-indole-7-carboxylate To a solution of methyl 5-iodoindoline-7-carboxylate (910 mg, 3 mmol, 1 equiv.) in toluene (16 mL) was added MnO2 (1357 mg, 15.61 mmol, 5.2 equiv.). The mixture was stirred at 75 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc, 30:1, v / v) to give the title compound (540 mg, 1.79 mmol, 60% yield) as a pale yellow solid. LCMS: [M+H] + 301.9.

[0277] Step 3: 5-Iodo-1H-indole-7-carboxylic acid To a solution of methyl 5-iodo-1H-indole-7-carboxylate (540 mg, 1.79 mmol, 1 equiv.) in MeOH (3 mL) and THF (3 mL) was added NaOH (4.3 mL, 12.9 mmol, 7.2 equiv.) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated and acidified with 1 M HCl solution. The resulting solid was collected by filtration to give the title compound (467 mg, 1.63 mmol, 91% yield) as a white solid. LCMS: [M+H] + 285.9.

[0278] Step 4: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-iodo-1H-indole-7-carboxamide A solution of 5-iodo-1H-indole-7-carboxylic acid (100 mg, 0.35 mmol, 1 equiv.), [2-fluoro-6-(trifluoromethyl)phenyl]methanamine (81 mg, 0.42 mmol, 1.2 equiv.), DIPEA (120 mg, 0.91 mmol, 2.6 equiv.), and HATU (160 mg, 0.42 mmol, 1.2 equiv.) in DMF (8 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 3:1, v / v) to give the title compound (150 mg, 0.33 mmol, 93% yield) as a gray solid. LCMS: [M+H] + 463.0.

[0279] Step 5: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxamide A solution of N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-iodo-1H-indole-7-carboxamide (150 mg, 0.32 mmol, 1 equiv.), imidazole (66 mg, 0.97 mmol, 3 equiv.), CuI (13 mg, 0.06 mmol, 0.2 equiv.), and K2CO3 (144 mg, 0.97 mmol, 3 equiv.) in DMF (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 3:1, v / v) to give the title compound (4.4 mg, 0.01 mmol, 3% yield) as a gray solid. LCMS: [M+H] + 403.0; 1 HNMR(400MHz,CD3OD)δ 9.28(br s,1H),8.09-8.06(m,1H),9.09(br s,1H),7.85-7.72(m,3H),7.63-7.45(m,5H),6.71(d,J=2.8,1H),4.86(s,2H).

[0280] Example 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide [ka]

[0281] Step 1: 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide A solution of 5-iodo-1H-indole-7-carboxylic acid (844 mg, 2.94 mmol, 1 equiv.) prepared in Example 5, Step 2, Int-B1 (611 mg, 3.53 mmol, 1.2 equiv.), DIPEA (1.33 mL, 7.64 mmol, 2.6 equiv.), and HATU (1.34 g, 3.53 mmol, 1.2 equiv.) in DMF (15 mL) was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc, 3:1, v / v) to give the title compound (740 mg, 1.67 mmol, 56% yield) as a gray solid. LCMS: [M+H] + 443.2.

[0282] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide To a mixture of 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol, 1 equiv.), PdCl(dppf) (18.4 mg, 0.02 mmol, 0.2 equiv.), CuI (4.3 mg, 0.02 mmol, 0.2 equiv.), and KCO (31.2 mg, 0.23 mmol, 2 equiv.) in DMF (4 mL) was added tributyl(thiazol-5-yl)stannane (63 mg, 0.17 mmol, 1.5 equiv.). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The mixture was filtered, diluted with water (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% TFA in MeOH / H2O) to give the title compound (2.3 mg, 0.006 mmol, 5.1% yield) as a yellow solid. LCMS: [M+H] + 400.1;HNMR(400MHz,DMSO-d6)δ 11.23(s,1H),9.03(s,1H),8.43(d,J=7.6Hz,1H),8.27(s,1H),7.99-7.95(m,2H),7.39(s,1H),6.54(s,1H),3.91-3.82(m,1H),3. 56-3.54(m,2H),3.44-3.42(m,2H),3.28-3.25(m,4H),2.07-2.04(m,2H),1.95-1.93(m,2H),1.50-1.40(m,2H),1.33-1.26(m,2H).

[0283] Example 7: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka] A solution of Int-A2 (23 g, 100 mmol, 1.0 equiv), Int-B1 (19.1 g, 110 mmol, 1.1 equiv), HATU (57.2 g, 150 mmol, 1.5 equiv), and DIPEA (32.4 g, 250 mmol, 2.5 equiv) in DMF (500 mL) was stirred at 35 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The crude product was purified by preparative HPLC eluting with ACN / HO to give the title compound (24.8 g, 64 mmol, 64% yield) as a white solid. LCMS: [M+H] + 385.15;1H NMR(300MHz,DMSO-d6)δ 12.08(s,1H),8.98(s,1H),8.96-8.89(m,1H),8.23(s,1H),8.03(t,J= 4.0Hz,1H),7.13(s,1H),6.71(d,J=3.1Hz,1H),3.99-3.85(m,1H),3.59 -3.56(m,2H),3.47-3.42(m,2H),3.33-3.30(m,1H),3.26(s,3H),2.09 -1.99(m,2H),1.91-1.83(m,2H),1.71-1.55(m,2H),1.45-1.21(m,2H).

[0284] Example 8: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indazole-7-carboxamide [ka]

[0285] Step 1: Methyl 2-amino-5-iodo-3-methylbenzoate To a solution of methyl 2-amino-3-methylbenzoate (1 g, 6.0 mmol, 1.0 equiv.) in ACN (50 mL) was added NIS (2.7 g, 12.0 mmol, 2.0 equiv.), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound (1.2 g, 68.1% yield) as a yellow solid. LCMS: [M+H] + 292.10.

[0286] Step 2: Methyl 5-iodo-1H-indazole-7-carboxylate To a solution of methyl 2-amino-5-iodo-3-methylbenzoate (1 g, 3.4 mmol, 1.0 equiv.) in CHCl3 (40 mL) was added Ac2O (807 mg, 7.9 mmol, 2.3 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 hour. Then, tert-butyl nitrite (744 mg, 7.22 mmol, 2.1 equiv) and KOAc (100 mg, 1.019 mmol, 0.30 equiv) were added sequentially at 0 °C, and the mixture was stirred at reflux overnight. The mixture was concentrated and purified by flash chromatography on silica gel eluting with DCM in petroleum ether (0-30%) to give the title compound (0.8 g, 77.1% yield) as a yellow solid. LCMS: [M+H] + 303.00.

[0287] Step 3: 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid To a solution of methyl 5-iodo-1H-indazole-7-carboxylate (600 mg, 1.99 mmol, 1.0 equiv) in DMF (10 mL) were added NaH (79.4 mg, 1.99 mmol, 1.0 equiv, 60%) and SEMCl (331.2 mg, 1.99 mmol, 1.0 equiv) sequentially at 0 °C, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (20 mL), and dried over NaSO. After concentration, the crude product was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0–100%) to give the title compound (300 mg, 36.1% yield) as a yellow oil. LCMS: [M+H] + 419.02.

[0288] Step 4: 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide A mixture of 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid (280 mg, 0.67 mmol, 1.0 equiv.), Int-B1 (231.9 mg, 1.34 mmol, 2.0 equiv.), HATU (509.0 mg, 1.34 mmol, 2.0 equiv.), and DIPEA (259.5 mg, 2.01 mmol, 3.0 equiv.) in DMF (5 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by flash chromatography on silica gel eluting with MeOH in DCM (0-10%) to afford the title compound (160 mg, 41.7% yield) as a yellow oil. LCMS: [M+H] + 574.15.

[0289] Step 5: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide A mixture of 5-iodo-N-((1r,4r)-4-(2-methoxyethoxycyclohexyl)-1((2-trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide (140 mg, 0.25 mmol, 1.0 equiv), CsCO (159.1 mg, 0.49 mmol, 2.0 equiv), 1,10-phenanthroline (132 mg, 0.73 mmol, 3.0 equiv), and 1H-imidazole (99.7 mg, 1.47 mmol, 6.0 equiv) in oxane (10 mL) under nitrogen was stirred at 120 °C overnight. The mixture was concentrated and purified by flash chromatography on silica gel eluting with MeOH in DCM (0–10%) to give the title compound (40 mg, 31.9% yield) as a yellow oil. LCMS: [M+H] + 514.30.

[0290] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indazole-7-carboxamide To a solution of 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide (35 mg, 0.068 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH 8-9 with 7 M ammonia in methanol. The mixture was concentrated and purified by flash chromatography on silica gel eluting with MeOH in DCM (0-10%) to give the title compound (15.3 mg, 57.4% yield) as an off-white solid. LCMS: [M+H] + 384.20. 1H NMR(400MHz,DMSO-d6)δ 13.26(s,1H),8.52(d,J=7.6Hz,1H),8.24(t,J=1.1Hz,1H),8.22(s,1H),8.18(d,J=1.9Hz,1H) ),8.13(d,J=2.0Hz,1H),7.77(t,J=1.3Hz,1H),7.15(t,J=1.1Hz,1H),3.94-3.81(m,1H),3.5 6(dd,J=5.9,3.8Hz,2H),3.44(dd,J=5.9,3.8Hz,2H),3.31-3.28(m,1H),3.26(s,3H),2.07(d ,J=12.1Hz,2H),1.97(d,J=12.6Hz,2H),1.43(q,J=11.8Hz,2H),1.28(q,J=11.2,10.7Hz,2H).

[0291] Example 9: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide [ka]

[0292] Step 1: 1-(3-bromo-4-nitrophenyl)-1H-imidazole A solution of 2-bromo-4-fluoro-1-nitrobenzene (1000 mg, 4.55 mmol, 1.0 equiv), 1H-imidazole (340 mg, 5.00 mmol, 1.1 equiv), and K2CO3 (949 mg, 6.82 mmol, 1.5 equiv) in DMF (12 mL) was stirred at 110 °C for 2.5 h. The reaction was quenched with water (20 mL). The resulting solution was extracted with 3 x 30 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (3:2) to give the title compound (990 mg, 81% yield) as a yellow solid. LCMS: [M+H] + 268.00.

[0293] Step 2: 7-Bromo-5-(1H-imidazol-1-yl)-2-methyl-1H-indole To a solution of 1-(3-bromo-4-nitrophenyl)-1H-imidazole (500 mg, 1.87 mmol, 1.0 equiv.) in THF (10 mL) under nitrogen at −40° C. was added 0.5 M prop-1-en-2-ylmagnesium bromide (15 mL, 7.46 mmol, 4.0 equiv.), and the resulting solution was stirred at −40° C. for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl. The resulting solution was extracted with 3×30 mL of EtOAc, and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied to a silica gel column eluting with EtOAc / petroleum ether (1:4) to afford the title compound (220 mg, 42.7%) as a pale yellow solid. LCMS: [M+H] + 276.05.

[0294] Step 3: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide A solution of 7-bromo-5-(1H-imidazol-1-yl)-2-methyl-1H-indole (200 mg, 0.72 mmol, 1.0 equiv.), Int-B1 (502 mg, 2.9 mmol, 4.0 equiv.), TEA (146.6 mg, 1.45 mmol, 2.0 equiv.), and Pd(dppf)Cl2 (53 mg, 0.072 mmol, 0.1 equiv.) in DMSO (2 mL) was stirred at 90 °C for 6 h under an atmosphere of CO (2 atm). The reaction was quenched with water. The resulting solution was extracted with 3 × 30 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (80 mg) was purified by preparative HPLC eluting with ACN / HO to give the title compound (20 mg, 7%) as a white solid. LCMS: [M+H] + 397.20. 1H NMR (400 MHz, DMSO-d6) δ 11.08(s,1H),8.35(d,J=7.7Hz,1H),8.17(s,1H),7.75(d,J=10.7Hz,2H),7.70( s,1H),7.12(s,1H),6.25(s,1H),3.87(dd,J=7.7,4.0Hz,1H),3.58-3.53(m,2H) ,3.46-3.41(m,2H),3.30~3.28(m,1H),3.25(s,3H),2.44(s,3H),2.06(d,J=12. 2Hz,2H),1.95(d,J=12.6Hz,2H),1.42(q,J=11.8Hz,2H),1.26(q,J=11.8Hz,2H).

[0295] Example 10: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide [ka]

[0296] Step 1: 2-(1H-imidazol-1-yl)-5-nitropyridin-4-amine A solution of 2-chloro-5-nitropyridin-4-amine (2.5 g, 14.4 mmol, 1 equiv.), 1H-imidazole (1.96 g, 28.81 mmol, 2 equiv.), and KCO (3.98 g, 28.81 mmol, 2 equiv.) in DMF (10 mL) was stirred at 100 °C for 2 h. The resulting solution was quenched with water, and the solid was collected by filtration to give the title compound (3 g) as a crude yellow solid. LCMS (ESI, m / z): 206.18 [M+H] + .

[0297] Step 2: 4-Bromo-2-(1H-imidazol-1-yl)-5-nitropyridine To a solution of 2-(1H-imidazol-1-yl)-5-nitropyridin-4-amine (3 g, 14.62 mmol, 1 equiv.) and CuBr (4.9 g, 21.93 mmol, 1.5 equiv.) in CHCN (10 mL) was added isopentyl nitrite (2.57 g, 21.93 mmol, 1.5 equiv.). The resulting solution was stirred at 65 °C for 1 h. The resulting mixture was concentrated, and the crude product was purified by C18 reverse-phase chromatography eluting with HO / CHCN to give the title compound (1.6 g, 40.6%) as a yellow solid. LCMS (ESI, m / z): 269.06 [M+H] + .

[0298] Step 3: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine To a solution of 4-bromo-2-(1H-imidazol-1-yl)-5-nitropyridine (1.6 g, 5.95 mmol, 1.0 equiv.) in THF (10 mL) under nitrogen at −78° C. was added 1 M vinylmagnesium bromide (23.8 mL, 23.79 mmol, 4.0 equiv.), and the resulting solution was stirred at −78° C. for 2 h. The resulting solution was quenched with saturated aqueous NH4Cl. After concentration, the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (45:55) to afford the title compound (180 mg, 11.5%) as a yellow solid. LCMS (ESI, m / z): 263.10 [M+H] + .

[0299] Step 4: Methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate A solution of 7-bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine (180 mg, 0.68 mmol, 1.0 equiv.), Pd(dppf)Cl (100.1 mg, 0.14 mmol, 0.2 equiv.), and TEA (276.9 mg, 2.74 mmol, 4.0 equiv.) in MeOH (10 mL) was stirred under carbon monoxide at 70 °C for 2 h. The resulting mixture was concentrated in vacuo, and the crude product was purified by C18 reverse-phase chromatography eluting with CHCN / HO to give the title compound (50 mg, 30%) as a yellow solid. LCMS (ESI, m / z): 243.24 [M+H] + .

