Heterobicyclic amides as CD38 inhibitors

Abstract

The present invention relates to heterobicyclic amides and related compounds, which are CD38 inhibitors and are useful in the treatment of cancer.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080066542.2, filed on July 30, 2020, with the invention name “Heterobicyclic amides as CD38 inhibitors”. Technical Field

[0002] The present invention relates to heterobicyclic amides and related compounds that are CD38 inhibitors and are useful in treating cancer. Background Art

[0003] CD38 (cluster of differentiation 38) is a member of the ADP-ribosyl cyclase family, which is widely expressed on the surface of multiple cell types and is responsible for the degradation of nicotinamide adenine dinucleotide (NAD + ). CD38 was originally described as a surface antigen on immune cells as an activation marker, which is located on the membranes of the plasma membrane and intracellular organelles (Quarona, V. et al., Cytometry BClin Cytom 84(4):207-217(2013)). Human CD38 contains 300 amino acid residues and includes a short N-terminal segment, a single 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 converts NAD + Converted to ADP-ribose (ADPR) or cyclic ADPR (cADPR) and nicotinamide (Chini EN et al., TrendsPharmacol Sci 39(4):424-436(2018)). + It is considered to be the main substrate for CD38, but other substrates (such as nicotinamide adenine dinucleotide phosphate (NADP) + ) and nicotinamide mononucleotide (NMN + )). Under some conditions, CD38 can also catalyze base exchange reactions using these same substrates (Preugschat, F et al., Arch Biochem Biophys, 479: 114-20 (2008)). This CD38-dependent NAD + Metabolism can regulate extracellular and intracellular metabolites, intracellular Ca 2+and signal transduction pathways (Horenstein, AL et al., Oncoimmunology 2(9):e26246(2013)); Chini EN et al., 2018). CD38 also serves as a receptor, and the receptor-ligand activity of CD38 can regulate the development, activation and differentiation of multiple immune cell types (Quorona B et al., 2013), and CD31 / PECAM-1 has been reported to be a ligand of CD38 (Deaglio S, J Immunol, 160:395-402(1998)).

[0004] CD38 plays a variety of physiological functions, and the characterization of CD38 knockout (KO) mice has elucidated the various roles played by this protein. CD38 KO mice are characterized by greatly reduced levels of endogenous cADPR in all analyzed tissues / organs 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, CD38 depletion impairs glucose-induced cADPR production, intracellular Ca 2+ and insulin secretion (Kato J et al., J Biol Chem, 274: 1869-72 (1999)). CD38 KO also impairs the acetylcholine-induced accumulation of cADPR in acinar cells, thereby significantly altering Ca 2+ signal transduction mode (Fukushi et al., J Biol Chem, 276: 649-55 (2001)). Similarly, in neutrophils, cADPR production has been shown to regulate intracellular Ca during chemotaxis. 2+ Release and extracellular Ca 2+Influx into both 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 impaired 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)), suppressed 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 clearly demonstrate the diverse biological roles played by CD38.

[0005] CD38 expression is also associated with the immunosuppressive function of regulatory T (Treg) cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) (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):736-749e718 (2017); Levy A Neuro Oncol 14(8):1037-1049 (2012)). CD38 KO Treg cells are sensitive to NAD. + Induced cell death is extremely sensitive due to its inability to consume NAD + (Chen J et al., J Immunol 176(8):4590-4599(2006); Hubert, SB et al., J Exp Med, 207:2561-8(2010)). In contrast, 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, an effect that can be inhibited by CD38 blockade (Karakasheva TA et al., Cancer Res 75(19):4074-4085 (2015)). Functional CD38 + Expansion of MDSCs has also been described in colorectal cancer, especially in patients who have previously undergone therapy (Karakasheva TA et al., JCI Insight 3(6)(2018)). A generalized systems immunology approach has revealed an association between tumor-infiltrating lymphocytes (TILs) expressing CD38 and a poor prognosis in clear cell renal cell carcinoma (ccRCC) and early lung adenocarcinoma (Chevrier S et al., 2017; Lavin Y et al., Cell 169(4):750-765e717(2017)). In ccRCC, CD38 was co-expressed with other markers of T cell exhaustion, while in lung adenocarcinoma, CD38 was not co-expressed with other markers of T cell exhaustion. 高 Treg cells are enriched in the tumor microenvironment (TME) (Chevrier S et al., 2017; Lavin et al., 2017). CD38 and CD101 are highly co-expressed on TILs in tumor tissue and are associated with poor survival in pancreatic cancer patients (Zhang M et al., Immunol Invest, 48:466-79 (2019)). Studies on exhausted T cell populations in humans with chronic infections and various cancers identified CD38 as a T cell exhaustion marker, and the presence of such exhausted T cells is associated with more severe diseases from TIL dysfunction in HIV infection and lung cancer (Bengsch B et al., Immunity 48 (5): 1029-1045e1025 (2018)). CD38 also indicates the metabolic adaptability of T cells, and inhibiting CD38 expression on T cells can upregulate NAD + It also activates T cells by promoting glutamine decomposition, enhancing oxidative phosphorylation, and changing mitochondrial dynamics (Chatterjee S et al., 2018). This study further confirmed that inhibiting CD38 can prevent T cell exhaustion and thereby enhance the efficacy of adoptive T cell therapy (Chatterjee S et al., Cell Metab 27(1):85-100e108(2018)).

[0006] The role of CD38 in tumor formation and immunosuppression is an active research area, in which multiple studies have linked CD38 to tumor progression. CD38 has been shown to promote cervical cancer cell growth by reducing the level of reactive oxygen species and inhibiting apoptosis (Liao S et al., Mol Carcinog 56(10):2245-2257(2017)), and CD38 loss in human lung adenocarcinoma cells can inhibit cell growth, invasion, and xenograft growth in nude mice (Bu X et al., Carcinogenesis 39(2):242-251(2017)). CD38 KO mice can resist tumor growth to a large extent and have been shown to effectively reject B16-F10 melanoma tumors (Baruch BB et al., Oncotarget, 9:31797-811(2018)). Similarly, targeting CD38 expression or its activity in the TME can inhibit glioma progression and prolong the lifespan of mice with glioma (Blacher E et al., Int J Cancer 136(6):1422-1433(2013)).CD38 has also been identified as a biomarker for aggressive localized prostate cancer (Sahoo D et al., Oncotarget, 9:6550-61(2018)).

[0007] The latest research has explored the role of CD38 in the production of NAD + Role in the exoenzyme cascade that generates immunosuppressive adenosine. In addition to CD38, this cascade also includes ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) and 5′-ectonucleotidase CD73. CD38 generates ADPR, which is further hydrolyzed by ENPP1 to produce AMP, and regulates the subsequent conversion of AMP to adenosine by CD73 (Ferretti E et al., Immunol Lett 205:25-30 (2019)). This atypical adenosine production pathway, which depends on CD38, occurs independently of ATP, and bypasses CD39 (Horenstein AL et al., 2013), plays a major role in generating immunosuppressive TME, in which dying cells provide NAD that is ultimately converted into adenosine. + (Haag F et al., Purinergic Signal 3(1-2):71-81 (2007); Zhu Y et al., Pharmacol Ther 200:27-41 (2019)).

[0008] In addition, recent studies have shown that cancer cells acquire resistance to immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) by upregulating CD38, which blocks CD8 through adenosine receptor signaling.+ T cell function (Chen L et al., Cancer Discov 8(9):1156-1175(2018)). CD38 blockade subsequently restores CD8 + T cell proliferation, anti-tumor cytokine secretion, and cytotoxic capacity. Pathological analysis of lung cancer samples revealed positive immunohistochemical staining of CD38 on tumor cells in 15-23% of cases, and bioinformatics analysis of datasets from non-small cell lung cancer (NSCLC) and melanoma patients revealed a strong correlation between CD38 expression and inflamed TME (Chen L et al., 2018).

[0009] CD38 is responsible for the age-related NAD + One of the main enzymes that is reduced in NAD (Hogan KA et al., Front Immunol 10:1187 (2019)). CD38 KO mice are always free from this progressive defect and age-related metabolic dysfunction (Camacho-Pereira J et al., Cell Metab, 23:1127-39 (2016)). CD38 inhibition can also reverse age-related NAD + Reduces and improves several metabolic, structural, and molecular features of aging in naturally aging and premature aging mice (Camacho-Pereira J et al., 2016). CD38 KO mice are also protected from diet-induced obesity, hepatic steatosis, and glucose intolerance caused by increased energy expenditure (Barbosa MT et al., FASEB J 21(13):3629-3639 (2007)).