[0300] Step 5: 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid To a solution of methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate (30 mg, 0.12 mmol, 1.0 equiv.) in MeOH / HO (1 mL / 0.2 mL) was added NaOH (9.9 mg, 0.25 mmol, 2.0 equiv.), and the resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo, and the crude product was purified on a C18 reverse-phase column eluted with CHCN / HO to give the title compound (10 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 229.21 [M+H] + .

[0301] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (15 mg, 0.066 mmol, 1 equiv.), Int-B1 (11.4 mg, 0.066 mmol, 1 equiv.), HATU (25 mg, 0.066 mmol, 1.0 equiv.), and DIPEA (17 mg, 0.13 mmol, 2.0 equiv.) in DMF (1 mL) was stirred at room temperature for 1 h. The resulting mixture was purified on a C18 reverse phase column eluted with CHCN / HO to afford the title compound (5 mg, 20%) as a white solid. LCMS: 384.25 [M+H] + . 1 H NMR(400MHz,CD3OD-d4)δ 8.52(d,J=1.3Hz,1H),7.94(d,J=1.4Hz,1H),7.83(s,1H),7.74(d,J=3.3Hz,1H),7.19(t,J=1.2Hz,1H),6.69(d,J=3.3Hz) ,1H),4.02-3.98(m,1H),3.70-3.61(m,2H),3.59-3.51(m,2H),3.46-3.38(m,4H),2.21-2.08(m,4H),1.59-1.34(m,4H).

[0302] Example 11: N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide [ka]

[0303] Step 1: Methyl 5-bromo-2-methyl-1H-indole-7-carboxylate To a solution of methyl 5-bromo-2-nitrobenzoate (1 g, 3.85 mmol, 1 equiv.) in THF (15 mL) under nitrogen, prop-1-en-2-ylmagnesium bromide (2.23 g, 15.38 mmol, 4.0 equiv.) was added, and the resulting solution was stirred at −50° C. for 2 h. The solution was quenched with saturated aqueous NH4Cl and extracted with 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to give the title compound (160 mg, 15.1% yield) as a yellow solid. LCMS (ESI, m / z): 268.00 [M+H] + .

[0304] Step 2: Methyl 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylate To a solution of methyl 5-bromo-2-methyl-1H-indole-7-carboxylate (70 mg, 0.26 mmol, 1.0 equiv.), Pd(dppf)Cl (76 mg, 0.10 mmol, 0.4 equiv.), CuI (15 mg, 0.078 mmol, 0.3 equiv.), and NaCO (55 mg, 0.52 mmol, 2.0 equiv.) in DMF (4 mL) under nitrogen, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (110 mg, 0.52 mmol, 2.0 equiv.) was added. The solution was stirred at 80 °C for 2 h. The solution was quenched with HO. The solids were filtered. The resulting mixture was extracted with 3 × 10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a C18 reverse phase column eluted with H2O / CH3CN to give the title compound (30 mg, 42% yield) as a brown solid. LCMS (ESI, m / z): 273.32 [M+H] + .

[0305] Step 3: 2-Methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylic acid To a solution of methyl 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylate (30 mg, 0.11 mmol, 1 equiv.) in THF / HO (2 mL / 0.4 mL) was added NaOH (9 mg, 0.22 mmol, 2.0 equiv.). The resulting solution was stirred at room temperature for 6 hours. The pH value was adjusted to 4 with 2 M HCl. The solid was filtered to give the title compound (22 mg, 77% yield) as a brown solid. LCMS (ESI, m / z): 259.30 [M+H] + .

[0306] Step 4: N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide A solution of 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylic acid (22 mg, 0.085 mmol, 1 equiv.), (2-fluoro-6-(trifluoromethyl)phenyl)methanamine (19.7 mg, 0.10 mmol, 2.0 equiv.), HATU (32.4 mg, 0.085 mmol, 1.0 equiv.), and DIPEA (22.0 mg, 0.17 mmol, 2.0 equiv.) in DMF (3 mL) was stirred at room temperature for 40 min. The resulting solution was quenched with HO and extracted with 3 × 10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (11.8 mg, 32% yield) as a white solid. LCMS (ESI, m / z): 434.00 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 11.10(s,1H),8.89(d,J=0.8Hz,2H),8.11(d,J=0.8Hz,1H),7.91-7.81(m ,2H),7.69-7.54(m,3H),7.50(t,J=9.0Hz,1H),4.87(m,2H),2.51(s,3H).

[0307] Example 12: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide [ka]

[0308] Step 1: 6-(1H-imidazol-1-yl)-3-nitropyridin-2-amine A solution of 6-chloro-3-nitropyridin-2-amine (10.0 g, 57.8 mmol, 1.0 equiv), KCO (16.0 g, 115.6 mmol, 2.0 equiv), and 1H-imidazole (11.3 g, 173.4 mmol, 3.0 equiv) in NMP (100 mL) was stirred at 80 °C for 5 h. The reaction was diluted with 1000 mL of water, and the solid was collected by filtration to give the title compound (12 g) as a crude light brown solid. LCMS (ESI, m / z): 206.18 [M+H] + .

[0309] Step 2: 2-Bromo-6-(1H-imidazol-1-yl)-3-nitropyridine To a solution of 6-(1H-imidazol-1-yl)-3-nitropyridin-2-amine (8 g, 39.0 mmol, 1.0 equiv.) and CuBr (13.1 g, 58.5 mmol, 1.5 equiv.) in CHCN (100 mL) was added isopentyl nitrite (6.8 g, 58.5 mmol, 1.5 equiv.). The resulting solution was stirred at 65 °C for 12 h. The resulting solution was quenched with water, and the solid was collected by filtration. The crude product was further purified on a C18 reverse phase column eluted with HO / CHCN to give the title compound (2.4 g, 13.9%) as a pale yellow solid. LCMS (ESI, m / z): 269.06 [M+H] + .

[0310] Step 3: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine To a solution of 2-bromo-6-(1H-imidazol-1-yl)-3-nitropyridine (1.2 g, 4.46 mmol, 1 equiv.) in THF (50 mL) under nitrogen at −60° C. was added bromo(ethenyl)magnesium (15.6 mL, 15.60 mmol, 3.5 equiv.), and the resulting solution was stirred at this temperature for 3 h. The resulting solution was quenched with saturated aqueous NH4Cl and extracted with 3×100 mL of EtOAc. The organic layers were combined, washed with 1×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a C18 reverse phase column eluted with HO / CH3CN to give the title compound (80 mg, 6%) as a brown solid. LCMS (ESI, m / z): 263.10 [M+H] + .

[0311] Step 4: Methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate A solution of 7-bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine (170 mg, 0.65 mmol, 1.0 equiv.), TEA (192 mg, 1.9 mmol, 2.9 equiv.), and Pd(dppf)Cl (46 mg, 0.063 mmol, 0.10 equiv.) in CHOH (10 mL) was stirred under carbon monoxide at 70 °C for 12 h. The resulting mixture was concentrated in vacuo, and the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to give the title compound (60 mg, 38%) as a brown solid. LCMS (ESI, m / z): 243.24 [M+H] + .

[0312] Step 5: 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid To a solution of methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (60 mg, 0.25 mmol, 1.0 equiv.) in MeOH / HO (5.0 mL / 1 mL) was added NaOH (29.7 mg, 0.74 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 40 minutes. The resulting solution was diluted with 3 mL of water. The pH value of the solution was adjusted to 4 with HCl (1 M). The solid was collected by filtration to give the title compound (34 mg, 60%) as a pale yellow solid. LCMS (ESI, m / z): 229.21 [M+H] + .

[0313] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (35 mg, 0.15 mmol, 1.0 equiv.), Int-B1 (32 mg, 0.18 mmol, 1.2 equiv.), HATU (58 mg, 0.15 mmol, 1.0 equiv.), and DIPEA (39.6 mg, 0.31 mmol, 2.0 equiv.) in DMF (5 mL) was stirred at room temperature for 40 min. The resulting mixture was quenched with water and extracted with 3 × 10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (13 mg, 23%) as a white solid. LCMS (ESI, m / z): 384.20 [M+H] + . 1H NMR(300MHz,M ethanol-d4)δ8.71(d,J=1.4Hz,1H),8.02-7.99(m,2H),7.71(dd,J=3.1,1.2Hz,1H),7.17(d,J=1.5Hz,1H),6.71(dd,J=3.2,1.2H z,1H),4.08-3.97(m,1H),3.74-3.62(m,2H),3.60-3.51(m,2H),3.44- 3.36(m,4H),2.27-1.94(m,4H),1.73-1.54(m,2H),1.52-1.26(m,2H).

[0314] Example 13: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide [ka]

[0315] Step 1: Methyl 2-amino-5-iodo-3-nitrobenzoate A solution of methyl 2-amino-3-nitrobenzoate (4.0 g, 20.39 mmol, 1.0 equiv.) and NIS (6.88 g, 30.59 mmol, 1.5 equiv.) in AcOH (60 mL) was stirred at room temperature for 2 hours. The reaction was then quenched with saturated aqueous sodium sulfite. The pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate. The solid was collected by filtration to give the title compound (6 g, 91%) as a yellow solid. LCMS (ESI, m / z): 323 [M+H] + .

[0316] Step 2: Methyl 2,3-diamino-5-iodobenzoate A solution of methyl 2-amino-5-iodo-3-nitrobenzoate (6.0 g, 18.63 mmol, 1.0 equiv.), Fe (1.6 g, 27.95 mmol, 1.50 equiv.), and HO (50 mL) in EtOH (200 mL) was stirred at 80 °C for 25 min. The insoluble solid was filtered. The resulting mixture was concentrated, and the crude product was applied to a silica gel column eluted with EtOAc / petroleum to give the title compound (4.2 g, 77%) as a red solid. LCMS (ESI, m / z): 293.0 [M+H] + .

[0317] Step 3: Methyl 5-iodo-2-methyl-1H-benzo[d]imidazole-7-carboxylate A solution of methyl 2,3-diamino-5-iodobenzoate (4.2 g, 14.38 mmol, 1.0 equiv.), 1,1,1-triethoxyethane (7.0 g, 43.14 mmol, 3.0 equiv.), and HSO (139.6 mg, 1.44 mmol, 0.10 equiv.) in MeOH (15 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated. The crude product was loaded onto a silica gel column eluted with EtOAc / petroleum. The crude product was further purified by C18 reverse-phase chromatography eluted with HO / CHCN to give the title compound (2.23 g, 49%) as a white solid. LCMS (ESI, m / z): 317.0 [M+H] + .

[0318] Step 4: Methyl 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylate Under nitrogen, a solution of methyl 5-iodo-2-methyl-1H-benzo[d]imidazole-7-carboxylate (300.0 mg, 0.95 mmol, 1.0 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (321 mg, 1.52 mmol, 1.6 equiv.), Pd(dppf)Cl (69 mg, 0.095 mmol, 0.10 equiv.), CuI (18.1 mg, 0.095 mmol, 0.10 equiv.), and CsF (288.3 mg, 1.90 mmol, 2.0 equiv.) in DMF (5 mL) was stirred at 80 °C for 2 h. The insoluble solid was filtered. The residue was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to give the title compound (128 mg, 49%) as a white solid. LCMS (ESI, m / z): 274.2 [M+H] + .

[0319] Step 5: 2-Methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylic acid A solution of methyl 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylate (128 mg, 0.47 mmol, 1.0 equiv.), NaOH (94 mg, 2.34 mmol, 5.0 equiv.), and HO (1.5 mL) in MeOH (4.5 mL) was stirred at room temperature for 3 h. The pH value of the solution was adjusted to 6 with 1 M aqueous HCl. After concentration, the crude product was applied to a silica gel column eluted with dichloromethane / methanol to give the title compound (110 mg, 90.6%) as a white solid. LCMS (ESI, m / z): 260.1 [M+H] + .

[0320] Step 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide A solution of 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylic acid (105 mg, 0.41 mmol, 1.0 equiv.), Int-B1 (84 mg, 0.47 mmol, 1.2 equiv.), DIPEA (157 mg, 1.22 mmol, 3.0 equiv.), and HATU (231 mg, 0.61 mmol, 1.5 equiv.) in DMF (3.5 mL) was stirred at room temperature for 1 h. The reaction was then quenched by the addition of 0.1 mL of ethanolamine. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to afford the title compound (80 mg, 47%) as a white solid. LCMS: [M+H] + 415.20. 1 HNMR(400MHz,DMSO-d6)δ:12.69(s,1H),9.75(s,1H),9.08(d,J=0.7Hz,1H),8.34(d,J=0.8Hz,1H),8.00(d,J=1.7Hz,1H),7.92(d,J=1.7Hz,1H), 3.89-3.85(m,1H),3.59-3.51(m,2H),3.50-3.40(m,2H),3.36-3.30(m, 1H), 3.26 (s, 3H), 2.59 (s, 3H), 2.01 (d, J=9.0Hz, 4H), 1.47-1.27 (m, 4H).

[0321] Example 14: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide [ka]

[0322] Step 1: 2-chloro-6-(1-ethoxyvinyl)-7H-purine Under nitrogen, a solution of 2,6-dichloro-7H-purine (3.78 g, 20.00 mmol, 1.0 equiv.), tributyl(1-ethoxyethenyl)stannane (8.67 g, 24.00 mmol, 1.2 equiv.), and Pd(PPh3)2Cl2 (1.4 g, 2.00 mmol, 0.10 equiv.) in DMF (30 mL) was stirred at 80 °C for 18 h. The reaction was then quenched with saturated aqueous KF. The insoluble solid was filtered. The resulting solution was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluting with (DCM:MeOH 10:1) to give the title compound (3 g, 67% yield). LCMS: [M+H] + 225.1.

[0323] Step 2: Ethyl 2-chloro-7H-purine-6-carboxylate A solution of 2-chloro-6-(1-ethoxyethenyl)-7H-purine (2.24 g, 9.97 mmol, 1.0 equiv), KMnO (315 mg, 1.99 mmol, 0.20 equiv), NaIO (10.7 g, 49.86 mmol, 5.0 equiv), and HO (40 mL) in dioxane (40 mL) was stirred at room temperature for 18 h. The resulting solution was diluted with water (100 mL) and extracted with DCM. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure to give the crude title compound (1 g, 44% yield). LCMS: [M+H] + 227.1.