[0010] CD38 is a cell surface marker for multiple myeloma and these cells are particularly sensitive to CD38 depletion, so CD38 provides a useful therapeutic target for this malignancy (Chini EN et al., 2018). Clinical trials have confirmed that CD38-targeted 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)), and the anti-CD38 antibody daratumumab has been approved by the FDA for the treatment of multiple myeloma. Several other therapeutic antibodies for CD38 are currently in clinical development for multiple myeloma and other cancers (van de Donk NWCJ 2018).

[0011] Numerous references exist in the literature reporting the potential therapeutic benefits of inhibiting aberrant expression or activity of CD38. For example, the following diseases are characterized by aberrant expression or activity of CD38: non-small cell lung cancer, melanoma, checkpoint therapy-resistant and / or resistant cancers, 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 mitochondriafunctions." Mol. Carcinog. 56, 2245-2257 (2017)); glioma (Blacher E et al., "Inhibition of glioma progression by a newly discovered CD38 inhibitor." Int. J. Cancer 136, 1422-1433 (2015)); colorectal 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)); clear cell renal 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)); Treg-infiltrating tumors (Lavin Y et al., “Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.” Cell 169, 750-757.e15 (2017)); MDSC-infiltrating tumors (Karakasheva TA et al., “CD38 +M-MDSC expansion characterizes a subset of advancedcolorectal 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 + axis regulates immunotherapeuticanti-tumor T cell response." Cell Metab. 27, 85-100.e8 (2018)); 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)).

[0012] In summary, CD38 is a multifunctional enzyme and signaling receptor that plays a crucial role in cancer progression, immunosuppressive TME generation, T cell metabolic adaptation, and NAD regulation in aging and other physiological conditions. +CD38 plays an important role in regulating its levels. Inhibiting CD38 in various disease states (including tumor growth) has shown clinical promise, and the development of potent and selective small molecule inhibitors will create therapeutic options for other conditions characterized by abnormal expression or activity of CD38. The compounds, compositions, and methods described herein will help meet these and other needs. Summary of the Invention

[0013] The present invention provides a compound of formula I:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein the constituent members are as defined herein.

[0016] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0017] The present invention also relates to a method of inhibiting CD38 function by contacting CD38 with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0018] The present invention also relates to a method for treating diseases associated with abnormal activity or expression of CD38, which is achieved by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0019] The present invention further relates to the compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating diseases associated with abnormal activity or expression of CD38.

[0020] The present invention further relates to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1A is the NAD in spleen at a single time point after administration of different amounts of Example 7 + Concentration graph.

[0022] Figure 1B is the NAD in the liver at a single time point after administration of different amounts of Example 7 + Concentration graph.

[0023] Figure 2A is the NAD in the liver at a single time point after administration of different amounts of Example 7 + Concentration graph.

[0024] Figure 2B is a graph of ADPR concentration in the liver at a single time point after administration of different amounts of Example 7.

[0025] Figure 3A is the NAD in spleen at a single time point after administration of different amounts of Example 115 + Concentration graph.

[0026] Figure 3B is the NAD in the liver at a single time point after administration of different amounts of Example 115 + Concentration graph.

[0027] Figure 4A is the NAD in spleen at a single time point after administration of different amounts of Example 191 + Concentration graph.

[0028] Figure 4B is the NAD in the liver at a single time point after administration of different amounts of Example 191 + Concentration graph.

[0029] Figure 5A is the NAD in spleen at a single time point after administration of different amounts of Example 195 + Concentration graph.

[0030] Figure 5B is the NAD in the liver at a single time point after administration of different amounts of Example 195 + Concentration graph.

[0031] Figure 6A is the NAD in spleen at a single time point after administration of different amounts of Example 189 + Concentration graph.

[0032] Figure 6B is the NAD in the liver at a single time point after administration of different amounts of Example 189 + Concentration graph.

[0033] Figure 7A is the NAD in spleen at a single time point after administration of different amounts of Example 193 + Concentration graph.

[0034] Figure 7B is the NAD in the liver at a single time point after administration of different amounts of Example 193 + Concentration graph.

[0035] Figure 8A is the NAD in spleen at a single time point after administration of different amounts of Example 182 + Concentration graph.

[0036] Figure 8B is the NAD in the liver at a single time point after administration of different amounts of Example 182 +Concentration graph.

[0037] Figure 9A is a graph of the mean B16-F10 tumor volume in mice dosed with Example 7.

[0038] Figure 9B is a graph of the mean B16-F10 tumor volume in mice dosed with Example 7 and anti-mPD-L1.

[0039] Figure 10 is a graph showing the survival percentage of B16-F10 tumor-bearing mice treated with anti-mPD-L1 (10 mg / kg) and the combination of Example 7 (300 mg / kg) and anti-mPD-L1 (10 mg / kg).

[0040] Figure 11A is a graph of the mean MC-38 tumor volume in mice dosed with Example 7.

[0041] Figure 11B is a graph of the mean MC-38 tumor volume in mice dosed with Example 7 and anti-mPD-L1.

[0042] Figure 12 is a graph showing the survival percentage of MC-38 tumor-bearing mice treated with Example 7 (60 mg / kg).

[0043] Figure 13 is a graph showing the survival percentage of MC-38 tumor-bearing mice treated with anti-mPD-L1 (5 mg / kg) and with the combination of Example 7 (60 mg / kg) and anti-mPD-L1 (5 mg / kg).

[0044] Figure 14A is a graph of the mean Cloudman S91 tumor volume in mice dosed with Example 7.

[0045] Figure 14B is a graph of mean Cloudman S91 tumor volumes in mice dosed with Example 7 and anti-mPD-L1.

[0046] Figure 15 is a graph showing the percent survival of Cloudman S91 tumor-bearing mice treated with Example 7 (60 mg / kg).

[0047] Figure 16 is a graph showing the survival percentage of Cloudman S91 tumor-bearing mice treated with anti-mPD-L1 (5 mg / kg) and with the combination of Example 7 (60 mg / kg) and anti-mPD-L1 (5 mg / kg). DETAILED DESCRIPTION

[0048] The present invention relates to CD38 inhibitory compounds of formula I:

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein:

[0051] V is N or CR V , where R V is H, halogen or C 1-4 alkyl;

[0052] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0053] The part represented by the formula:

[0054]

[0055] Selected from:

[0056]

[0057] 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 optionally substituted by 1, 2 or 3 ring-forming heteroatoms independently selected from halogen and C 1-4 Substitution of alkyl groups;

[0058] Each R N Independently selected from 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0059] R A 、R B and R C Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0060] L is C 1-4 alkylene linker;

[0061] n is 0 or 1;

[0062] Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 2-10Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from Cy 1 、CN、NO2、OR a1SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0063] Wherein Q is not H when n is 0;

[0064] Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 aSR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0065] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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-C1-4 Alkyl, CN, NO2, OR a2 SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0066] 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7Cycloalkyl, 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, where 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 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NRc3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0067] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2Rb3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0068] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0069] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0070] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 R d3NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0071] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from 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 Substitution of haloalkoxy substituents;

[0072] R e 、R e1 、R e2 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0073] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0074] 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); and

[0075] The condition is when:

[0076] V is CH;

[0077] W is CH;

[0078] The part represented by the formula:

[0079]

[0080] yes

[0081]

[0082] n is 0; and

[0083] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR a1 、C(O)R b1 、C(O)NR c1 R d1 、C(O)ORa1 、OC(O)R b1 、OC(O)NR c1 R d1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0084] Then ring A is not:

[0085]

[0086] In some embodiments:

[0087] V is N or CR V , where R V is H, halogen or C 1-4 alkyl;

[0088] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0089] The part represented by the formula:

[0090]

[0091] Selected from:

[0092]

[0093] 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 optionally substituted by 1, 2 or 3 ring-forming heteroatoms independently selected from halogen and C 1-4 Substitution of alkyl groups;

[0094] Each R N Independently selected from 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NRc R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0095] R A 、R B and R C Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)ORa NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0096] L is C 1-4 alkylene linker;

[0097] n is 0 or 1;

[0098] Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 c1R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 Substituents substituted;

[0099] Wherein Q is not H when n is 0;

[0100] Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR a 、C(O)R b 、C(O)NR c R d 、C(O)ORa 、OC(O)R b 、OC(O)NR c R d 、C(=NR e )NR c R d NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0101] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR a2 、C(O)R b2 、C(O)NRc2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0102] 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where 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 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0103] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3Substituents substituted;

[0104] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0105] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)ORa3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0106] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 Rd3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0107] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents;

[0108] R e 、R e1 、R e2 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0109] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0110] 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); and

[0111] The condition is when:

[0112] V is CH;

[0113] W is CH;

[0114] The part represented by the formula:

[0115]

[0116] yes

[0117]

[0118] n is 0; and

[0119] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0120] Then ring A is not:

[0121]

[0122] In some embodiments:

[0123] V is N or CR V , where R V is H, halogen or C 1-4 alkyl;

[0124] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0125] The part represented by the formula:

[0126]

[0127] Selected from:

[0128]

[0129] 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 optionally substituted by 1, 2 or 3 ring-forming heteroatoms independently selected from halogen and C 1-4 Substitution of alkyl groups;

[0130] Each R N Independently selected from 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NRc R d Substituents substituted;

[0131] R A 、R B and R C Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NRc S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0132] L is C 1-4 alkylene linker;

[0133] n is 0 or 1;

[0134] Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 Rd1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0135] Wherein Q is not H when n is 0;

[0136] Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR 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 NR c C(=NR e )NR c R d NR c Rd NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0137] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NRc2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0138] 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where 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 C1-6 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3Substituents substituted;

[0139] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0140] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)ORa3 、OC(O)R b3 、OC(O)NR c3 R d3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0141] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NRc3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0142] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NRc3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0143] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents;

[0144] Re、Re 1 、Re 2 and Re 3 Each independently selected from H, C1-4 alkyl and CN;

[0145] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0146] 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); and

[0147] The condition is when:

[0148] V is CH;

[0149] W is CH;

[0150] The part represented by the formula:

[0151]

[0152] yes

[0153]

[0154] n is 0; and

[0155] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NRc1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0156] Then ring A is not

[0157]

[0158] In some embodiments, the moiety represented by the formula:

[0159]

[0160] Selected from:

[0161]

[0162]

[0163] In some embodiments, the moiety represented by the formula:

[0164]

[0165] yes

[0166]

[0167] In some embodiments, the moiety represented by the formula:

[0168]

[0169] yes

[0170]

[0171] In some embodiments, R A 、R B and R C Each independently selected from H and C 1-4 In some embodiments, R A is H. In some embodiments, R B is H. In some embodiments, R C It’s H.

[0172] In some embodiments, V is N.

[0173] In some embodiments, V is CR VIn some embodiments, V is CH.

[0174] In some embodiments, W is N.

[0175] In some embodiments, W is CR W In some embodiments, W is CH.

[0176] 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 CR W .

[0177] In some embodiments, at least one of V and W is N.

[0178] In some embodiments, Ring A is selected from:

[0179]

[0180] In some embodiments, Ring A is

[0181] In some embodiments, R 1 、R 2 and R 3 Each independently selected from H and C 1-4 In some embodiments, R 1 、R 2 and R 3 Each is H.

[0182] In some embodiments, Q is C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from Cy 1 、CN、NO2、OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 Rd1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0183] 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 the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0184] 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 the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NRc1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0185] In some embodiments, Q is C 1-4 Alkyl, C 1-4 Halogenated alkyl, phenyl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 1-4 Alkyl, phenyl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NRe1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0186] In some embodiments, Q is C 1-10 Alkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0187] In some embodiments, Q is C 1-10 Alkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 Rd1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0188] In some embodiments, Q is C 1-10 Alkyl or C 1-10 haloalkyl, wherein the C 1-10 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NRc1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0189] In some embodiments, Q is C 1-4 alkyl.

[0190] In some embodiments, Q is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0191] In some embodiments, Q is phenyl, which is optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NRc1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0192] In some embodiments, Q is phenyl, optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2Rb1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0193] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a1 Substituents substituted phenyl, wherein C 1-6 The alkyl group is optionally substituted with CN.

[0194] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from halo, C 1-6 Haloalkyl and OR a1 A phenyl group substituted with a substituent.

[0195] In some embodiments, Q is C 3-14 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NRc1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0196] In some embodiments, Q is C 3-14 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)ORa1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0197] In some embodiments, Q is C 4-7 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0198] In some embodiments, Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NRc1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0199] In some embodiments, Q is C 3-14 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NRc1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0200] In some embodiments, Q is C 4-7 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NRc1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0201] In some embodiments, Q is C 4-7 Cycloalkyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0202] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 and NR c1 C(O)R b1 Substituents substituted C 4-7 Cycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0203] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from C 1-6 Halogenated alkyl, OR a1 and NR c1 R d1 Substituents substituted C 4-7 Cycloalkyl.

[0204] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 Substituents substituted C 4-7 Cycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1substituted by a substituent.

[0205] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a1 and NR c1 R d1 Substituents substituted C 4-7 Cycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1 or 2 independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0206] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 Substituents substituted cyclohexyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0207] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a1 and NR c1 R d1 Substituents substituted cyclohexyl, wherein C 1-6 The alkyl group is optionally composed of 1 or 2 independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NRc1 C(O)R b1 substituted by a substituent.

[0208] In some embodiments, Q is replaced by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 Substituents substituted C 4-7 Cycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0209] In some embodiments, Q is replaced by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 Substituents substituted cyclohexyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0210] In some embodiments, Q is replaced by C 1-6 Alkyl-substituted cyclohexyl, wherein C 1-6 The alkyl group is optionally composed of 1 or 2 independently selected from OH, CN, C 1-6 Alkoxy, C(O)NRc1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0211] In some embodiments, Q is a 5-14 membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0212] In some embodiments, Q is a 5-14 membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0213] In some embodiments, Q is a 5-14 membered heteroaryl group optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein the C 1-6 Alkyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy, NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0214] In some embodiments, Q is optionally replaced by Cy 1 , halogen, C 1-6 Alkyl or OR a1 substituted 5- or 6-membered heteroaryl, wherein C1-6 The alkyl group is optionally composed of C 1-6 Alkoxy substitution.

[0215] In some embodiments, Q is optionally replaced by Cy 1 , halogen, C 1-6 Alkyl or OR a1 substituted 5- or 6-membered heteroaryl, wherein C 1-6 The alkyl group is optionally substituted with a methoxy group.

[0216] In some embodiments, Q is optionally replaced by OR a1 substituted 5- or 6-membered heteroaryl.

[0217] In some embodiments, Q is optionally replaced by Cy 1 , halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or OR a1 substituted 5- or 6-membered heteroaryl, wherein the C 1-6 Alkyl and C 2-6 Alkynyl is optionally C 1-6 Alkoxy or NR c1 R d1 replace.

[0218] In some embodiments, Q is a 4-14 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NRc1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0219] In some embodiments, Q is a 4-14 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NRc1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 substituted by a substituent.

[0220] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 、C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 substituted 5-10 membered heterocycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0221] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 A 5- to 10-membered heterocycloalkyl group substituted with a substituent.

[0222] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 、C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 substituted 5- or 6-membered heterocycloalkyl, wherein C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

[0223] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 A 5- or 6-membered heterocycloalkyl group substituted with a substituent.

[0224] In some embodiments, Q is optionally substituted by 1 or 2 independently selected from Cy 1 、C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 A 5- or 6-membered heterocycloalkyl group substituted with a substituent.

[0225] In some embodiments, Q is optionally replaced by C 1-6 Alkyl-substituted 9- or 10-membered heterocycloalkyl, wherein C 1-6 The alkyl group is optionally composed of C 1-6 Alkoxy substitution.

[0226] In some embodiments, Q is optionally replaced by C 1-6 Alkyl or C(O)R b1 Substituted 9- or 10-membered heterocycloalkyl, wherein C 1-6 The alkyl group is optionally composed of C 1-6 Alkoxy substitution.