[0324] Step 3: Ethyl 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate A solution of ethyl 2-chloro-7H-purine-6-carboxylate (460 mg, 2.03 mmol, 1.0 equiv.), [2-(chloromethoxy)ethyl]trimethylsilane (406 mg, 2.44 mmol, 1.20 equiv.), and NaH (60%, 160 mg, 4.06 mmol, 2.0 equiv.) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction was then quenched with water. The resulting solution was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether / EtOAc (1 / 1) to afford the title compound (400 mg, 56% yield) as a white solid. LCMS: [M+H] + 357.1.

[0325] Step 4: Ethyl 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate Under nitrogen, a solution of ethyl 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate (200 mg, 0.56 mmol, 1.0 equiv), 1H-imidazole (191 mg, 2.80 mmol, 5.0 equiv), Pd(dba) (77 mg, 0.084 mmol, 0.15 equiv), tBuXphos (60 mg, 0.14 mmol, 0.25 equiv), and KPO (238 mg, 1.12 mmol, 2.0 equiv) in toluene (6 mL) was stirred at 110 °C for 3 h. The reaction was quenched with water. The resulting solution was extracted with EtOAc. The organic layer was dried over NaSO and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH 10:1) to give the title compound (210 mg, 96% yield) as a white solid. LCMS: [M+H] + 389.20.

[0326] Step 5: 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylic acid A solution of ethyl 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate (210 mg, 0.54 mmol, 1.0 equiv.) and NaOH (65 mg, 1.62 mmol, 3.0 equiv.) in HO (4 mL) and MeOH (4 mL) was stirred at room temperature for 4 h. The pH value of the solution was adjusted to 5 with 1 M HCl. The resulting solution was extracted with n-BuOH. The organic layer was concentrated to give the crude title compound (160 mg, 82% yield) as a white solid. LCMS: [M+H] + 361.15.

[0327] Step 6: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide A solution of 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylic acid (120 mg, 0.33 mmol, 1.0 equiv), Int-B1 (69 mg, 0.40 mmol, 1.2 equiv), HATU (165 mg, 0.43 mmol, 1.3 equiv), and DIPEA (86 mg, 0.67 mmol, 2.0 equiv) in DMF (2 mL) was stirred at room temperature for 1 h. After concentration, the crude product was purified by preparative HPLC to give the title compound (130 mg, 75% yield) as a white solid. LCMS: [M+H] + 516.30.

[0328] Step 7: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide A solution of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide (120 mg, 0.23 mmol, 1.0 equiv) in DCM (10 mL) and TFA (2 mL) was stirred at room temperature for 1 h. After concentration, the crude product was purified by preparative HPLC to give the title compound (47 mg, 52% yield) as a white solid. LCMS: [M+H] + 386.25; 1 H NMR (300 MHz, DMSO-d6) δ 13.56(s,1H),9.01-8.91(m,2H),8.79(s,1H),8.24(s,1H),7.15(s,1H),3.91( d,J=10.2Hz,1H),3.56(dd,J=5.9,3.8Hz,2H),3.43(dd,J=5.9,3.7Hz,2H),3.2 8-3.23(m,4H),2.07(d,J=12.3Hz,2H),1.89(d,J=12.8Hz,2H),1.66(d,J=12.6 Hz,1H),1.58(d,J=12.3Hz,1H),1.32(d,J=12.2Hz,1H),1.24(d,J=11.9Hz,1H).

[0329] Example 15: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide [ka]

[0330] Step 1: 6-(1H-imidazol-1-yl)-2-methyl-3-nitropyridine A solution of 6-bromo-2-methyl-3-nitropyridine (3.0 g, 13.82 mmol, 1.0 equiv.), K2CO3 (3.8 g, 27.71 mmol, 2.0 equiv.), and 1H-imidazole (1.9 g, 27.62 mmol, 2.0 equiv.) in DMF (15 mL) was stirred at 100 °C for 2 h. The resulting solution was quenched with water and extracted with 3 x 100 mL of EtOAc. The organic layers were combined, washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then applied to a silica gel column eluted with EtOAc / petroleum ether to give the title compound (1.03 g, 37%). LCMS: 205.19 [M+H]. + .

[0331] Step 2: 6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine A solution of 6-(1H-imidazol-1-yl)-2-methyl-3-nitropyridine (1.03 g, 5.04 mmol, 1.0 equiv.) and Pd / C (100 mg, 0.94 mmol, 0.19 equiv.) in MeOH (20 mL) was stirred at room temperature for 2 hours, and the solid was filtered. The resulting solution was concentrated in vacuo to give the title compound (810 mg, 92%) as a brown solid. LCMS (ESI, m / z): 175.21 [M+H] + .

[0332] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine A solution of 6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine (520 mg, 2.99 mmol, 1.0 equiv.) and NBS (797 mg, 4.48 mmol, 1.5 equiv.) in TFA (10 mL) was stirred at 0° C. for 1.5 h. The mixture was diluted with 30 mL of ice water, and the pH was adjusted to 8 with 20% NaOH. The resulting solution was extracted with 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography eluting with HO / ACN to give the title compound (460 mg, 61%) as a yellow solid. LCMS (ESI, m / z): 253.10 [M+H] + .

[0333] Step 4: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine A solution of 4-bromo-6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine (460 mg, 1.82 mmol, 1.0 equiv), acetic anhydride (930 mg, 9.11 mmol, 5.0 equiv), and KOAc (54 mg, 0.55 mmol, 0.30 equiv) in CHCl3 (20 mL) was stirred at 0 °C in a water / ice bath for 2 h. Isopentyl nitrite (534 mg, 4.56 mmol, 2.5 equiv) was then added, and the resulting solution was stirred at 0 °C for 30 min and at 60 °C for an additional 3 h. The resulting mixture was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc to afford the title compound (350 mg, 73%) as a brown solid. LCMS (ESI, m / z): 264.09 [M+H] + .

[0334] Step 5: Methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate A solution of 7-bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine (220 mg, 0.83 mmol, 1.0 equiv.), TEA (250 mg, 2.47 mmol, 3.0 equiv.), and Pd(dppf)Cl (61 mg, 0.084 mmol, 0.10 equiv.) in MeOH (10 mL) was stirred at 70 °C for 12 h under an atmosphere of carbon monoxide. The resulting solution was concentrated in vacuo and loaded onto a silica gel column eluted with EtOAc to give the title compound (73 mg, 36%) as a pale yellow solid. LCMS (ESI, m / z): 244.23 [M+H] + .

[0335] Step 6: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid To a solution of methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (73 mg, 0.30 mmol, 1.0 equiv.) in MeOH (3.0 mL) was added NaOH (36 mg, 0.90 mmol, 3.0 equiv.) in HO (0.6 mL). The resulting solution was stirred at room temperature for 40 minutes, then concentrated in vacuo and diluted with 1 mL of water. After adjusting the pH to 4 with 1 M HCl, the solid was collected by filtration to give the title compound (40 mg, 58%) as a pale yellow solid. LCMS (ESI, m / z): 230.20 [M+H] + .

[0336] Step 7: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (40 mg, 0.18 mmol, 1.0 equiv.), HATU (66 mg, 0.18 mmol, 1.0 equiv.), DIPEA (45 mg, 0.35 mmol, 2.0 equiv.), and (2-fluoro-6-(trifluoromethyl)phenyl)methanamine (34 mg, 0.18 mmol, 1.0 equiv.) in DMF (2.0 mL) was stirred at room temperature for 40 minutes. The reaction was quenched with water and extracted with 3 × 10 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on a C18 reverse phase column eluted with HO / CH3CN to give the title compound (26 mg, 37%) as a white solid. LCMS (ESI, m / z): 405.05 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ13.81(s,1H),9.41(s,1H),8.55-8.36(m,2H),8.13(s,1H),7.9 5(t,J=1.3Hz,1H),7.68(d,J=5.5Hz,3H),7.15(t,J=1.2Hz,1H),4.81(d,J=4.3Hz,2H).

[0337] Example 16: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide [ka]

[0338] Step 1: 2-(1H-imidazol-1-yl)-4-methyl-5-nitropyridine A solution of 2-chloro-4-methyl-5-nitropyridine (5.0 g, 28.98 mmol, 1.0 equiv.), KCO (8.0 g, 58.03 mmol, 2.0 equiv.), and 1H-imidazole (4.0 g, 58.02 mmol, 2.0 equiv.) in DMF (20 mL) was stirred at 100 °C for 2 h. The resulting solution was quenched with water and extracted with 3 × 100 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with EtOAc to give the title compound (1.3 g, 22%) as a brown solid. LCMS (ESI, m / z): 205.19 [M+H] + .

[0339] Step 2: 6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine A solution of 2-(1H-imidazol-1-yl)-4-methyl-5-nitropyridine (1.30 g, 6.37 mmol, 1.0 equiv.) and Pd / C (130 mg, 1.22 mmol, 0.19 equiv.) in MeOH (30 mL) was stirred at room temperature for 4 hours under an atmosphere of hydrogen. After filtering the solid, the resulting mixture was concentrated in vacuo to give the title compound (1.17 g) as a crude brown solid. LCMS (ESI, m / z): 175.21 [M+H] + .

[0340] Step 3: 2-Bromo-6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine A solution of 6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine (550 mg, 3.16 mmol, 1.0 equiv.) and NBS (843 mg, 4.74 mmol, 1.5 equiv.) in TFA (6.0 mL) was stirred at 0° C. for 1.5 h. The resulting solution was quenched with ice water. The pH value of the resulting solution was adjusted to 8 with NaOH (15% in water). The resulting solution was extracted with 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified on a C18 reverse phase column eluted with HO / ACN to give the title compound (360 mg, 45%) as a pale yellow solid. LCMS (ESI, m / z): 253.10 [M+H] + .

[0341] Step 4: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine A solution of 2-bromo-6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine (360 mg, 1.42 mmol, 1.0 equiv) and AcO (728 mg, 7.13 mmol, 5.0 equiv) in CHCl (15 mL) was stirred at 0 °C for 2 h. KOAc (42 mg, 0.43 mmol, 0.30 equiv) and isopentyl nitrite (418.0 mg, 3.57 mmol, 2.5 equiv) were added. The resulting solution was stirred at 0 °C for 30 min and at 60 °C for 3 h. The resulting mixture was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc to give the title compound (340 mg, 91%) as a brown solid. LCMS (ESI, m / z): 264.09 [M+H] + .

[0342] Step 5: Methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate A solution of 7-bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine (230 mg, 0.87 mmol, 1.0 equiv.), TEA (265 mg, 2.62 mmol, 3.0 equiv.), and Pd(dppf)Cl (64 mg, 0.087 mmol, 0.10 equiv.) in MeOH (10 mL) was stirred at 70 °C for 12 h under an atmosphere of carbon monoxide. The resulting mixture was concentrated in vacuo, and the crude mixture was applied to a silica gel column eluted with EtOAc to give the title compound (100 mg, 47%) as a pale yellow solid. LCMS (ESI, m / z): 244.23 [M+H] + .

[0343] Step 6: 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid To a solution of methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (100 mg, 0.41 mmol, 1.0 equiv.) in MeOH / HO (4.0 mL / 0.8 mL), NaOH (49 mg, 1.23 mmol, 3.0 equiv.) was added, and the resulting solution was stirred at room temperature for 30 minutes. The resulting solution was diluted with 3 mL of water. The pH value was adjusted to 4 with 1 M HCl, and the solid was collected by filtration to give the title compound (64 mg, 68%) as a yellow solid. LCMS (ESI, m / z): 230.20 [M+H] + .

[0344] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide To a solution of 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (65 mg, 0.28 mmol, 1.0 equiv.), HATU (108 mg, 0.28 mmol, 1.0 equiv.), and DIPEA (73 mg, 0.57 mmol, 2.0 equiv.) in DMF (5.0 mL) was added Int-B1 (49.1 mg, 0.28 mmol, 1.0 equiv.). The resulting solution was stirred at room temperature for 40 min. The resulting mixture was quenched with water and extracted with 3 × 20 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified on a C18 reverse-phase column eluted with HO / ACN to afford the title compound (46.9 mg, 43%) as a white solid. LCMS (ESI, m / z): 385.25 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ13.85(s,1H),8.93(d,J=1.3Hz,1H),8.74(d,J=8.7H z,1H),8.37(dd,J=2.8,1.0Hz,2H),8.23(s,1H),7.16(s,1H),4.05-3.79(m,1 H),3.57(dd,J=5.9,3.7Hz,2H),3.44(dd,J=5.9,3.7Hz,2H),3.34-3.30(m,4 H),2.08(d,J=12.3Hz,2H),1.90(d,J=11.9Hz,2H),1.64(m,2H),1.29(m,2H).

[0345] Example 17: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide [ka]

[0346] Step 1: 5-Nitro-2-(thiazol-5-yl)isonicotinic acid A solution of 2-chloro-5-nitroisonicotinic acid (1.00 g, 4.94 mmol, 1.0 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (1.58 g, 7.49 mmol, 1.5 equiv), Pd(dppf)Cl (362 mg, 0.50 mmol, 0.10 equiv), CuI (190 mg, 1.0 mmol, 0.20 equiv), and KCO (1.4 g, 9.91 mmol, 2.0 equiv) in DMF (20 mL) was stirred at 80 °C for 5 h. Upon completion, the reaction mixture was cooled to room temperature and the solid was collected by filtration to give the title compound (700 mg, 56%) as a gray solid. LCMS (ESI, m / z): 252.22 [M+H] + .

[0347] Step 2: Methyl 5-nitro-2-(thiazol-5-yl)isonicotinate A solution of 5-nitro-2-(thiazol-5-yl)isonicotinic acid and SOCl (10 mL) in CHOH (30 mL) was stirred at 70 °C for 12 h, the resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether to give the title compound (343 mg, 68%) as a pale yellow solid. LCMS (ESI, m / z): 266.24 [M+H] + .

[0348] Step 3: Methyl 5-amino-2-(thiazol-5-yl)isonicotinate A solution of methyl 5-nitro-2-(thiazol-5-yl)isonicotinate (360 mg, 1.36 mmol, 1.0 equiv.) and Pd / C (36 mg, 0.34 mmol, 0.25 equiv.) in CHOH (10 mL) was stirred at room temperature under a hydrogen atmosphere for 10 hours. The solid was filtered, and the resulting solution was concentrated in vacuo to give the title compound (300 mg, 94%) as a light brown solid. LCMS (ESI, m / z): 236.26 [M+H] + .