[0227] In some embodiments, Q is optionally replaced by C 1-6 Alkyl-substituted 9- or 10-membered heterocycloalkyl, wherein C 1-6 The alkyl group is optionally substituted with a methoxy group.

[0228] In some embodiments, each Cy 1 is independently selected from phenyl, morpholinyl, piperidinyl and isothiazolidinyl-1,1-dione, wherein the piperidinyl is optionally substituted with a 4-6 membered heterocycloalkyl. 1 Independently selected from phenyl, morpholinyl, piperidinyl and isothiazolidinyl-1,1-dione, wherein the piperidinyl is optionally substituted with morpholinyl.

[0229] In some embodiments, each Cy 1 independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and isothiazolidinyl-1,1-dione, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, OH and 4-6 membered heterocycloalkyl.

[0230] In some embodiments, each Cy 1independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and isothiazolidinyl-1,1-dione, each of which is optionally substituted by 1 or 2 groups independently selected from C 1-6 The substituents are alkyl, halo, OH, CN and 4-6 membered heterocycloalkyl.

[0231] In some embodiments, each Cy 1 independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and isothiazolidinyl-1,1-dione, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, OH and morpholinyl.

[0232] In some embodiments, each Cy 1 independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and isothiazolidinyl-1,1-dione, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, F, OH, CN and morpholinyl.

[0233] In some embodiments, L is a methylene linker.

[0234] In some embodiments, L is an ethylene linker.

[0235] In some embodiments, n is 0.

[0236] In some embodiments, n is 1.

[0237] In some embodiments, 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, where R a 、R b 、R c 、R d 、R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and Rd2 The C 1-6 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from CN, OR a3 、C(O)NR c3 R d3 and NR c3 R d3 substituted by a substituent.

[0238] In some embodiments, 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, where 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 C 1-6 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl is optionally substituted by 1, 2 or 3 groups independently selected from CN, OR a3 、C(O)NR c3 R d3 and NR c3 R d3 substituted by a substituent.

[0239] In some embodiments, R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally substituted by 1, 2 or 3 groups independently selected from OH, di(C 1-6alkyl)amino and C 1-6 The substituents of the alkoxy group are substituted.

[0240] In some embodiments, R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from OH, dimethylamino and methoxy.

[0241] In some embodiments:

[0242] V is N or CR V , where R V is H, halogen or C 1-4 alkyl;

[0243] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0244] The part represented by the formula:

[0245]

[0246] Selected from:

[0247]

[0248] Each R N Independently selected from H and C 1-4 alkyl;

[0249] R A 、R B and R C Each independently selected from H and C 1-4 alkyl;

[0250] Ring A is selected from:

[0251]

[0252] R 1 、R 2 and R 3 Each independently selected from H and C 1-4 alkyl;

[0253] L is a methylene group;

[0254] n is 0 or 1;

[0255] Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein C 1-6The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 Substituents substituted;

[0256] Wherein Q is not H when n is 0;

[0257] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0258] R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 The 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0259] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 Rd3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0260] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0261] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NRc3 R d3 Substituents substituted;

[0262] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from 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 Substitution of haloalkoxy substituents;

[0263] R e1 、R e2 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0264] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0265] 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); and

[0266] The condition is when:

[0267] V is CH;

[0268] W is CH;

[0269] The part represented by the formula:

[0270]

[0271] yes

[0272]

[0273] n is 0; and

[0274] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0275] Then ring A is not:

[0276]

[0277] In some embodiments:

[0278] V is N or CR V , where R V is H, halogen or C 1-4 Alkyl; W is N or CR W , where R W is H, halogen or C 1-4 Alkyl; a moiety represented by the formula:

[0279]

[0280] Selected from:

[0281]

[0282] Each R N Independently selected from H and C 1-4 alkyl;

[0283] R A 、R B and R C Each independently selected from H and C 1-4 Alkyl; Ring A is selected from:

[0284]

[0285] R 1 、R 2 and R 3 Each independently selected from H and C 1-4 alkyl;

[0286] L is a methylene group;

[0287] n is 0 or 1;

[0288] Q is C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0289] Wherein Q is not H when n is 0;

[0290] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0291] R a1 、R b1 、R c1 、R d1 、R a2 、Rb2 、R c2 and R d2 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 and R d2 The 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NRc3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0292] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)Rb3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0293] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0294] Each Cy 2 It is C6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0295] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7Cycloalkyl, 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 the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents;

[0296] R e1 、R e2 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0297] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0298] 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); and

[0299] The condition is when:

[0300] V is CH;

[0301] W is CH;

[0302] The part represented by the formula:

[0303]

[0304] yes

[0305]

[0306] n is 0; and

[0307] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0308] Then ring A is not:

[0309]

[0310] In some embodiments:

[0311] V is N or CR V , where RV is H, halogen or C 1-4 alkyl;

[0312] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0313] wherein at least one of V and W is N;

[0314] The part represented by the formula:

[0315]

[0316] Selected from:

[0317]

[0318] 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 optionally substituted by 1, 2 or 3 ring-forming heteroatoms independently selected from halogen and C 1-4 Substitution of alkyl groups;

[0319] Each R N Independently selected from 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 dNR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0320] R A 、R B and R C Each independently selected from H, halogen, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0321] L is C 1-4 alkylene linker;

[0322] n is 0 or 1;

[0323] Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Halogenated alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted, wherein the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from Cy 1 、CN、NO2、OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0324] Wherein Q is not H when n is 0;

[0325] Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR a 、C(O)R b 、C(O)NR c R d 、C(O)OR a 、OC(O)R b 、OC(O)NRc R d 、C(=NR e )NR c R d NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents substituted;

[0326] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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 SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents substituted;

[0327] 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where 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 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 Rd3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0328] or R c and R d Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0329] or Rc1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0330] or R c2 and R d2 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0331] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0332] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Halogenated 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 Each alkyl radical is optionally substituted by 1, 2 or 3 radicals independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkylamino, di(C 1-6Alkyl)amino, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents;

[0333] R e 、R e1 、R e2 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0334] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O); and

[0335] One or more ring-forming S atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by one or two oxo (=O).

[0336] In some embodiments:

[0337] V is N or CR V , where R V is H, halogen or C 1-4 alkyl;

[0338] W is N or CR W , where R W is H, halogen or C 1-4 alkyl;

[0339] The part represented by the formula:

[0340]

[0341] Selected from:

[0342]

[0343] Ring A is selected from:

[0344]

[0345] Each R N Independently selected from H and C 1-4 alkyl;

[0346] R A and R B Each independently selected from H and C 1-4 alkyl;

[0347] R 1 、R 2 and R 3 Each independently selected from H and C 1-4 alkyl;

[0348] L is C 1-4 alkylene linker;

[0349] n is 0 or 1;

[0350] Q is C 1-4 Alkyl, C 1-4 Halogenated alkyl, phenyl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein the C 1-4 Alkyl, phenyl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NRc1 R d1 Substituents substituted, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 Substituents substituted;

[0351] Each Cy 1 independently selected from phenyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and isothiazolidinyl-1,1-dione, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, OH and morpholinyl;

[0352] R a1 、R b1 、R c1 and R d1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated 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, where R a1 、R b1 、R c1 and R d1 The 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 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0353] or R c1 and R d1 Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 independently selected halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 SR a3 、C(O)R b3 、C(O)NR c3 R d3 、C(O)OR a3 、OC(O)R b3 、OC(O)NR c3 Rd3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0354] Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, each of which is optionally composed of 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NRe3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents substituted;

[0355] R a3 、R b3 、R c3 and R d3 Each independently selected from H, C 1-6 Alkyl and C 1-6 haloalkyl, wherein the C 1-6 Alkyl and C 1-6 Each haloalkyl group is optionally substituted by 1, 2 or 3 groups independently selected from OH, di(C 1-6 alkyl)amino and C 1-6 Substitution of alkoxy groups;

[0356] R e1 and R e3 Each independently selected from H, C 1-4 Alkyl and CN;

[0357] wherein one or more ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally substituted by oxo (═O);

[0358] 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);

[0359] The condition is when:

[0360] V is CH;

[0361] W is CH;

[0362] The part represented by the formula:

[0363]

[0364] yes

[0365]

[0366] n is 0; and

[0367] Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 、Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted;

[0368] Then ring A is not

[0369]

[0370] In some embodiments, provided herein are compounds of Formula IIa:

[0371]

[0372] or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, provided herein is a compound of Formula IIb:

[0374]

[0375] or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, provided herein is a compound of Formula IIIa:

[0377]

[0378] or a pharmaceutically acceptable salt thereof, wherein R Q It's Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 , where C 1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0379] In some embodiments, provided herein is a compound of Formula IIIb:

[0380]

[0381] or a pharmaceutically acceptable salt thereof, wherein R Q It's Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 , where C1-6 The alkyl group is optionally composed of 1, 2 or 3 groups independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

[0382] It will be further appreciated that certain features of the invention described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination.