[0349] Step 4: Methyl 3-amino-2-bromo-6-(thiazol-5-yl)isonicotinate A solution of methyl 5-amino-2-(thiazol-5-yl)isonicotinate (300 mg, 1.28 mmol, 1.0 equiv) and NBS (273 mg, 1.53 mmol, 1.2 equiv) in TFA (5 mL) was stirred at 0 °C for 1.5 h. The resulting solution was quenched with water, and the pH was adjusted to 8 with NaOH (15% in water). The resulting mixture was extracted with 3 × 20 mL of EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified on a C18 reverse phase column eluted with HO / ACN to give the title compound (80 mg, 20%) as a pale yellow solid. LCMS (ESI, m / z): 314.16 [M+H] + .

[0350] Step 5: Methyl 3-amino-2-methyl-6-(thiazol-5-yl)isonicotinate A solution of methyl 3-amino-2-bromo-6-(thiazol-5-yl)isonicotinate (86 mg, 0.27 mmol, 1.0 equiv), KCO (76 mg, 0.55 mmol, 2.0 equiv), X-Phos (26 mg, 0.055 mmol, 0.20 equiv), Pd(dba) (25 mg, 0.027 mmol, 0.10 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (207 mg, 1.65 mmol, 6.0 equiv), and HO (0.5 mL) in t-BuOH (6 mL) was stirred at 80° C. for 2 h. The resulting solution was concentrated, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether to give the title compound (56 mg, 82%) as a light brown solid. LCMS (ESI, m / z): 250.29 [M+H] + .

[0351] Step 6: Methyl 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate A solution of methyl 3-amino-2-methyl-6-(thiazol-5-yl)isonicotinate (50 mg, 0.20 mmol, 1.0 equiv), acetic anhydride (102 mg, 1.0 mmol, 5.0 equiv), and KOAc (5.5 mg, 0.04 mmol, 0.2 equiv) in CHCl3 (5.0 mL) was stirred at 0 °C for 1.5 h, after which isopentyl nitrite (58.0 mg, 0.50 mmol, 2.5 equiv) was added dropwise. The resulting solution was stirred at 0 °C for 20 min and at 60 °C for an additional 2 h. The resulting solution was concentrated in vacuo, and the residue was applied to a silica gel column eluting with EtOAc / petroleum ether to afford the title compound (60 mg) as a pale yellow solid. The crude solid was carried forward without further purification. LCMS (ESI, m / z): 261.27 [M+H] + .

[0352] Step 7: 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid To a solution of methyl 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate (60 mg, 0.23 mmol, 1.0 equiv.) in CHOH / HO (3.0 mL / 0.5 mL) was added NaOH (28 mg, 0.69 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 40 minutes, and then diluted with 2 mL of water. The pH of the resulting solution was adjusted to 4 with 1 M HCl, and the solid was collected by filtration to give the title compound (25 mg, 44%) as a pale yellow solid. LCMS (ESI, m / z): 247.24 [M+H] + .

[0353] Step 8: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide A solution of 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (20 mg, 0.08 mmol, 1.0 equiv.), Int-B1 (14 mg, 0.081 mmol, 1.0 equiv.), HATU (31 mg, 0.081 mmol, 1.0 equiv.), and DIPEA (32 mg, 0.24 mmol, 3.0 equiv.) in DMF (0.5 mL) was stirred at room temperature for 40 min, and the resulting solution was purified on a C18 reverse phase column eluted with HO / ACN to give the title compound (8.4 mg, 26%) as a white solid. LCMS (ESI, m / z): 402.25 [M+H] + . 1 H NMR(300MHz, methanol-d4)δ 9.11(d,J=9.1Hz,1H),8.58(s,1H),8.45(d,J=9.1Hz,1H),8.38(d,J=4.5Hz,1H),4.06-3.99(m,1H) ),3.69-3.66(m,2H),3.57-3.54(m,2H),3.42-3.32(m,4H),2.28-2.12(m,4H),1.59-1.41(m,4H).

[0354] Example 18: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide [ka]

[0355] Step 1: 2-chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine Under a nitrogen atmosphere, a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (4.08 g, 19.9 mmol, 1.0 equiv.), tributyl(1-ethoxyethenyl)stannane (8.62 g, 23.88 mmol, 1.2 equiv.), and Pd(PPh3)2Cl2 (1.40 g, 1.99 mmol, 0.10 equiv.) in DMF (40 mL) was stirred at 80 °C for 2 h. The resulting solution was cooled to room temperature and quenched with saturated aqueous KF. The insoluble solid was filtered. The resulting solution was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column elution with (DCM:MeOH 10:1) to give the title compound (3.5 g, 73% yield). LCMS: [M+H] + 241.1.

[0356] Step 2: Ethyl 2-chlorothieno[3,2-d]pyrimidine-4-carboxylate A solution of 2-chloro-4-(1-ethoxyethenyl)thieno[3,2-d]pyrimidine (2.40 g, 9.97 mmol, 1.0 equiv), KMnO (630.3 mg, 3.99 mmol, 0.40 equiv), and NaIO (10.66 g, 49.85 mmol, 5.0 equiv) in HO (50 mL) and dioxane (50 mL) was stirred at room temperature for 16 h. The resulting solution was quenched with water and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The crude product was applied to a silica gel column eluting with EtOAc:petroleum ether (2:3) to give the title compound (500 mg, 21% yield). LCMS: [M+H] + 243.1.

[0357] Step 3: Ethyl 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylate Under nitrogen, a solution of ethyl 2-chlorothieno[3,2-d]pyrimidine-4-carboxylate (243 mg, 1.00 mmol, 1.0 equiv), 1H-imidazole (340 mg, 5.00 mmol, 5.0 equiv), Pd(dba) (136 mg, 0.15 mmol, 0.15 equiv), tBuXphos (85 mg, 0.20 mmol, 0.20 equiv), and KPO (420 mg, 2.00 mmol, 2.0 equiv) in toluene (10 mL) was stirred at 110 °C for 3 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with (DCM:MeOH 10:1) to give the title compound (220 mg, 81% yield) as a white solid. LCMS: [M+H] + 275.1.

[0358] Step 4: 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylic acid A mixture of ethyl 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylate (220 mg, 0.80 mmol, 1.0 equiv.) and NaOH (96 mg, 2.41 mmol, 3.0 equiv.) in HO (4 mL) and MeOH (4 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 5 with 1 M HCl. The resulting solution was extracted with 10 mL of n-BuOH. The organic layer was concentrated to give the crude title compound (200 mg) as a white solid. [M+H] + 247.1.

[0359] Step 5: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide A solution of 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylic acid (123 mg, 0.50 mmol, 1.0 equiv.), Int-B1 (87 mg, 0.50 mmol, 1.0 equiv.), HATU (228 mg, 0.60 mmol, 1.2 equiv.), and DIPEA (129 mg, 1.00 mmol, 2.0 equiv.) in DMF (2 mL) was stirred at room temperature for 1 h. The resulting solution was concentrated in vacuo. The crude product was purified by preparative HPLC eluting with ACN / HO to afford the title compound (43.1 mg, 21% yield) as a white solid. LCMS: [M+H] + 402.05; 1 H NMR (300 MHz, DMSO-d6) δ 9.21(s,1H),9.14(d,J=8.6Hz,1H),8.74(d,J=5.6Hz,1H),8.35(t,J=1.4Hz, 1H),7.70(d,J=5.6Hz,1H),7.28(d,J=1.7Hz,1H),4.10-3.99(m,1H),3.58(dd ,J=6.0,3.7Hz,2H),3.46-3.32(m,6H),2.10(d,J=12.3Hz,2H),1.91(d,J=13 .2Hz,2H),1.69(d,J=13.4Hz,1H),1.60(d,J=11.9Hz,1H),1.39-1.25(m,2H).

[0360] Example 19: 2-(aminomethyl)-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide [ka]

[0361] Step 1: 1-(3-bromo-4-nitrophenyl)-1H-imidazole A mixture of 2-bromo-4-fluoro-1-nitrobenzene (11.00 g, 50.00 mmol, 1.0 equiv), 1H-imidazole (4.80 g, 70.51 mmol, 1.41 equiv), and K2CO3 (6.90 g, 49.93 mmol, 1.0 equiv) in DMF (50 mL) was stirred at 80 °C for 1 h. The reaction was quenched with water. The solid was collected by filtration to give the title compound (12.9 g, 96% yield) as a pale yellow solid. LCMS: [M+H] + 268.00.

[0362] Step 2: 2-Bromo-4-(1H-imidazol-1-yl)aniline A mixture of 1-(3-bromo-4-nitrophenyl)-1H-imidazole (1.60 g, 5.97 mmol, 1.0 equiv.), NHNH.HO (5.0 mL, 99.90 mmol, 17.2 equiv.), and Raney Ni (0.50 g, 5.85 mmol, 0.98 equiv.) in EtOH (50 mL) was stirred at room temperature for 4 h. After filtration, the filtrate was concentrated and purified by silica gel chromatography eluting with EtOAc / petroleum ether (4 / 1) to give the title compound (1.0 g, 70% yield) as a white solid. LCMS: [M+H] + 237.99.

[0363] Step 3: 2-Bromo-4-(1H-imidazol-1-yl)-6-iodoaniline A solution of 2-bromo-4-(1H-imidazol-1-yl)aniline (11.00 g, 46.20 mmol, 1.0 equiv) and NIS (10.4 g, 46.2 mmol, 1.0 equiv) in TFA (100 mL) was stirred at room temperature for 2 days. The reaction was quenched with water and extracted with 3×200 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1 / 1) to give the title compound (14.0 g, 83% yield) as a yellow oil. LCMS: [M+H] + 363.89.

[0364] Step 4: tert-butyl (3-(2-amino-3-bromo-5-(1H-imidazol-1-yl)phenyl)prop-2-yn-1-yl)carbamate Under nitrogen, a mixture of 2-bromo-4-(1H-imidazol-1-yl)-6-iodoaniline (7.28 g, 20.00 mmol, 1.0 equiv.), tert-butyl prop-2-yn-1-ylcarbamate (3.11 g, 20.04 mmol, 1.0 equiv.), Pd(PPh3)2Cl2 (1.40 g, 1.99 mmol, 0.10 equiv.), CuI (0.38 g, 2.00 mmol, 0.10 equiv.), and 1,1,3,3-tetramethylguanidine (10.0 mL) in DMF (100 mL) was stirred at 50 °C overnight. The reaction was quenched with water and extracted with 3 × 200 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1 / 1) to give the title compound (4.5 g, 58% yield) as a yellow oil. LCMS: [M+H] + 391.07.

[0365] Step 5: tert-butyl ((7-bromo-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate A mixture of tert-butyl (3-(2-amino-3-bromo-5-(1H-imidazol-1-yl)phenyl)prop-2-yn-1-yl)carbamate (1.86 g, 4.75 mmol, 1.0 equiv) and NaAuCl4.2HO (80 mg, 0.20 mmol, 0.04 equiv) in EtOH (30 mL) was stirred at 80 °C for 2 days. After concentration, the mixture was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1 / 1) to give the title compound (700 mg, 38% yield) as a yellow solid. LCMS: [M+H] + 391.07.

[0366] Step 6: tert-butyl ((7-cyano-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate A mixture of tert-butyl ((7-bromo-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate (560 mg, 1.43 mmol, 1.0 equiv), dicyanozinc (336 mg, 2.86 mmol, 2.0 equiv), and Pd(PPh3)4 (165 mg, 0.14 mmol, 0.10 equiv) in DMF (10 mL) under nitrogen was stirred at 90 °C for 2 h. The reaction was quenched with water and extracted with 3 × 50 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1 / 1) to give the title compound (360 mg, 75%) as a yellow solid. LCMS: [M+H] + 338.15.

[0367] Step 7: 2-((tert-butoxycarbonylamino)methyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxylic acid A mixture of tert-butyl ((7-cyano-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate (337 mg, 1 mmol, 1.0 equiv.), KOH (1.68 g, 29.94 mmol, 30 equiv.), and HO (4.0 mL, 0.006 mmol, 0.11 equiv.) in EtOH (40 mL) was stirred at 80° C. for 1 day. The pH value of the solution was adjusted to 4 with 2 M HCl and extracted with 3×50 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (100 mg, 28%) as a yellow solid. LCMS: [M+H] + 357.15.

[0368] Step 8: tert-butyl ((5-(1H-imidazol-1-yl)-7-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate A mixture of 2-((tert-butoxycarbonylamino)methyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxylic acid (100 mg, 0.28 mmol, 1.0 equiv.), DIPEA (108 mg, 0.84 mmol, 3 equiv.), HATU (129 mg, 0.34 mmol, 1.2 equiv.), and Int-B1 (59 mg, 0.34 mmol, 1.2 equiv.) in DMF (1.0 mL) was stirred at room temperature for 1 h. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (120 mg, 84%) as a white solid. LCMS: [M+H] + 512.28.

[0369] Step 9: 2-(aminomethyl)-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide A mixture of tert-butyl ((5-(1H-imidazol-1-yl)-7-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate (120 mg, 0.24 mmol, 1.0 equiv) and TFA (1.0 mL) in DCM (5.0 mL) was stirred at room temperature for 1 h. After concentration, the crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (26.5 mg, 28%) as a white solid. LCMS: [M+H] + 412.10. 1 H-NMR (400MHz, methanol-d4) δ 8.12(t,J=1.2Hz,1H),7.87(d,J=2.0Hz,1H),7.79(d,J=2.0Hz,1H),7.60(t, J=1.4Hz,1H),7.18(t,J=1.2Hz,1H),6.61(s,1H),4.15(d,J=0.8Hz,2H),4.0 4-3.93(m,1H),3.70-3.64(m,2H),3.59-3.52(m,2H),3.39(s,3H),3.44-3.3 3(m,1H),2.17(d,J=11.6Hz,2H),2.09(d,J=12.4Hz,2H),1.54-1.45(m,4H).

[0370] Example 20: N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide [ka]

[0371] Step 1: 2-chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine Under nitrogen, a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (10.0 g, 48.77 mmol, 1.0 equiv.), tributyl(1-ethoxyethenyl)stannane (21.1 g, 58.52 mmol, 1.2 equiv.), and Pd(PPh3)2Cl2 (3.42 g, 4.88 mmol, 0.1 equiv.) in DMF (150 mL) was stirred at 80 °C for 1 h. The solid was filtered. The reaction was quenched with water, and the resulting solution was extracted with 2 × 100 mL of EtOAc. The organic layers were combined and concentrated under vacuum. The resulting solid was washed with 2 × 10 mL of EtOH to give the title compound (2.5 g, 21% yield) as a white solid. LCMS: [M+H] + 241.01.

[0372] Step 2: 4-(1-ethoxyvinyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine A solution of 2-chloro-4-(1-ethoxyethenyl)thieno[3,2-d]pyrimidine (2.40 g, 9.97 mmol, 1.0 equiv.), 5-(tributylstannyl)-1,3-thiazole (5.60 g, 14.96 mmol, 1.5 equiv.), and Pd(PPh3)2Cl2 (0.70 g, 0.99 mmol, 0.1 equiv.) in DMF (30 mL) was stirred at 80 °C for 1 h. The reaction was quenched with water. The resulting solution was extracted with 2 × 30 mL of EtOAc, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (1:3) to afford the title compound (900 mg, 31% yield) as a white solid. LCMS: [M+H] +290.03.

[0373] Step 3: Ethyl 2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxylate A solution of 4-(1-ethoxyvinyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine (1.10 g, 3.80 mmol, 1.0 equiv.), KMnO (0.24 g, 1.52 mmol, 0.4 equiv.), and NaIO (4.07 g, 19.01 mmol, 5 equiv.) in HO (12 mL) and dioxane (12 mL) was stirred at room temperature for 1 h. The reaction was quenched with water. The resulting solution was extracted with 3 × 20 mL of EtOAc, and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was washed with 2 × 10 mL of EtOH to give the title compound (400 mg, 36.1% yield) as a white solid. LCMS: [M+H] + 292.01.

[0374] Step 4: N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide Under nitrogen, a solution of ethyl 2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxylate (150 mg, 0.52 mmol, 1.0 equiv.), 1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine (149 mg, 0.77 mmol, 1.5 equiv.), and AlMe3 (74 mg, 1.03 mmol, 2 equiv.) in toluene (2 mL) was stirred at 80 °C for 1 h. The resulting solution was extracted with 2 × 20 mL of EtOAc, and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC eluting with ACN / HO to give the title compound (74 mg, 33% yield) as a white solid. LCMS: [M+H] + 439.10. 1H NMR(300MHz,DMSO-d6)δ 9.41(t,J=5.5Hz,1H),9.25(d,J=0.8Hz,1H),9.03(d,J=0.8Hz,1H),8.66(d,J=5.6Hz,1H),7.70-7.55(m,4H),4.85(d,J=5.4Hz,2H).

[0375] Example 21: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide [ka]

[0376] Step 1: 5-(4-methyl-5-nitropyridin-2-yl)thiazole A solution of 2-chloro-4-methyl-5-nitropyridine (1.50 g, 8.69 mmol, 1.00 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (2.20 g, 10.43 mmol, 1.20 equiv.), Pd(dppf)Cl (636 mg, 0.87 mmol, 0.1 equiv.), KF (2.52 g, 43.46 mmol, 5.00 equiv.), and CuI (331 mg, 1.74 mmol, 0.20 equiv.) in DMF (15 mL) was stirred at 80 °C for 1 h. The resulting solution was quenched with water and extracted with 3 × 150 mL of EtOAc. The organic layers were combined, washed with 250 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was subjected to a silica gel column eluting with EtOAc / petroleum ether to give the title compound (1.46 g, 60%) as a brown solid. LCMS (ESI, m / z): 222.23 [M+H] + .

[0377] Step 2: 4-methyl-6-(thiazol-5-yl)pyridin-3-amine A solution of 5-(4-methyl-5-nitropyridin-2-yl)thiazole (1.08 g, 4.88 mmol, 1.00 equiv.) and Pd / C (104 mg, 0.98 mmol, 0.20 equiv.) in MeOH (30 mL) was stirred under hydrogen at room temperature for 10 h. The solid was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with CH3CN / HO to give the title compound (697 mg, 75%) as a yellow solid. LCMS (ESI, m / z): 192.25 [M+H] + .

[0378] Step 3: 2-Bromo-4-methyl-6-(thiazol-5-yl)pyridin-3-amine A solution of 4-methyl-6-(thiazol-5-yl)pyridin-3-amine (800 mg, 4.18 mmol, 1.00 equiv) and NBS (893 mg, 5.020 mmol, 1.2 equiv) in TFA (9 mL) was stirred at 0 °C for 2 h. The resulting solution was diluted with 30 mL of DCM and concentrated in vacuo, and the crude product was purified by C18 reverse-phase chromatography eluting with CHCN / HO to give the title compound (655 mg, 58%) as a brown solid. LCMS (ESI, m / z): 270.15 [M+H] + .

[0379] Step 4: 5-(7-bromo-1H-pyrazolo[3,4-c]pyridin-5-yl)thiazole A solution of 2-bromo-4-methyl-6-(thiazol-5-yl)pyridin-3-amine (481 mg, 1.88 mmol, 1.00 equiv) and acetic anhydride (959 mg, 9.39 mmol, 5.00 equiv) in CHCl3 (10 mL) was stirred at 0 °C for 2 h. KOAc (55 mg, 0.56 mmol, 0.30 equiv) and isopentyl nitrite (550 mg, 4.70 mmol, 2.50 equiv) were added. The resulting solution was stirred at 0 °C for 20 min and at 60 °C for an additional 1.5 h. The resulting mixture was concentrated in vacuo, and the crude product was applied to a silica gel column eluting with EtOAc / petroleum ether to afford the title compound (433 mg, 82%) as a yellow solid. LCMS (ESI, m / z): 281.13 [M+H]+ .

[0380] Step 5: tert-Butyl 7-bromo-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate A solution of 5-(7-bromo-1H-pyrazolo[3,4-c]pyridin-5-yl)thiazole (353 mg, 1.26 mmol, 1.00 equiv.), DMAP (31 mg, 0.25 mmol, 0.20 equiv.), and di-tert-butyl dicarbonate (411 mg, 1.88 mmol, 1.50 equiv.) in DMF (4 mL) was stirred at room temperature for 12 h. The resulting solution was quenched with water and extracted with 3×40 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (338 mg, 71%) as a yellow solid. LCMS (ESI, m / z): 381.25 [M+H] + .

[0381] Step 6: tert-Butyl 7-(1-ethoxyvinyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate To a solution of tert-butyl 7-bromo-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (300.00 mg, 0.79 mmol, 1.00 equiv.) and Pd(PPh3)2Cl2 (55 mg, 0.079 mmol, 0.10 equiv.) in DMF (3.5 mL) under nitrogen, tributyl(1-ethoxyethenyl)stannane (426 mg, 1.18 mmol, 1.50 equiv.) was added. The resulting solution was stirred at 80 °C for 1 h. The resulting solution was quenched with 40 mL of saturated aqueous KF and extracted with 3 × 40 mL of EtOAc. The organic layers were combined, washed with 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was subjected to a silica gel column eluting with EtOAc / petroleum ether to give the title compound (100 mg, 85%) as a yellow solid. LCMS (ESI, m / z): 373.44 [M+H] + .

[0382] Step 7: Ethyl 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate To a solution of tert-butyl 7-(1-ethoxyvinyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (100 mg, 0.37 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added NaIO (236 mg, 1.10 mmol, 3.00 equiv) in HO (2 mL). KMnO (17.41 mg, 0.110 mmol, 0.30 equiv) in HO (2 mL) was added dropwise. The resulting solution was stirred at room temperature for 40 min. The resulting solution was diluted with 20 mL of HO and extracted with 3 × 30 mL of EtOAc. The organic portions were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (80 mg, 79%) as a yellow solid. LCMS (ESI, m / z): 275.30 [M+H] + .

[0383] Step 8: 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid To a solution of ethyl 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (70 mg, 0.26 mmol, 1.00 equiv.) in MeOH / HO (4 mL / 0.8 mL) was added LiOH (15 mg, 0.64 mmol, 2.50 equiv.). The resulting solution was stirred at room temperature for 1.5 hours. Upon completion, the pH value was adjusted to 4 with 1 M HCl, and the resulting solution was concentrated under vacuum. The crude product was purified by C18 reverse-phase chromatography eluting with CH3CN / HO to afford the title compound (14 mg, 90%) as a yellow solid. LCMS (ESI, m / z): 247.24 [M+H] + .

[0384] Step 9: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide To a solution of 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (14 mg, 0.057 mmol, 1.00 equiv.), DIPEA (22 mg, 0.17 mmol, 3.00 equiv.), and HATU (22 mg, 0.057 mmol, 1.00 equiv.) in DMF (0.5 mL) was added Int-B1 (11 mg, 0.063 mmol, 1.10 equiv.). The resulting solution was stirred at room temperature for 40 min. The reaction was quenched with HO and extracted with 3 × 10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with CHCN / HO to afford the title compound (6 mg, 25%) as a white solid. LCMS (ESI, m / z): 402.10 [M+H] + . 1 H NMR(400MHz,CD3OD-d4)δ 9.03(d,J=0.7Hz,1H),8.56(d,J=0.7Hz,1H),8.46(s,1H),8.30(s,1H),4.03(ddt,J=11.1,7.4,3.9Hz,1H),3.71-3.6 4(m,2H),3.60-3.53(m,2H),3.49-3.34(m,1H),3.40(s,3H),2.21-2.10(m,4H),1.68-1.55(m,2H),1.52-1.39(m,2H).

[0385] Example 22: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka]

[0386] Step 1: 2-(1H-imidazol-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid A solution of ethyl 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (257 mg, 1.0 mmol, 1.00 equiv), 60% NaH (60 mg, 2.50 mmol, 2.50 equiv), and MeI (213 mg, 1.50 mmol, 1.50 equiv) in DMF (5 mL) was stirred at 35° C. for 2 h. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (100 mg, 41%) as a white solid. LCMS: [M+H] + 244.08.

[0387] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of 2-(1H-imidazol-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (63 mg, 0.26 mmol, 1.00 equiv.), Int-B1 (54 mg, 0.31 mmol, 1.20 equiv.), HATU (148 mg, 0.39 mmol, 1.50 equiv.), and DIPEA (100 mg, 0.78 mmol, 3.00 equiv.) in DMF (1 mL) was stirred at room temperature for 1 h. The crude product was purified by reverse-phase column chromatography to give the title compound (11 mg, 11% yield) as a white solid. LCMS: [M+H] + 399.20. 1 H NMR(300MHz, methanol-d4)δ 8.77(s,1H),8.10(s,1H),7.86(d,J=3.2Hz,1H),7.14(s,1H),6.69(d,J=3.2Hz,1H),4.04(s,3H),4.03-3.90(m,1H),3.65 (dd,J=5.9, 3.4Hz,2H),3.54(dd,J=5.8,3.4Hz,2H),3.40-3.38(m,1H),3.37(s,3H),2.21-2.06(m,4H),1.60-1.20(m,4H).

[0388] Example 23: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide [ka]

[0389] Step 1: 5-chloro-7-(1-ethoxyvinyl)-1H-pyrazolo[4,3-d]pyrimidine To a solution of 5,7-dichloro-1H-pyrazolo[4,3-d]pyrimidine (1.00 g, 5.29 mmol, 1.00 equiv.) in dioxane (4 mL) under nitrogen, tributyl(1-ethoxyvinyl)stannane (2.29 g, 6.35 mmol, 1.2 equiv.) and Pd(PPh3)2Cl2 (0.37 g, 0.53 mmol, 0.1 equiv.) were added. The resulting solution was stirred at 60 °C for 1.5 h. The reaction was quenched with saturated aqueous KF solution. The solid was filtered. The filtrate was diluted with 150 mL of EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (4 / 1) to give the title compound (620 mg, 40% yield) as a yellow solid. LCMS: [M+H] + 225.65.

[0390] Step 2: 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine To a solution of 5-chloro-7-(1-ethoxyvinyl)-1H-pyrazolo[4,3-d]pyrimidine (520 mg, 1.74 mmol, 1.00 equiv.) in toluene (2 mL) under nitrogen, 1H-imidazole (237 mg, 3.49 mmol, 2 equiv.), Pd(dba) (160 mg, 0.17 mmol, 0.1 equiv.), KPO (1.11 g, 5.23 mmol, 3.0 equiv.), and tBuXPhos (148 mg, 0.35 mmol, 0.2 equiv.) were added, and the resulting mixture was stirred at 80 °C for 5 h. The mixture was diluted with 150 mL of EtOAc and washed with 3 × 50 mL of HO. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was subjected to a silica gel column eluting with EtOAc / petroleum (54 / 46) to give the title compound (80 mg, 9% yield) as a yellow oil. LCMS: [M+H] + 257.26.

[0391] Step 3: Ethyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylate To a solution of 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine (75 mg, 0.29 mmol, 1.00 equiv.) in dioxane (4 mL) and HO (4 mL) was added NaIO (250 mg, 1.17 mmol, 4 equiv.) and KMnO (9 mg, 0.059 mmol, 0.2 equiv.), and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with 30 mL of EtOAc and washed with 2×10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with EtOAc to give the title compound (35 mg, 37% yield) as a white solid. LCMS: [M+H] + 259.24.

[0392] Step 4: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide To a solution of ethyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylate (30 mg, 0.12 mmol, 1.00 equiv.) in toluene (4 mL) was added Int-B1 (20 mg, 0.12 mmol, 1 equiv.) in toluene (0.17 mL, 1.5 equiv.) and 1 M AlMe3, and the mixture was stirred at 100 °C for 24 h. The mixture was diluted with 30 mL of DCM and washed with 2 × 10 mL of water. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN (58:42) to give the title compound (8.5 mg, 19% yield) as a white solid. LCMS: [M+H] + 386.25. 1 H NMR(300MHz,DMSO-d6)δ 9.13-9.00(m,2H),8.52(s,1H),8.25(t,J=1.2Hz,1H),7.17(t,J=1.5Hz,1H),4.01-3.90(m,1H),3.58(dd,J=5.2,3.3Hz,2H),3.45(dd,J =5.9,3.7Hz,2H),3.25(s,3H),3.24-3.20(m,1H),2.09(d,J=10.8Hz,2H),1.92(d,J=10.5Hz,2H),1.70-1.58(m,2H),1.36-1.24(m,2H).

[0393] Example 24: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-b]pyridine-7-carboxamide [ka]

[0394] Step 1: Methyl 3-(3-methoxy-3-oxopropanamido)thiophene-2-carboxylate A solution of methyl 3-aminothiophene-2-carboxylate (7.85 g, 49.9 mmol, 1.00 equiv), TEA (6.06 g, 59.88 mmol, 1.20 equiv), and methyl 3-chloro-3-oxopropanoate (7.50 g, 54.93 mmol, 1.10 equiv) in DCM (100 mL) was stirred at 25 °C for 2 h. The resulting mixture was washed with 3 × 30 mL of HO. The organic layer was concentrated in vacuo to give the title compound (12 g, 89% yield) as a yellow oil. LCMS: [M+H] + 258.10.

[0395] Step 2: Methyl 5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate A mixture of methyl 3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate (9.6 g) and t-BuOK (11.9 g) in t-BuOH (200 mL) was stirred at 70° C. for 1 hour. After concentration, the resulting mixture was concentrated to give the title compound (9.5 g, crude) as a yellow solid. LCMS: [M+H] + 226.10.