[0383] At various places in this specification, substituents of compounds of the invention are disclosed in groups or ranges. The invention is expressly intended to include every individual subcombination of the members of such groups and ranges. For example, the term "C 1-6 "Alkyl" is specifically intended to disclose individually methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0384] At various positions in this specification, various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be connected to the rest of the molecule at any ring member allowed by valence. For example, the term "pyridyl (pyridinyl, pyridyl)" or "pyridine ring" can refer to pyridin-2-yl, pyridin-3-yl or pyridin-4-yl rings.

[0385] The term "n-membered" (where "n" is an integer) generally describes a moiety in which the number of ring atoms is the same as the number of ring atoms in the moiety "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 ring.

[0386] For compounds of the invention in which a variable occurs more than once, each variable can be a different portion independently selected from the group defining the variable. For example, where a structure is described as having two R groups simultaneously present on the same compound, the two R groups can represent different portions independently selected from the group defining R.

[0387] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0388] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

[0389] As used herein, the term "C i-j ” (where i and j are integers) specifies a range of carbon atoms in a chemical group using ij to define the range. For example, C 1-6 Alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0390] As used herein, the term "alkyl," when employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight 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, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0391] As used herein, the term "alkylene," employed alone or in combination with other terms, refers to a linked alkyl group.

[0392] As used herein, "alkenyl," when employed 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. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0393] As used herein, "alkynyl," when employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary 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.

[0394] As used herein, "halo" or "halogen" when employed alone or in combination with other terms includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0395] As used herein, the term "haloalkyl" when employed alone or in combination with other terms refers to an alkyl group having the most full valence of halogen atom substituents (which may be the same or different). In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0396] As used herein, the term "alkoxy" when employed alone or in combination with other terms refers to a group of the formula -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0397] As used herein, "haloalkoxy" when employed alone or in combination with other terms refers to a group of the formula -O-(haloalkyl). In some embodiments, the haloalkoxy group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF3.

[0398] As used herein, "amino" alone or in combination with other terms refers to NH2.

[0399] As used herein, the term "alkylamino" when employed alone or in combination with other terms refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0400] As used herein, the term "dialkylamino" when employed alone or in combination with other terms refers to a group of the formula -N(alkyl). Exemplary 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.

[0401] As used herein, the term "cycloalkyl," when used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon (including cyclized alkyl and alkenyl groups). Cycloalkyl groups may comprise monocyclic or polycyclic (e.g., having two, three, or four fused, bridged, or spirocyclic) ring systems. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl) fused to (i.e., having a common bond with) the cycloalkyl ring, such as cyclopentane, cyclohexene, cyclohexane, and the like, or pyridyl derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylene groups. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantane-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane, and the like). In some embodiments, the cycloalkyl group 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 group is monocyclic. In some embodiments, the cycloalkyl group is C3-7 Monocyclic cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthyl, octahydronaphthyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0402] As used herein, the term "cycloalkylalkyl" when taken alone or in combination with other terms refers to a radical of the formula cycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the cycloalkyl moiety has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl is a monocyclic or bicyclic ring. In some embodiments, the cycloalkyl moiety is a monocyclic ring. In some embodiments, the cycloalkyl moiety is C 3-7 Monocyclic cycloalkyl.

[0403] As used herein, the term "heterocycloalkyl," when employed alone or in combination with other terms, refers to a non-aromatic ring or ring system having the following characteristics: it 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 may comprise monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro) 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 in 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-tetrahydro-quinoline and the like. In cases where the heterocycloalkyl group contains a fused aromatic ring, the heterocycloalkyl group may be attached to the main structure via the aromatic or non-aromatic ring. Heterocycloalkyl groups may also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl] and the like). In some embodiments, heterocycloalkyl groups have 3 to 10 ring atoms, 4 to 10 ring atoms, or about 3 to 8 ring 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 in the heterocycloalkyl ring may be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidative linkages), or nitrogen atoms may be quaternized. In some embodiments, the heterocycloalkyl moiety is C 2-7 Monocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a tetrahydropyran ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.

[0404] As used herein, the term "heterocycloalkylalkyl" when taken alone or in combination with other terms refers to a radical of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. 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 is a monocyclic or bicyclic ring. In some embodiments, the heterocycloalkyl moiety is a monocyclic ring. In some embodiments, the heterocycloalkyl moiety is C 2-7 Monocyclic heterocycloalkyl.

[0405] As used herein, the term "aryl," when employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., 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.

[0406] As used herein, the term "arylalkyl," when employed alone or in combination with other terms, refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is a methylene group. In some embodiments, the aryl moiety is a phenyl group. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is a benzyl group.

[0407] As used herein, the term "heteroaryl" when employed 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, heteroaryl is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, or the like. Carbon atoms or heteroatoms in the heteroaryl ring may be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized linkage), or nitrogen atoms may be quaternized, provided that the aromatic nature of the ring is retained. 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 atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0408] As used herein, the term "heteroarylalkyl" when employed alone or in combination with other terms refers to a group of the formula heteroaryl-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 a methylene group. 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.

[0409] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers (e.g., enantiomers and diastereomers) are intended to be encompassed. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in optically active or racemic form. Methods for preparing optically active forms from optically inert starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of alkenes, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention can be separated as isomer mixtures or as individual isomer forms.

[0410] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of single bonds with adjacent double bonds, along with the concomitant migration of protons. Tautomeric forms include proton transfer tautomers that are isomeric protonation states with the same empirical formula and total charge. Example proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs; and cyclic forms in which protons can occupy two or more positions in a heterocyclic ring system, such as 1H- and 3H-imidazoles, 1H-1,2,4-triazoles, 2H-1,2,4-triazoles and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or sterically locked into one form due to appropriate substitution. Tautomeric forms may also include transmethyl tautomers, which result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a methyl group. Transmethyl tautomers may include, for example, 2-methyl-2H-pyrazolo[3,4-c]pyridine and 1-methyl-1H-pyrazolo[3,4-c]pyridine.

[0411] The compounds of the present invention also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium. In some embodiments, the compounds of the present invention contain at least one deuterium atom.

[0412] Unless otherwise indicated, the term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the drawn structure.

[0413] All compounds and pharmaceutically acceptable salts thereof may be obtained together with other substances (eg, water and solvents) (eg, in the form of hydrates and solvates) or may be isolated.

[0414] In some embodiments, the compounds of the present invention or their salts are substantially separated. "Substantially separated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, a composition rich in the compounds of the present invention. Substantial separation may include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or their salts. Methods for separating compounds and their salts are conventional methods in the industry.

[0415] As used herein, the phrase "pharmaceutically acceptable" 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 problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0416] 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 in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), alkaline or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds 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 an appropriate base or acid in water or an organic solvent, or in 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), the entire contents of each of which are incorporated herein by reference.

[0417] synthesis

[0418] 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 variety of possible synthetic routes.

[0419] The reaction to prepare the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature that can range from the solidification temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, one skilled in the art can select a solvent that is suitable for the specific reaction step.

[0420] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. One skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemical properties of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley & Sons Inc., New York (1999), the entire contents of which are incorporated herein by reference.

[0421] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectrometry), or by chromatography (eg, high performance liquid chromatography (HPLC) or thin layer chromatography).

[0422] The expressions "ambient temperature," "room temperature," and "RT" as used herein are understood in the art and generally refer to a temperature approximately the temperature of the chamber in which the reaction is carried out (eg, reaction temperature), for example, a temperature of about 20°C to about 30°C.

[0423] Compounds of formula I can be prepared according to a number of preparative routes known in the literature. Exemplary synthetic methods for preparing compounds of the present invention are provided in the reaction schemes below. Unless otherwise stated, all substituents are as defined herein.