[0396] Step 3: 5,7-Dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylic acid A mixture of methyl 5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate (9.50 g, 42.18 mmol, 1.00 equiv) and t-BuOK (11.90 g, 0.11 mmol) in HO (200 mL) was stirred at 60 °C overnight. After concentration, the resulting mixture was concentrated to give the title compound (20 g, crude) as a yellow solid. LCMS: [M+H] + 212.10.

[0397] Step 4: Thieno[3,2-b]pyridine-5,7(4H,6H)-dione A solution of 5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylic acid (20.0 g, 94.70 mmol, 1.00 equiv) in 6 M HCl (100 mL) was stirred at room temperature for 1 hour. After concentration, the solid was collected by filtration to give the title compound (4 g, 32% yield) as a yellow solid. LCMS: [M+H] + 167.95.

[0398] Step 5: 5,7-Dichlorothieno[3,2-b]pyridine A solution of thieno[3,2-b]pyridine-5,7(4H,6H)-dione (4.00 g, 23.9 mmol, 1.00 equiv) in phosphorus oxychloride (30 mL) was stirred at 100° C. overnight. After concentration, the solid was diluted with 200 mL of DCM and washed with 3×50 H2O. The organic layers were combined and concentrated to give the title compound (2.5 g, 51% yield) as a white solid. LCMS: [M+H] + 203.95.

[0399] Step 6: 7-Chloro-5-(1H-imidazol-1-yl)thieno[3,2-b]pyridine A mixture of 5,7-dichlorothieno[3,2-b]pyridine (1.72 g, 8.43 mmol, 1.00 equiv.), 1H-imidazole (0.74 g, 10.94 mmol, 1.30 equiv.), Pd(dba) CHCl (0.87 g, 0.84 mmol, 0.10 equiv.), tBuXPhos (0.35 g, 0.84 mmol, 0.10 equiv.), and KPO (3.57 g, 16.82 mmol, 2.00 equiv.) in dioxane (15 mL) was stirred under nitrogen at 80 °C overnight. The insoluble solid was filtered off. The filtrate was concentrated and purified by C reverse-phase chromatography eluting with HO / CHCN to give the title compound (150 mg, 28% yield) as a yellow solid. LCMS: [M+H] + 236.05.

[0400] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-b]pyridine-7-carboxamide A mixture of 7-chloro-5-(1H-imidazol-1-yl)thieno[3,2-b]pyridine (100 mg, 0.42 mmol, 1.00 equiv.), Int-B1 (246 mg, 1.42 mmol, 3.35 equiv.), Pd(dppf)Cl2 (53 mg, 0.07 mmol, 0.17 equiv.), dppf (53 mg, 0.09 mmol, 0.23 equiv.), and TEA (0.50 mL) in NMP (3 mL) was stirred at 120 °C under CO for 2.5 h. The resulting solution was concentrated. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the compound (36 mg, 21%) as a pale green solid. LCMS: [M+H] + 401.10; 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=7.6Hz,1H),8.59(d,J=1.2Hz,1H),8.32(d,J=5.6Hz,1H),8.24(s,1H),8.03 (t,J=1.4Hz,1H),7.60(d,J=5.6Hz,1H),7.20(t,J=1.2Hz,1H),3.91-3.83(m,1H),3.56 (dd,J=5.9,3.9Hz,2H),3.44(dd,J=5.8,3.9Hz,2H),3.29(d,J=4.2Hz,1H),3.26(s,3H) ,2.06(d,J=12.3Hz,2H),1.97(d,J=12.5Hz,2H),1.49-1.40(m,2H),1.34-1.24(m,2H).

[0401] Example 25: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo[4,5-d]pyrimidine-7-carboxamide [ka]

[0402] Step 1: 7-chloro-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine Under nitrogen, a solution of 5,7-dichlorothiazolo[4,5-d]pyrimidine (1.80 g, 8.74 mmol, 1.00 equiv.), IH-imidazole (0.59 g, 8.67 mmol, 0.99 equiv.), Pd(dba) (0.80 g, 0.87 mmol, 0.1 equiv.), tBuXPhos (0.93 g, 2.18 mmol, 0.25 equiv.), and KPO (3.71 g, 17.47 mmol, 2 equiv.) in toluene (30 mL) was stirred at 60 °C for 3 h. The resulting mixture was concentrated and extracted with 3 × 150 mL of EtOAc. The organic layers were combined and concentrated. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (40:60) to give the title compound (1.1 g, 53% yield) as a yellow solid. LCMS: [M+H] + 237.99.

[0403] Step 2: 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine Under nitrogen, a solution of 7-chloro-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine (1.10 g, 4.63 mmol, 1.00 equiv.), tributyl(1-ethoxyethenyl)stannane (3.34 g, 9.26 mmol, 2 equiv.), Pd(PPh3)2Cl2 (0.32 g, 0.46 mmol, 0.1 equiv.), and DMF (15 mL) was stirred at 60 °C for 3 h. The reaction was quenched with saturated aqueous KF. The insoluble solid was filtered. The resulting solution was extracted with 3 × 50 mL of DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by reverse-phase column chromatography to give the title compound (600 mg, 47% yield) as a yellow solid. LCMS: [M+H] + 274.07.

[0404] Step 3: Ethyl 5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine-7-carboxylate A solution of 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine (600 mg, 2.20 mmol, 1.00 equiv.), KMnO (139 mg, 0.88 mmol, 0.40 equiv.), and NaIO (1.88 g, 8.78 mmol, 4 equiv.) in HO (10 mL) and dioxane (10 mL) was stirred at room temperature for 30 min. The resulting solution was extracted with 3 × 10 mL of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by reverse-phase column chromatography to give the title compound (220 mg, 36% yield) as a white solid. LCMS: [M+H] + 276.05.

[0405] Step 4: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo[4,5-d]pyrimidine-7-carboxamide Under nitrogen, a solution of ethyl 5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine-7-carboxylate (200 mg, 0.78 mmol, 1.00 equiv.), Int-B1 (404 mg, 2.33 mmol, 3 equiv.), and 1 M AlMe3 in toluene (10.0 mL) was stirred at 75 °C for 2 h. The reaction was quenched with water and extracted with 3 x 150 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by reverse-phase column chromatography to give the title compound (14 mg, 5% yield) as a white solid. LCMS: [M+H] + 403.15. 1 H NMR(300MHz,DMSO-d6)δ 9.85(s,1H),9.34(s,1H),8.85(d,J=8.5Hz,1H),8.68(s,1H),7.30(s,1H),4.00-3.77(m,1H),3.56(dd,J=5.9,3.8Hz,2H),3.44 (dd,J=5.9,3.7Hz,2H),3.28-3.22(m,4H),2.05(d,J=11.7Hz,2H),1.87(d,J=12.3Hz,2H),1.65-1.52(m,2H),1.34-1.22(m,2H).

[0406] Example 26: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide [ka]

[0407] Step 1: 2,6-Dichloropyridine-3,4-diamine Under nitrogen, a solution of 2,6-dichloro-3-nitropyridin-4-amine (7.50 g, 0.036 mmol, 1.00 equiv.), Fe (10.07 g, 0.180 mmol, 5 equiv.) in acetic acid (120 mL) was stirred at 80° C. for 1 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with EtOAc / petroleum ether (3:1) to give the title compound (5.5 g, 86% yield) as a yellow solid. LCMS: [M+H] + 177.99.

[0408] Step 2: 4,6-Dichloro-3H-imidazo[4,5-c]pyridine A solution of 2,6-dichloropyridine-3,4-diamine (5.50 g, 30.90 mmol, 1.00 equiv.), trimethyl orthoformate (19.67 g, 185.37 mmol, 6 equiv.) in acetic acid (100 mL) was stirred at 80° C. for 1 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1:4) to give the title compound (5.5 g, 95% yield) as a yellow solid. LCMS: [M+H] + 187.97.

[0409] Step 3: 6-chloro-4-(1-ethoxyvinyl)-3H-imidazo[4,5-c]pyridine Under nitrogen, a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.50 g, 29.25 mmol, 1.00 equiv), tributyl(1-ethoxyethenyl)stannane (15.85 g, 43.88 mmol, 1.50 equiv), and Pd(PPh)Cl (2.05 g, 2.92 mmol, 0.1 equiv) in DMF (93 mL) was stirred at 100° C. for 1 h. The reaction was quenched with water, and the resulting solution was extracted with 2×100 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product (5 mL) was purified by preparative HPLC eluting with a gradient increasing from 5 / 95 H2O / ACN to 50 / 50 H2O / ACN to give, after concentration, the title compound (3 g, 45.85% yield) as a white solid. LCMS: [M+H] + 224.05.

[0410] Step 4: 4-(1-ethoxyvinyl)-6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine Under nitrogen, a solution of 6-chloro-4-(1-ethoxyvinyl)-3H-imidazo[4,5-c]pyridine (2.50 g, 11.18 mmol, 1.00 equiv.), 1H-imidazole (15.22 g, 223.55 mmol, 20 equiv.), CuI (4.26 g, 22.36 mmol, 2 equiv.), and KCO (3.09 g, 22.36 mmol, 2 equiv.) in NMP (35 mL) was stirred at 150 °C for 1 h. The reaction was quenched with water. The resulting solution was extracted with 3 × 100 mL of dichloromethane, and the organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by preparative HPLC eluting with HO / ACN to give the title compound (120 mg, 4% yield) as a white solid after concentration. LCMS: [M+H] + 256.11.

[0411] Step 5: Ethyl 6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylate A solution of 4-(1-ethoxyvinyl)-6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine (130 mg, 0.51 mmol, 1.00 equiv.), KMnO (32 mg, 0.20 mmol, 0.4 equiv.), and NaIO (436 mg, 2.04 mmol, 4 equiv.) in HO (3 mL) and dioxane (3 mL) was stirred at room temperature for 1 h. The reaction was quenched with water, and the resulting solution was extracted with 3 × 20 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the title compound (60 mg, 46% yield) as a yellow solid. LCMS: [M+H] + 258.09.

[0412] Step 6: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide Under nitrogen, a solution of ethyl 6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylate (50 mg, 0.19 mmol, 1.00 equiv.), Int-B1 (101 mg, 0.58 mmol, 3 equiv.), and 1M AlMe3 in toluene (1 mL) (0.78 mL, 4 equiv.) was stirred at 80 °C for 1 h. The crude product (5 mL) was purified by preparative HPLC to give the title compound (14 mg, 19% yield) as a white solid. LCMS: [M+H] + 385.20. 1 H NMR(400MHz,DMSO-d6)δ 13.05(s,1H),8.93(s,1H),8.72(s,1H),8.53(s,1H),8.32-8.27(m,2H),7.13(t,J=1.2Hz,1H),3.90(m,1H),3.57(dd,J=5.9,3.8Hz,2H), 3.44(dd,J=5.9,3.8Hz,2H),3.34-3.23(m,4H),2.07(d,J=12.0Hz,2H),1.89(d,J=12.2Hz,2H),1.63(q,J=12.7,12.2Hz,2H),1.31(m,2H).

[0413] Example 27: 2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka]

[0414] To a solution of Int-A2 (150 mg, 0.65 mmol, 1.00 equiv) in DMF (2 mL), DIPEA (508 mg, 3.93 mmol, 6 equiv), HATU (348 mg, 0.92 mmol, 1.4 equiv), and tetrahydro-2H-pyran-3-amine hydrochloride (126 mg, 0.92 mmol, 1.4 equiv) were added, and the mixture was stirred at room temperature for 0.5 h. The mixture was purified by C18 reverse-phase chromatography eluting with HO / CH3CN (55:45) to afford the title compound (83 mg, 41% yield) as a white solid. LCMS: [M+H] + 313.10. 1 H NMR(300MHz,DMSO-d6)δ 12.15(s,1H),9.03(s,1H),8.89(d,J=8.4Hz,1H),8.25(t,J=1.2Hz,1H),8.04(t,J=3.0Hz,1H),7.18( s,1H),6.72-6.74(m,1H),4.18-4.08(m,1H),3.93-3.78(m,2H),3.49-3.26(m,2H),1.97-1.60(m,4H).

[0415] Examples 28a and 28b: (S)-2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide and (R)-2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide [ka]

[0416] The compound of Example 27 (58 mg) was further purified by chiral HPLC under the following conditions (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: hexane:DCM=3:1 (10 M NH3-MeOH), mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 20% B maintained for 13 min; 220 / 254 nm) to give the title compounds with retention times of 2.39 min (Example 28a) and 2.87 min (Example 28b). The absolute stereochemistry of Examples 28a and 28b was not confirmed.

[0417] Example 28a: Isolated as a white solid (19.8 mg, 34% yield). LCMS: [M+H] + 313.20. 1 H NMR(300MHz, methanol-d4)δ 8.94(t,J=1.2Hz,1H),8.23(t,J=1.2Hz,1H),8.00(d,J=3.3Hz,1H),7.16(t,J=1.2Hz,1H),6.73(d,J=3.0Hz,1H),4.25- 4.19(m,1H),3.99(dd,J=10.7,4.0Hz,1H),3.94-3.81(m,1H),3.66-3.48(m,2H),2.12-2.05(m,1H),2.00-1.71(m,3H).

[0418] Example 28b: Isolated as a white solid (18.4 mg, 32% yield). LCMS: [M+H] + 313.20. 1 H NMR(300MHz, methanol-d4)δ 8.94(t,J=1.1Hz,1H),8.23(t,J=1.4Hz,1H),8.00(d,J=3.1Hz,1H),7.16(t,J=1.3Hz,1H),6.73(d,J=3.2Hz,1H),4.25- 4.18(m,1H),3.99(dd,J=10.8,3.7Hz,1H),3.94-3.81(m,1H),3.66-3.48(m,2H),2.13-2.02(m,1H),2.01-1.71(m,3H).

[0419] Example 29: 4-Fluoro-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide [ka]

[0420] Step 1: 1-(5-bromo-2-fluoro-4-nitrophenyl)-1H-imidazole A mixture of 1-bromo-4,5-difluoro-2-nitrobenzene (3.30 g, 13.87 mmol, 1.00 equiv), K2CO3 (2.87 g, 20.77 mmol, 1.50 equiv), and 1H-imidazole (1.41 g, 20.71 mmol, 1.49 equiv) in DMF (30 mL) was stirred at 25 °C overnight. The reaction was quenched with water. The solid was collected by filtration to give the title compound (3.6 g, 91%) as a yellow solid. LCMS: [M+H] + 285.95.

[0421] Step 2: 7-Bromo-4-fluoro-5-(imidazol-1-yl)-1H-indole To a solution of 1-(5-bromo-2-fluoro-4-nitrophenyl)-1H-imidazole (3.3 g, 0.012 mol, 1.00 equiv.) in THF (100 mL) under nitrogen was added bromo(ethenyl)magnesium in THF (46.2 mL, 0.030 mol, 4 equiv.) dropwise at −45° C. The resulting solution was stirred at −45° C. for 2 h. The reaction was quenched with NH4Cl / HO and extracted with 3×100 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to give the title compound (550 mg, 17% yield) as a white solid. LCMS: [M+H] + 279.98.

[0422] Step 3: 4-Fluoro-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide A mixture of 7-bromo-4-fluoro-5-(imidazol-1-yl)-1H-indole (286 mg, 1.02 mmol, 1.00 equiv.), Int-B1 (346 mg, 2.0 mmol, 1.96 equiv.), Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.10 equiv.), and TEA (1 mL) in DMSO (5 mL) was stirred at 80 °C overnight under CO. The reaction was quenched with water and extracted with 3 x 50 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by C18 reverse-phase chromatography eluting with HO / CH3CN to give the title compound (71 mg, 17%) as a dark yellow solid. LCMS: [M+H] + 401.10. 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),8.37(d,J=7.6Hz,1H),8.00(d,J=1.3Hz,1H),7.90(d,J=6.9Hz,1H),7.55(q, J=1.3Hz,1H),7.48(t,J=2.8Hz,1H),7.14(d,J=1.2Hz,1H),6.66(dd,J=3.2,2.0Hz,1H),3. 88-3.78(m,1H),3.54(dd,J=5.9,3.8Hz,2H),3.42(dd,J=5.8,3.9Hz,2H),3.27(s,3H),3.2 6-3.21(m,1H),2.04-1.95(m,2H),1.91-1.82(m,2H),1.42-1.31(m,2H),1.30-1.25(m,2H).

[0423] Example 30: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide [ka]

[0424] Step 1: Methyl 5-(1H-imidazol-1-yl)-2-nitrobenzoate A mixture of methyl 5-fluoro-2-nitrobenzoate (5 g, 25.1 mmol, 1 equiv.), 1H-imidazole (1.88 g, 27.62 mmol, 1.10 equiv.), and K2CO3 (5.21 g, 37.66 mmol, 1.5 equiv.) in DMF (80 mL) was stirred at 120 °C for 2 h. The reaction was quenched with water / ice and extracted with 3 x 100 mL of EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (9 / 1) to give the title compound (4.4 g, 71%) as a yellow solid. LCMS: [M+H] + 248.10.

[0425] Step 2: Methyl 2-amino-5-(1H-imidazol-1-yl)benzoate A mixture of methyl 5-(1H-imidazol-1-yl)-2-nitrobenzoate (29.6 g, 119.74 mmol, 1 equiv.) and Pd / C (2 g, 18.79 mmol, 0.16 equiv.) in MeOH (800 mL) was stirred under hydrogen at room temperature for 24 hours. The insoluble solid was filtered and rinsed with MeOH. The filtrate was concentrated to give the title compound (22.77 g, 82%) as a yellow solid. LCMS: [M+H] + 218.10.

[0426] Step 3: Methyl 2-amino-5-(1H-imidazol-1-yl)-3-nitrobenzoate A mixture of methyl 2-amino-5-(1H-imidazol-1-yl)benzoate (1.00 g, 4.60 mmol, 1.00 equiv.), KNO3 (931 mg, 9.21 mmol, 2.00 equiv.) in TFA (10 mL) was stirred at 50 °C for 2 h. The resulting mixture was concentrated and dissolved in saturated NaHCO3 (30 mL). The resulting solution was extracted with 3 x 30 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (960 mg) as a solid. LCMS: [M+H] + 263.10.

[0427] A mixture of methyl 2-amino-5-(1H-imidazol-1-yl)-3-nitrobenzoate (960 mg, 3.66 mmol, 1.00 equiv.) and Pd / C (3.00 g) in MeOH (50 mL) was stirred at room temperature for 0.5 hours. The insoluble solid was filtered and washed with MeOH. The filtrate was concentrated to give the title compound (450 mg) as a solid. LCMS: [M+H] + 233.10.

[0428] Step 5: Methyl 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylate A solution of methyl 2,3-diamino-5-(1H-imidazol-1-yl)benzoate (200 mg, 0.86 mmol, 1.00 equiv.), 40% acetaldehyde (269 mg, 2.58 mmol, 3.00 equiv.), and NaHSO (134 mg, 1.29 mmol, 1.50 equiv.) in EtOH (2 mL) and HO (2 mL) was stirred at 80 °C for 2 h. The reaction was quenched with aqueous NaOH. The resulting solution was extracted with 3 × 10 EtOAc. The organic layers were combined and concentrated. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (1 / 9) to give the title compound (80 mg, 36%) as a solid. LCMS: [M+H] + 257.10.

[0429] Step 6: 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylic acid A solution of methyl 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylate (80 mg, 0.31 mmol, 1.00 equiv.), KOH (18 mg, 0.31 mmol, 1.00 equiv.) in MeOH (1.0 mL) and HO (0.20 mL) was stirred at room temperature for 2 h. The pH value was adjusted to 3 with 1 M HCl. The mixture was concentrated to give the title compound (50 mg) as a crude solid, which was carried forward without further purification. LCMS: [M+H] + 243.10.

[0430] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylic acid (50 mg, 0.21 mmol, 1.00 equiv.), Int-B2 (43 mg, 0.25 mmol, 1.20 equiv.), DIPEA (40 mg, 0.31 mmol, 1.50 equiv.), and HATU (94 mg, 0.25 mmol, 1.20 equiv.) in DMF (2 mL) was stirred at room temperature for 2 h. The crude product was purified on a reverse-phase column eluted with ACN / HO to give the title compound (18 mg, 22% yield) as a white solid. LCMS: [M+H] + 398.20. 1 H NMR(300MHz,DMSO-d6)δ 12.68(d,J=168.4Hz,1H),9.87(d,J=7.5Hz,1H),8.22(s,1H),7.99-7.67(m,3H),7.12(s,1H),3.90-3.34(m,1H),3.55(dd,J=6.0,3 .7Hz,2H),3.44(t,J=4.8Hz,2H),3.39-3.34(m,1H),3.26(s,3H),2.57(d,J=20.2Hz,3H),2.00(d,J=9.8Hz,4H),1.53-1.21(m,4H).

[0431] Example 31: N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide [ka]

[0432] Step 1: Methyl indoline-7-carboxylate A mixture of methyl 1H-indole-7-carboxylate (95 g, 542 mmol, 1 equiv.), NaBHCN (170.4 g, 2.70 mol, 5 equiv.) in AcOH (1000 mL) was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with 3×1000 mL of EtOAc. The organic layers were combined and washed with 3×300 mL of HO. The organic layers were dried over sodium sulfate and concentrated. The crude product was applied to a silica gel column eluting with EtOAc / petroleum ether (1:20) to give the title compound (69 g, 72%) as a white solid. LCMS [M+H] + 178.1.

[0433] Step 2: Methyl 5-iodoindoline-7-carboxylate A solution of methyl indoline-7-carboxylate (67 g, 378.5 mmol, 1 equiv.) and NIS (89.3 g, 397 mmol, 1.05 equiv.) in AcOH (1200 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with water. The precipitated solid was collected by filtration. The solid was washed with 500 mL of water. This gave the title compound (100 g, 87.26%) as a white solid. LCMS [M+H] + 304.05.

[0434] Step 3: Methyl 5-iodo-1H-indole-7-carboxylate A mixture of methyl 5-iodoindoline-7-carboxylate (95 g, 313.43 mmol, 1 equiv.) and MnO2 (408.7 g, 4.7 mol, 15 equiv.) in THF (800 mL) was stirred at 75 °C for 16 h. The insoluble solid was filtered off. The filtrate was concentrated to give the title compound (91 g, 96%) as a pale yellow solid. LCMS [M+H] + 302.10.

[0435] Step 4: Methyl 5-(thiazol-5-yl)-1H-indole-7-carboxylate A mixture of methyl 5-iodo-1H-indole-7-carboxylate (500 mg, 1.661 mmol, 1 equiv.), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (351 mg, 1.66 mmol, 1.00 equiv.), KCO (459 mg, 3.32 mmol, 2.0 equiv.), CuI (32 mg, 0.17 mmol, 0.1 equiv.), and Pd(dppf)Cl (122 mg, 0.17 mmol, 0.10 equiv.) in EtOH (12 mL) and HO (3 mL) under nitrogen was stirred at 60 °C for 1 h. The resulting solution was concentrated and applied to a silica gel column eluted with EtOAc / petroleum ether (40 / 60) to give the title compound (500 mg) as a white solid, which was carried on without further purification. LCMS: [M+H] + 259.05.

[0436] Step 5: 5-(thiazol-5-yl)-1H-indole-7-carboxylic acid To a solution of methyl 5-(thiazol-5-yl)-1H-indole-7-carboxylate (500 mg, 1.94 mmol, 1 equiv.) in MeOH (20 mL) was added 2 mL of 5 M aqueous NaOH. The mixture was stirred at room temperature for 6 h. The pH value was adjusted to 6 with HCl (2 M). The resulting mixture was...

Claims

1. Compounds of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: V is N or CR Ｖ wherein R Ｖ is H, halo, or C １－４ is alkyl; W is N or CR Ｗ wherein R Ｗ is H, halo, or C １－４ is alkyl; 【Chemistry 2】 The part represented by 【Chemistry 3】 Selected from: Ring A is a 5-membered heteroaryl group having 1, 2 or 3 ring-forming heteroatoms selected from N, O and S, wherein said 5-membered heteroaryl group of Ring A is selected from halo and C １－４ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｎ is H, C １－４ Alkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ｎ The above C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ The cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R Ａ , R Ｂ , and R Ｃ is H, halo, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ａ , R Ｂ , and R Ｃ The above C １－４ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ The cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C １－４ is an alkylene linker; n is 0 or 1; Q is H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C １－１０ Haloalkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ２－１０ Alkenyl, the C ２－１０ Alkynyl, the C １－１０ haloalkyl, the C ６－１０ aryl, the C ３－１４ The cycloalkyl, the 5- to 14-membered heteroaryl, and the 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ alkyl, the C ２－６ alkenyl, and the C ２－６ Alkynyl is Cy １ , C.N., N.O. ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ optionally with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy １ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ 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 , and S(O) ２ NR ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ The above C １－６ alkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R ｃ and R ｄ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy ２ is C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Alkyl is each selected from OH, CN, amino, halo, and C １－６ Alkyl, C １－６ Alkylamino, di(C １－６ alkyl)amino, C １－６ Alkoxy, C １－６ Haloalkyl, and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ , R ｅ１ , R ｅ２ , and R ｅ３ is H, C １－４ alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and However, if V is CH; W is CH; 【Chemistry 4】 The part represented by 【Chemistry 5】 and n is 0; and Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is 【Chemistry 6】 The compound of formula I, or a pharmaceutically acceptable salt thereof, which is other than:

2. V is N or CR Ｖ wherein R Ｖ is H, halo, or C １－４ is alkyl; W is N or CR Ｗ wherein R Ｗ is H, halo, or C １－４ is alkyl; 【Chemistry 7】 The part represented by 【Chemistry 8】 is selected from Ring A is a 5-membered heteroaryl group having 1, 2 or 3 ring-forming heteroatoms selected from N, O and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C １－４ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｎ But H, C １－４ Alkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ｎ The above C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R Ａ , R Ｂ , and R Ｃ But, H, halo, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ａ , R Ｂ , and R Ｃ The above C １－４ alkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ The cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each selected from Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C １－４ is an alkylene linker; n is 0 or 1; Q is H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C １－１０ Haloalkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ２－１０ alkenyl, the C ２－１０ Alkynyl, the C １－１０ haloalkyl, the C ６－１０ aryl, the C ３－１４ cycloalkyl, said 5- to 14-membered heteroaryl, and said 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ optionally substituted with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy １ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ 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 , and S(O) ２ NR ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ The above C １－６ alkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ The alkyl is Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R ｃ and R ｄ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy ２ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Each of the alkyl groups is selected from OH, CN, amino, halo, and C １－６ Alkyl, C １－６ Alkylamino, di(C １－６ alkyl)amino, C １－６ Alkoxy, C １－６ Haloalkyl, and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ , R ｅ１ , R ｅ２ , and R ｅ３ But H, C １－４ alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; 【Chemistry 9】 The part represented by 【Chemistry 10】 and n is 0; and Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is 【Chemistry 11】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is other than:

3. V is N or CR Ｖ wherein R Ｖ is H, halo, or C １－４ is alkyl; W is N or CR Ｗ wherein R Ｗ is H, halo, or C １－４ is alkyl; 【Chemistry 12】 The part represented by 【Chemistry 13】 Selected from: Ring A is a 5-membered heteroaryl group having 1, 2 or 3 ring-forming heteroatoms selected from N, O and S, wherein the 5-membered heteroaryl group of Ring A is selected from halo and C １－４ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｎ But H, C １－４ Alkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ｎ The above C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ The cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each selected from Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R Ａ , R Ｂ , and R Ｃ But, H, halo, C １－４ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein R Ａ , R Ｂ , and R Ｃ The above C １－４ alkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C １－６ haloalkyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, and the 4- to 10-membered heterocycloalkyl are each Cy, Cy-C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from L is C １－４ is an alkylene linker; n is 0 or 1; Q is H, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C １－１０ Haloalkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ２－１０ alkenyl, the C ２－１０ Alkynyl, the C １－１０ haloalkyl, the C ６－１０ aryl, the C ３－１４ cycloalkyl, said 5- to 14-membered heteroaryl, and said 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy is C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ , S.R. ａ , C(O)R ｂ , C(O)NR ｃ R ｄ , C(O)OR ａ , O.C.(O.)R ｂ , OC(O)NR ｃ R ｄ , C(=NR ｅ ) NR ｃ R ｄ , N.R. ｃ C (=NR ｅ ) NR ｃ R ｄ , N.R. ｃ R ｄ , N.R. ｃ C(O)R ｂ , N.R. ｃ C(O)OR ａ , N.R. ｃ C(O)NR ｃ R ｄ , N.R. ｃ S(O)R ｂ , N.R. ｃ S (O) ２ R ｂ , N.R. ｃ S (O) ２ NR ｃ R ｄ , S(O)R ｂ , S(O)NR ｃ R ｄ , S(O) ２ R ｂ , and S(O) ２ NR ｃ R ｄ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Cy １ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ 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 , and S(O) ２ NR ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein R ａ , R ｂ , R ｃ , R ｄ , R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ The above C １－６ alkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ The alkyl is Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R ｃ and R ｄ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy ２ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein １－６ alkyl, the C １－６ haloalkyl, the C ２－６ alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Each of the alkyl groups is selected from OH, CN, amino, halo, and C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ , R ｅ１ , R ｅ２ , and R ｅ３ But H, C １－４ alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; 【Chemistry 14】 The part represented by 【Chemistry 15】 and n is 0; and Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is 【Chemistry 16】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is other than:

4. 【Chemical 17】 The part represented by 【Chemistry 18】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from:

5. 【Chemical 19】 The part represented by 【Chemistry 20】 4. The compound according to claim 1, wherein:

6. 【Catalog 21】 The part represented by 【Chemical 22】 4. The compound according to claim 1, wherein:

7. Each R Ａ , R Ｂ , and R Ｃ However, H and C １－４ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

8. R Ａ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is H.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein V is N.