[0424] Reaction Scheme 1

[0425]

[0426] Reaction Scheme 1 shows the synthesis of analogs following a general approach utilizing established chemistry. Substituted halogenated aromatic esters can be coupled to 5-membered heteroaromatic rings (step 1) via several different methods known to those skilled in the art. These methods include coupling aromatic tributylstannanes in the presence of a Pd catalyst (e.g., Pd(PPh3)2Cl2) in a polar solvent (e.g., DMF) at elevated temperatures, coupling boronic acids or boronic esters in the presence of a Pd / Cu catalyst (e.g., Pd(dppf)Cl2 and CuI) and a base (e.g., sodium carbonate or cesium fluoride) in a solvent (e.g., DMF), and coupling substituted imidazoles in the presence of a Pd catalyst (e.g., Pd2dba3), a ligand (e.g., tBuXPhos), and a base (e.g., K3PO4) in a non-polar solvent (e.g., toluene) at elevated temperatures. The resulting ester can be hydrolyzed by a base (such as sodium hydroxide) in the presence of water to give the carboxylic acid (step 2), which can then be coupled to an amine NH2 (L) n Q uses an amide coupling reagent (such as HATU) in the presence of a base (such as diisopropylethylamine) in a polar solvent (such as DMF) to convert the carboxylic acid into the desired amide analog (step 3). Alternatively, the amine NH2 (L) can be used to convert the carboxylic acid into the desired amide analog. n The substituted ester product of step 1 is converted directly to the desired amide analog by treatment of Q in the presence of trimethylaluminum in a nonpolar solvent such as toluene (step 4).

[0427] Reaction Scheme 2

[0428]

[0429] Reaction Scheme 2 shows the synthesis of substituted aromatic ester intermediates following a route utilizing established chemistry. Aromatic dichlorides, which are commercially available or can be prepared via routes known to those skilled in the art, can be converted to enol ethers by coupling with tributyl(1-ethoxyvinyl)stannane in the presence of a Pd catalyst (e.g., Pd(PPh3)Cl2) in a polar solvent (e.g., DMF) at elevated temperatures (Step 1). The five-membered heteroaromatic compound can be introduced using the coupling conditions described in Reaction Scheme 1, Step 1 (Step 2). The enol ether is treated with KMnO4, NaIO4, and water in a nonpolar solvent (e.g., dioxane) at room temperature to provide the substituted ester (Step 3), which can then be converted to the amide analog using the conditions described in Reaction Scheme 1, Steps 2 and 3 or Step 4.

[0430] Reaction Scheme 3

[0431]

[0432] Reaction Scheme 3 shows an alternative route to substituted aromatic esters that can be prepared from aromatic dichlorides by treatment with carbon monoxide in the presence of a Pd catalyst (e.g., Pd(dppf)Cl), an amine base (e.g., triethylamine), and an alcohol (e.g., methanol) in a polar solvent (e.g., DMF) at elevated temperature (Step 1). The resulting chloroester can then be coupled to a 5-membered heteroaromatic ring using the coupling conditions described in Reaction Scheme 1 - Step 1.

[0433] Reaction Scheme 4

[0434]

[0435] Reaction Scheme 4 shows 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 (e.g., KCO) in a polar solvent (e.g., DMF) at elevated temperature (Step 1). The amine can then be converted to the bromide by treatment with CuBr and isoamyl nitrite in a polar solvent (e.g., acetonitrile) at elevated temperature (Step 2). Reaction with vinylmagnesium bromide in an aprotic solvent (e.g., THF) at low temperature (Step 3) is followed by treatment with an amine in the presence of carbon monoxide, a Pd catalyst (e.g., Pd(dppf)Cl), an amine base (e.g., triethylamine) in a polar solvent (e.g., DMSO) at elevated temperature (Step 4) to provide the imidazole-substituted amide analog.

[0436] How to use

[0437] The compounds of the present invention can inhibit CD38 activity. For example, the compounds of the present invention can be used to inhibit the activity or function of the enzyme in cells or individuals or patients in need of CD38 inhibition by administering an inhibitory amount of the compounds of the present invention to the cells, individuals or patients. As used herein, the term "in a cell" includes both the inside of the cell membrane and the surface of the cell membrane.

[0438] The compounds of the present invention can act as CD38 inhibitors to increase NAD + Therefore, the present invention further relates to increasing NAD levels in a sample or patient. + A method for treating a patient with a substance containing NAD1 or a pharmaceutically acceptable salt thereof, wherein the increased NAD + Levels are relative to NAD prior to exposure or administration. + level.

[0439] The compounds of the present invention can be used to treat various diseases associated with abnormal expression or activity of CD38. For example, the compounds of the present invention can be used to treat cancer. In some embodiments, the cancer is characterized by abnormal expression or activity of CD38, such as increased expression or activity compared to normal cells. In some embodiments, cancers treatable according to the present invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper aerodigestive tract) cancer, urinary tract cancer, colon cancer, and others.

[0440] The compounds of the present invention can be used to treat tumors with exhausted T cells (for example, see 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 immune scores (for example, see 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).

[0441] In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies (such as leukemias and lymphomas). Example lymphomas include Hodgkin's lymphoma 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. Example leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0442] In some embodiments, the cancer that can be treated by administering the compounds of the present invention is lung cancer.

[0443] In some embodiments, the cancer treatable by administering the compounds of the invention is melanoma.

[0444] In some embodiments, the cancer that may be treated by administering the compounds of the present invention is colon cancer.

[0445] Other cancers that may be treated by administering the compounds of the invention include checkpoint therapy-treated cancers, checkpoint therapy-resistant cancers, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0446] Other cancers that can be treated by administering 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, stomach cancer, gastrointestinal tumors, glioma, head and neck cancer (upper aerodigestive tract 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, clear cell renal carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0447] In some embodiments, cancers that can be treated by administering the compounds of the present invention are multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive tract cancer), kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, and breast cancer.

[0448] Other cancers that may be treated by administering the compounds of the invention include checkpoint therapy-treated cancers, checkpoint therapy-resistant cancers, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0449] 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, rheumatoid arthritis, ataxia telangiectasia, sleep disorders, epilepsy, exercise intolerance, hypertension, hypoxic pulmonary vasoconstriction, Hansen's disease, tuberculosis, leishmaniasis, cardiomegaly, 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, sarcopenic obesity, metabolic syndrome, end-stage renal disease, dyslipidemia, hearing loss, liver disease, steatosis, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, 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.

[0450] The CD38 inhibitors of the present invention may also have therapeutic use in CD38-related disorders, particularly in disease areas where the disease is characterized by overexpression or increased activity of CD38, such as cardiology, virology, neurodegeneration, inflammation, and pain.

[0451] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a tissue sample removed from an organism (e.g., a mammal). In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that survives within an organism (e.g., a mammal).

[0452] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" CD38 or "contacting" cells with a compound of the invention includes administering a compound of the invention to an individual or patient (e.g., a human) having CD38, as well as, for example, introducing a compound of the invention into a sample containing cells or a purified preparation containing CD38.

[0453] As used herein, the terms "subject" or "patient" are used interchangeably and refer to mammals, and particularly humans. An individual or patient may be in need of treatment.

[0454] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

[0455] As used herein, the terms "treating" or "treatment" refer to: 1) inhibiting a disease in a subject experiencing or displaying conditions or symptoms of a disease (i.e., preventing further development of the condition or symptom); or 2) ameliorating a disease in a subject experiencing or displaying conditions or symptoms of a disease (i.e., reversing the condition or symptom).

[0456] As used herein, the term "preventing" or "prevention" refers to preventing a disease in an individual who may be susceptible to the disease but has not yet experienced or displayed the condition or symptoms of the disease. In some embodiments, the present invention relates to a method of preventing a 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.