10. V is CR Ｖ 9. The compound according to any one of claims 1 to 8, wherein:

11. The compound according to any one of claims 1 to 10, wherein W is N, or a pharmaceutically acceptable salt thereof.

12. W is CR Ｗ 11. The compound according to any one of claims 1 to 10, wherein:

13. Ring A is 【Chemical 23】 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

14. R １ , R ２ , and R ３ are H and C, respectively. １－４ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein:

15. Q is C １－１０ Alkyl, C １－１０ Haloalkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ６－１０ aryl, the C ３－１４ cycloalkyl, said 5- to 14-membered heteroaryl, or said 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl and the C ２－６ Alkynyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally selected by one, two, or three substituents independently selected from:

16. Q is C １－１０ Alkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ６－１０ aryl, the C ３－１４ cycloalkyl, said 5- to 14-membered heteroaryl, or said 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

17. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－１０ alkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

18. Q is C １－４ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is alkyl.

19. Q is C １－４ Alkyl and C １－４ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from haloalkyl.

20. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and wherein said C is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

21. Q is Halo, C １－６ Alkyl, C １－６ Haloalkyl, CN, and OR ａ１ and wherein the C is a phenyl optionally substituted with 1 or 2 substituents independently selected from １－６ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with CN.

22. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ３－１４ cycloalkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

23. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ４－７ cycloalkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

24. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ４－７ cycloalkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy, C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , and N.R. ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

25. Q is Cy １ , Haro, C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)NR ｃ１ R ｄ１ , and N.R. ｃ１ C(O)R ｂ１ C optionally substituted with 1 or 2 substituents independently selected from ４－７ cycloalkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

26. Q is Cy １ , Haro, C １－６ Alkyl, C １－６ Haloalkyl, CN, OR ａ１ , N.R. ｃ１ R ｄ１ , C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , and S(O) ２ R ｂ１ C optionally substituted with 1 or 2 substituents independently selected from ４－７ cycloalkyl, wherein said C １－６ Alkyl is OH, CN, C １－６ Alkoxy, C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , and N.R. ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

27. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and wherein said C is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

28. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and wherein said C is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl and the C ２－６ Alkynyl is OH, CN, C １－６ Alkoxy, NR ｃ１ R ｄ１ , and N.R. ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally selected by one, two, or three substituents independently selected from:

29. Q is Cy １ , Haro, C １－６ Alkyl, or OR ａ１ wherein said C is a 5- or 6-membered heteroaryl optionally substituted with １－６ The alkyl is C １－６ 15. The compound of any one of claims 1, 2, and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally substituted with alkoxy.

30. Q is Cy １ , Haro, C １－６ Alkyl, C １－６ haloalkyl, or OR ａ１ wherein said C is a 5- or 6-membered heteroaryl optionally substituted with １－６ Alkyl and the C ２－６ Alkynyl is C １－６ Alkoxy or NR ｃ１ R ｄ１ 15. The compound of any one of claims 1, 2, and 4 to 14, or a pharmaceutically acceptable salt thereof, optionally selected from the group consisting of:

31. Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and wherein said C is a 4-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ 15. The compound of any one of claims 1, 2, and 4-14, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from:

32. Q is Cy １ , Haro, C １－６ Alkyl, C １－６ Haloalkyl, C(O)R ｂ１ , and S(O) ２ R ｂ１ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a 5-10 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from:

33. Q is Cy １ , Haro, C １－６ Alkyl, C １－６ Haloalkyl, C(O)R ｂ１ , and S(O) ２ R ｂ１ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a 5- or 6-membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from:

34. 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein L is a methylene linker.

35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 0.

36. 35. The compound according to any one of claims 1 to 34, wherein n is 1, or a pharmaceutically acceptable salt thereof.

37. V is N or CR Ｖ wherein R Ｖ is H, halo, or C １－４ is alkyl; W is N or CR Ｗ wherein R Ｗ is H, halo, or C １－４ is alkyl; 【Chemistry 24】 The part represented by 【Chemistry 25】 Selected from: Each R Ｎ However, H and C １－４ independently selected from alkyl; Each R Ａ , R Ｂ , and R Ｃ However, H and C １－４ independently selected from alkyl; Ring A is 【Chemical 26】 Selected from: R １ , R ２ , and R ３ are H and C, respectively. １－４ independently selected from alkyl; L is methylene; n is 0 or 1; Q is C １－１０ Alkyl, C ６－１０ Aryl, C ３－１４ cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, １－１０ alkyl, the C ６－１０ aryl, the C ３－１４ cycloalkyl, said 5- to 14-membered heteroaryl, or said 4- to 14-membered heterocycloalkyl are each selected from Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from １－６ Alkyl is OH, CN, C １－６ Alkoxy and NR ｃ１ C(O)R ｂ１ optionally substituted with 1, 2, or 3 substituents independently selected from wherein when n is 0, then Q is other than H; Each Cy １ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is independently selected from halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, 4-10 membered heterocycloalkyl-C １－４ Alkyl, CN, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. 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 , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ 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 , and S(O) ２ NR ｃ２ R ｄ２ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein R ａ１ , R ｂ１ , R ｃ１ , R ｄ１ , R ａ２ , R ｂ２ , R ｃ２ , and R ｄ２ The above C １－６ alkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ cycloalkyl, the 5- to 10-membered heteroaryl, the 4- to 10-membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ The alkyl is Cy ２ , Cy ２ -C １－４ Alkyl, halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R ｃ１ and R ｄ１ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: or R ｃ２ and R ｄ２ together with the N atom to which they are attached, form halo, C １－４ Alkyl, C １－４ Haloalkyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ forming a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each Cy ２ But C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, CN, OR ａ３ , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , O.C.(O.)R ｂ３ , OC(O)NR ｃ３ R ｄ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)NR ｃ３ R ｄ３ , N.R. ｃ３ C(O)OR ａ３ , C(=NR ｅ３ ) NR ｃ３ R ｄ３ , N.R. ｃ３ C (=NR ｅ３ ) NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , and S(O) ２ NR ｃ３ R ｄ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ３ , R ｂ３ , R ｃ３ , and R ｄ３ But H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ６－１０ Aryl, C ３－７ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C ６－１０ Aryl-C １－４ Alkyl, C ３－７ Cycloalkyl-C １－４ Alkyl, 5-10 membered heteroaryl-C １－４ Alkyl, and 4-10 membered heterocycloalkyl-C １－４ alkyl, wherein １－６ alkyl, the C １－６ haloalkyl, the C ２－６ Alkenyl, the C ２－６ Alkynyl, the C ６－１０ aryl, the C ３－７ the cycloalkyl, the 5-10 membered heteroaryl, the 4-10 membered heterocycloalkyl, the C ６－１０ Aryl-C １－４ alkyl, the C ３－７ Cycloalkyl-C １－４ alkyl, the 5- to 10-membered heteroaryl-C １－４ alkyl, and the 4- to 10-membered heterocycloalkyl-C １－４ Each of the alkyl groups is selected from OH, CN, amino, halo, and C １－６ Alkyl, C １－６ Alkylamino, di(C １－６ alkyl)amino, C １－６ Alkoxy, C １－６ Haloalkyl, and C １－６ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; Each R ｅ１ , R ｅ２ , and R ｅ３ But H, C １－４ alkyl, and CN; wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by an oxo (=O) group; wherein one or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O) groups; and however, V is CH; W is CH; 【Chemical 27】 The part represented by 【Chemical Formula 28】 and n is 0; and Q is Cy １ , Cy １ -C １－４ Alkyl, halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, CN, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ cyclohexyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Ring A is 【Chemical 29】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is other than:

38. 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-7-carboxamide; N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indazole-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(aminomethyl)-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-b]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo[4,5-d]pyrimidine-7-carboxamide; 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; (S)-2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; (R)-2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 4-fluoro-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-6-(thiazol-5-yl)-3I-imidazo[4,5-c]pyridine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(2-methyl-1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(2H-1,2,3-triazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(5-methyl-1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(4-methyl-1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-4-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(trifluoromethyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)benzo[d]isothiazole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(1H-imidazol-1-yl)-7H-purine-6-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-3H-imidazo[4,5-c]pyridine-4-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide; N-(2-fluoro-6-(trifluoromethyl)benzyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(2-methoxyethyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2-methoxyethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-cyclohexyl-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-methylpiperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(4-(2-methoxyethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(1-acetylpiperidin-4-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,3r)-3-(2-methoxyethoxy)cyclobutyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,3r)-3-methoxycyclobutyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-(methylamino)ethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-(dimethylamino)ethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-methylpyrrolidin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-cyclobutyl-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(cyclohexylmethyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-benzyl-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-(methylamino)-2-oxoethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-phenyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(5-methoxypyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(6-methoxypyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1H-pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(3-chlorophenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(2-chlorophenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-cyclopentyl-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(tetrahydrofuran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-cycloheptyl-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-methyl-1H-imidazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(3-chloro-4-fluorophenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-morpholinoethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; and 2-(1H-imidazol-1-yl)-N-(3-(2-methoxyethoxy)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; or any pharmaceutically acceptable salt thereof.

39. 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(cyanomethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1s,4s)-4-((2,2-difluoroethyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4,4-difluorocyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methyl(3,3,3-trifluoropropyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(methyl(3,3,3-trifluoropropyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(acetamidomethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)-8-methyl-7H-purine-6-carboxamide; N-[4-(1-cyano-1-methyl-ethyl)phenyl]-2-imidazol-1-yl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((R)-2-hydroxy-3-methylbutoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1S,4r)-4-((S)-2-hydroxy-3-methylbutoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethyl)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-(trifluoromethyl)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((3R,4R)-3-fluoropiperidin-4-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1S,3S)-3-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1S,3R)-3-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((R)-2-hydroxypropoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((S)-2-hydroxypropoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((R)-2-hydroxy-2,3-dimethylbutoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((S)-2-hydroxy-2,3-dimethylbutoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1R,4r)-4-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1R,4r)-4-((S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-methoxy-4-methylcyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4-cyanophenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(3-fluoro-4-(2-methoxyethoxy)phenyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(methoxymethyl)-1H-pyrazol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(5-chloropyridin-2-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(4-methyltetrahydro-2H-pyran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; N-(6-chloropyridin-3-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyridin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(2-chloropyridin-4-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(5-chloropyridin-3-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4-chloropyridin-2-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-(2-morpholinoacetyl)piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(6-chloropyridin-2-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(6-(2-morpholinoethoxy)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-7H-purine-6-carboxamide; N-((1r,4r)-4-cyanocyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyrimidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)-7H-purine-6-carboxamide; 2-(1H-imidazol-1-yl)-N-(pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-morpholinocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(5-chloro-6-(2-morpholinoethoxy)pyridin-3-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(2-(4,4-difluorocyclohexyl)ethyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4,4-difluorocyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-(trifluoromethyl)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-(isoxazol-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(1-phenylcyclopropyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(2-(2-methoxyethoxy)pyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(((1r,4r)-4-cyanocyclohexyl)methyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-fluorocyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1s,4s)-4-morpholinocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methylcarbamoyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-(2-acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(1,1-dioxidoisothiazolidin-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-((3,3-difluoropropyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1s,4s)-4-((3,3-difluoropropyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(cyanomethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1s,4s)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxypropan-2-yl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; and 3. The compound of claim 1 or 2, selected from 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; or a pharmaceutically acceptable salt of any of the foregoing.

40. N-(6-(3-(dimethylamino)prop-1-yn-1-yl)pyridin-3-yl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1S,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1R,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1s,4s)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-methyl-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[2,3-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-(methylamino)-2-oxoethyl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-(6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-(4-cyanophenyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2,2-difluoroethylamino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1S,4r)-4-((S)-2-hydroxypropoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1R,4r)-4-((R)-2-hydroxypropoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(acetamidomethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-(isoindolin-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(4-cyanophenoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methylsulfonyl)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(cyanomethoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(cyanomethoxy)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methylcarbamoyl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(cyanomethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2,2,2-trifluoroethylamino)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(2,2-difluoroethylamino)cyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((3,3,3-trifluoropropyl)amino)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide; N-(6-(2-(dimethylamino)ethoxy)pyridin-3-yl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-(6-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)pyridin-3-yl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-(isoindolin-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-(2-acetylisoindolin-5-yl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methylcarbamoyl)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(acetamidomethyl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-(3,3-difluoropropyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(methyl(2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(3,3,3-trifluoropropoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; and N-((1s,4s)-4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; or a pharmaceutically acceptable salt of any of the foregoing.

41. N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1s,4s)-4-(3-fluoro-3-methylazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(3-fluoro-3-methylazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,4r)-4-(3-cyano-3-methylazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1s,4s)-4-(3-cyano-3-methylazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoroethyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1R,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1S,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)-5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxamide; N-((1r,3r)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; N-((1r,3r)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; N-((1R,4r)-4-((R)-1-hydroxyethyl)cyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; N-((1S,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)-2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-(3-cyanoazetidin-1-yl)cyclohexyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)thieno[2,3-c]pyridine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1r,4r)-4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-methyl-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; and 5-(1H-imidazol-1-yl)-N-((1s,4s)-4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide; or a pharmaceutically acceptable salt of any of the foregoing.

42. 42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

43. 42. A method for inhibiting the function of CD38, comprising contacting CD38 with a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

44. 44. The method of claim 43, wherein the CD38 is intracellular.

45. 44. The method of claim 43, wherein said contacting occurs in vitro.

46. 44. The method of claim 43, wherein said contacting occurs in vivo.

47. 42. A method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

48. 48. The method of claim 47, wherein the cancer is selected from a cancer treated with checkpoint therapy, a resistant cancer treated with checkpoint therapy, an adenosine-dependent tumor, a Treg-infiltrated tumor, and an MDSC-infiltrated tumor.

49. 48. The method of claim 47, wherein the cancer is lung cancer.

50. 48. The method of claim 47, wherein the cancer is melanoma.

51. 48. The method of claim 47, wherein the cancer is colon cancer.

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