[0457] Combination therapy

[0458] One or more other agents or treatment methods (e.g., chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressants, immunotherapy, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or kinase (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors) may be used in combination with the compounds of the present invention. The agents may be combined with the compounds of the present invention into a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0459] Suitable agents for treating cancer in combination with the compounds of the present invention include chemotherapeutic agents, targeted cancer therapies, immunotherapy, or radiation therapy. The compounds of the present invention can be combined with anti-hormonal agents to effectively treat breast cancer and other tumors. Suitable examples are anti-estrogen agents (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, anastrozole, and exemestane), adrenocortical steroids (e.g., prednisone), progestogens (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable anti-hormonal agents for treating prostate cancer and other cancers can also be combined with the compounds of the present invention. These agents include antiandrogens (including but not limited to 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 inhibit androgen production (e.g., abiraterone).

[0460] 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 of nodes in 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).

[0461] Angiogenesis inhibitors can be effectively combined with FGFR inhibitors for some tumors. These inhibitors include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include (but are not limited to) sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0462] Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide, and cytoxan. TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylene phosphoramide sulfide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0463] Other anticancer agents include antibody therapeutics directed against checkpoints or costimulatory molecules (e.g., CTLA-4, PD-1, PD-L1, or 4-1BB), or antibodies directed against cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Other anticancer agents include antibody therapeutics directed against surface molecules of hematological cancers, such as ofatumumab, rituximab, and alemtuzumab.

[0464] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in "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.

[0465] Pharmaceutical formulations and dosage forms

[0466] When used as a medicament, 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 in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be oral, topical (including ophthalmic administration and application to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, transdermal and transdermal), ocular or parenteral.

[0467] The present invention also includes pharmaceutical compositions that may contain one or more of the above-mentioned compounds of the present invention as active ingredients and one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted or encapsulated in such a carrier in the form of (for example) a capsule, a sachet, paper or other container by an excipient. When the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which is used as a vehicle, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, pills, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (containing, for example, up to 10% by weight of active compounds), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0468] The composition may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects or 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.

[0469] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered will generally be determined by a physician based on relevant circumstances including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0470] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 mg to about 500 mg of the active ingredient of the invention.

[0471] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form having a long-lasting effect advantage. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being an encapsulated form of the former. These two components can be separated by an enteric layer that resists decomposition in the stomach and allows the inner component to enter the duodenum intact or to be delayed in release. Such enteric layers or coatings can be made from a variety of materials, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0472] Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or injection administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0473] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may 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 aerosolized using an inert gas. The aerosolized solution can be inhaled directly from the aerosolizing device or the aerosolizing device can be connected to a mask curtain or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0474] The amount of the compound or composition administered to a patient will vary depending on the drug being administered, the purpose of the administration (e.g., prophylaxis or treatment), the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and overall condition, and the like.

[0475] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packaged for use as is or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration.

[0476] The therapeutic dose of the compounds of the present invention may vary depending on, for example, the specific use for which the treatment is being performed, the manner in which the compound is administered, the patient's health and physical condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition may vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in the form of an aqueous physiological buffer solution containing from about 0.1% w / v to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be extrapolated from a dose-response curve obtained from an in vitro or animal model test system.

[0477] The compounds of the present invention may also be formulated in combination with one or more other active ingredients, including any pharmaceutical agent such as an antiviral agent, an anticancer agent, a vaccine, an antibody, an immunopotentiator, an immunosuppressant, an anti-inflammatory agent, and the like.

[0478] Example

[0479] The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to obtain substantially the same results. The compounds of the examples are found to be CD38 inhibitors according to one or more of the assays provided herein.

[0480] equipment: Recorded at 300 or 400 MHz using a Bruker AVANCE 300MHz / 400MHz spectrometer 1 H NMR spectra. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. In the event of two adjacent peaks of equal or unequal height, these peaks were labeled as a multiplet or doublet. In the case of a doublet, coupling constants were assigned using this software. In any given instance, one or more protons may not be observed due to obscuration by water and / or solvent peaks. LCMS equipment and conditions were as follows:

[0481] 1. LC (basic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Kinetex 2.6 μm EVO C18 100A, 50 x 3.0 mm, 2.6 μm. Mobile phase: A: water / 5 mM NH₄HCO₃, B: acetonitrile. Flow rate: 1.2 mL / min, 40°C. Detection: 254 nm, 220 nm. Gradient stop time: 2.9 min. Timetable:

[0482] T(min) A(％) B(％) 0.01 90 10 2.10 5 95 2.70 5 95 2.90 90 10

[0483] 2. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Poroshell HPH-C18 50 x 3.0 mm, 2.7 μm. Mobile phase A: 0.04% ammonium hydroxide, mobile phase B: acetonitrile. Flow rate: 1.2 mL / min, 40°C. Detectors: 254 nm, 220 nm. Gradient stop time: 3.0 min, timetable:

[0484] T(min) A(％) B(％) 0.01 90 10 2.0 5 95 2.7 5 95 2.8 90 10

[0485] 3. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Ascentis Express C18, 50 x 3.0 mm, 2.7 μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min, 40°C. Detection: 254 nm, 220 nm. Gradient stop time: 2.9 min. Timetable:

[0486] T(min) A(％) B(％) 0.01 90 5 2.10 5 95 2.70 5 95 2.90 90 5

[0487] 4. LC (acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: Accucore C18 50 x 2.1 mm, 2.6 μm. Mobile phase A: water / 0.1% FA, mobile phase B: acetonitrile / 0.1% FA. Flow rate: 1.0 mL / min, 40°C. Detectors: 254 nm, 220 nm. Gradient stop time: 3.0 min, timetable:

[0488] T(min) A(％) B(％) 0.01 95 5 2.0 5 95 2.7 5 95 2.8 95 5

[0489] 1.S: LCMS-2020, quadrupole LC / MS, ion source: ES-API, TIC: 90-900 m / z, fragmentor voltage: 60, drying gas flow rate: 15 L / min, nebulizing gas flow rate: 1.5 L / min, drying gas temperature: 250°C, Vcap: 1100 V.

[0490] 2. Sample preparation: Dissolve the sample in ACN or methanol at a concentration of 1-10 mg / mL and filter through a 0.22 μm filter membrane. Injection volume: 1-10 μL.

[0491] definition: 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 (cuprous 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); DMS O (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 hexafluorophosphate 3-oxide); 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 (molarity); MeOH (methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters); mmol (millimolar); NaCl (sodium chloride); NaH (sodium hydride) ); n-BuOH (1-butanol); NH4Cl (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); preparative 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 isopropoxide); TsCl (toluenesulfonyl chloride); tR (retention time); TFA (trifluoroacetic acid); TLC (thin layer chromatography); v / v (volume / volume); XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl).

[0492] Synthesis of intermediates

[0493] Intermediate A1: 5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0494]

[0495] Step 1: Methyl 6-bromo-3H-benzimidazole-4-carboxylate

[0496] To a solution of 2,3-diamino-5-bromo-benzoic acid methyl ester (500 mg, 2.0 mmol, 1 equivalent) in 1M HCl (1.5 mL, 2.0 mmol, 1 equivalent) was added trimethoxymethane (5 mL, 2.0 mmol, 1 equivalent), 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 provide the title compound (506 mg, 2.0 mmol, 97% yield) as a gray solid. LCMS: [M+H] + 256.9.

[0497] Step 2: Methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate

[0498] At 0 ° C and N2 atmosphere, NaH (212 mg, 8.82 mmol, 1.5 eq) was slowly added to a solution of methyl 6-bromo-3H-benzimidazole-4-carboxylate (1.5 g, 5.89 mmol, 1 eq) in anhydrous THF (15 mL) and the mixture was stirred at 0 ° C for 1 h. SEMCl (824 mg, 7.06 mmol, 1.2 eq) was added and the mixture was further stirred for 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: EtOAc, 20: 1 to 2: 1) to provide the title compound (800 mg, 2.1 mmol, 35% yield). LCMS: [M+H] + 385.1.

[0499] Step 3: 6-Bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid

[0500] To a solution of methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate (200 mg, 0.52 mmol, 1 eq) in THF (3 mL) was added a solution of lithium hydroxide (65 mg, 1.6 mmol, 3 eq) in water (1 mL). The mixture was stirred at 25 ° C. overnight. The mixture was adjusted to pH 3-4 using 2N HCl and diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to provide the title compound (180 mg, 0.5 mmol, 93% yield) as a brown solid. LCMS: [M+H] + 373.1.

[0501] Intermediate A2: 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid

[0502]

[0503] Step 1: 2-Chloro-4-(1-ethoxyvinyl)-5H-pyrrolo[3,2-d]pyrimidine

[0504] Under nitrogen, a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (112 g, 597 mmol, 1 equivalent), tributyl(1-ethoxyvinyl)stannane (226 g, 627 mmol, 1.1 equivalents) and Pd(PPh 3 ) 2 Cl 2 (42 g, 60 mmol, 0.1 equivalents) in DMF (900 mL) was stirred at 70 ° C for 3 h. The resulting solution was cooled to room temperature and quenched with a saturated aqueous solution of KF. The solid was filtered out, and 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 eluted with EtOAc: petroleum ether (1: 5) to provide the title compound (105 g, 79% yield). LCMS: [M+H] + 224.1,226.1.

[0505] Step 2: 4-(1-ethoxyvinyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine

[0506] Under nitrogen, a solution of 2-chloro-4-(1-ethoxyvinyl)-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 applied to a silica gel column eluted with EtOAc: petroleum ether (1:1) to provide the title compound (54 g, 85% yield). LCMS: [M+H] + 256.1.

[0507] Step 3: Ethyl 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate

[0508] 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), KMnO4 (13.4 g, 84.61 mmol, 0.40 equiv) and NaIO4 (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 Na2SO4 and concentrated under reduced pressure to give the title compound (41.0 g, 76% yield) as a white solid. LCMS: [M+H] + 258.1.

[0509] Step 4: 2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid

[0510] 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 H2O (350 mL) and EtOH (350 mL) was stirred at room temperature for 2 h. The pH of the solution was adjusted to 5 using concentrated HCl. The solid was collected by filtration. The solid was further purified by slurrying in CH3CN and filtering to provide the title compound (30.0 g, 86% yield) as a white solid. [M+H] + 230.1.

[0511] Intermediate A3: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0512]

[0513] Step 1: Ethyl 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate

[0514] A solution of NaIO4 (20.2 g, 94.44 mmol, 4.0 equiv) in H2O (80 mL) was added to a solution of 2-chloro-4-(1-ethoxyvinyl)-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 KMnO4 (1.48 g, 9.37 mmol, 0.40 equiv) in H2O (20 mL), and the resulting mixture was stirred at 25 ° C for 1 h. The solid was filtered off. 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 provide the title compound (5 g, 94% yield) as a yellow solid. LCMS: [M+H] + 226.03.

[0515] Step 2: 2-Chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid

[0516] A mixture of ethyl 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (4.5 g, 19.94 mmol, 1.0 equiv), hydrated lithium hydroxide (1.68 g, 40.04 mmol, 2.0 equiv) in THF (30 mL) and H2O (10 mL) was stirred at 25°C for 2 h. The resulting mixture was concentrated to remove THF, and the pH was adjusted to 3 using 2M HCl. The solid was collected by filtration to provide the title compound (2.3 g, 58% yield) as a yellow solid. LCMS: [M+H] + 198.00.

[0517] Step 3: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0518] 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 intermediate 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 3×100 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by recrystallization from MeOH to provide the title compound (2.4 g, 58% yield) as a yellow solid. LCMS: [M+H] + 353.13.

[0519] Intermediate A4: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid

[0520]

[0521] Step 1: 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester

[0522] A solution of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (100g, 584.4mmol, 1 equivalent), K2CO3 (185.8g, 1.34mmol, 2.3 equivalents) and 1-(chloromethyl)-4-methoxy-benzene (111.7g, 713.0mmol, 1.2 equivalents) in DMF (1.10L) was stirred at 50 ° C for 4h. After completion, the reaction was quenched with H2O (1.5L) and extracted with ethyl acetate (3×1.2L). The organic layers were combined and washed with 3×300mL brine. The mixture was dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude product was purified by a silica gel column eluted with ethyl acetate / petroleum ether (1:3) to provide the title compound (170.0g, 99%) as a yellow oil. LCMS: [M+H] + 292.15

[0523] Step 2: 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxamide

[0524] 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 under vacuum, the crude product was slurried in H2O and then filtered and rinsed to provide the title compound as a white solid (149.0 g, 92.2%). LCMS: [M+H] + 277.10.

[0525] Step 3: 4-amino-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide

[0526] Under H2 atmosphere, a solution of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole-3-carboxamide (80 g, 289.8 mmol, 1 eq), Pd / C (20.0 g) in DCM (1.2 L) and EtOH (1.6 L) was stirred at room temperature for 2 h. The solid was filtered off. The resulting mixture was concentrated under vacuum to provide the title compound as a pink solid (79.2 g, % yield). LCMS: [M+H] + 247.15.

[0527] Step 4: 5-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

[0528] To a solution of 4-amino-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxamide (260 g, 1.06 mol, 1 equiv) in 1,4-dioxane (5.0 L) was slowly added thiophosgene (265.4 g, 2.32 mol, 2.2 equiv) at room temperature. The mixture was stirred at 95 ° C for 4 h. After concentration under vacuum, the crude product was slurried in petroleum ether / EtOAc (2: 1, 800 ml) and then filtered and rinsed to provide the title compound (257 g, 83%) as a yellow solid. LCMS [M+H] + :291.10.

[0529] Step 5: 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one

[0530] Under N2 atmosphere, a solution of 5-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (257 g, 886.2 mmol, 1 eq), imidazole (211 g, 3.1 mol, 3.5 eq), Pd2(dba)3·CHCl3 (55 g, 53.14 mmol, 0.06 eq) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (34 g, 80.1 mmol, 0.09 eq) in toluene (4500 mL) was stirred at 110°C for 2 h. After completion, the solid was collected by filtration and slurried in 600 mL of MeOH, and then filtered and rinsed to provide the title compound (200 g, 70%) as a brown solid.

[0531] Step 6: 7-Chloro-5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine

[0532] 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 eq), SOCl2 (500 mL, 6.89 mol, 35.26 eq) and DMF (20 mL) was stirred at 90 °C for 2.5 h. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 1000 mL of DCM and 200 mL of H2O. The pH of the solution was adjusted to 8.0 using a saturated aqueous solution of Na2CO3. The resulting solution was extracted with 3 x 500 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the title compound (58.3 g, 88%) as a yellow solid. LCMS: [M+H] + 341.20.

[0533] Step 7: 5-(1H-imidazol-1-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-d]pyrimidine-7-carbonitrile

[0534] Under N2 atmosphere, 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 eq), XantPhos (3.5 g, 6.04 mmol, 0.05 eq), zinc cyanide (14.9 g, 126.72 mmol, 1.05 eq), DMF (350 mL), and Pd2(allyl)2Cl2 (2.2 g, 6.06 mmol, 0.05 eq) was stirred at 80 °C for 2.0 h. The resulting solution was diluted with 500 mL of H2O. The solid was filtered off and the residue was applied to a silica gel column with DCM / MeOH (97:3). This afforded the title compound (16.0 g) as a brown solid, which was used further without additional purification.

[0535] Step 8: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylic acid

[0536] 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 eq) and HCl (37% w / w, 150 mL) was stirred at 70 ° C for 12 h. The resulting mixture was concentrated under vacuum and then diluted with 10 mL of H2O. The pH of the solution was adjusted to 5.0 using aqueous NaOH (2.0 M). The solid was filtered and slurried with CH3CN (25 ml) and filtered to provide the title compound (4.0 g, 36%) as a brown solid. LCMS: [M+H] +231.00.

[0537] Intermediate B1: (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine

[0538]

[0539] Step 1: (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol

[0540] A mixture of (1r,4r)-4-aminocyclohexan-1-ol (30.0 g, 260.5 mmol, 1.0 eq), benzyl bromide (133 g, 777.6 mmol, 3 eq) and K2CO3 (72.0 g, 520.9 mmol, 2 eq) 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 provide the title compound as a white solid (65 g, 85%). LCMS: [M+H] + 296.2.

[0541] Step 2: (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexane-1-amine

[0542] A mixture of (1r, 4r) -4- (dibenzylamino) cyclohexane-1-ol (59g, 199.7mmol, 1 equivalent), 1-bromo-2-methoxyethane (82.6g, 594.3mmol, 3 equivalents) and t-BuOK (33.6g, 299.2mmol, 1.5 equivalents) in DCM (1 L) was stirred at room temperature for 4h. The reaction was quenched with water and extracted with 3×500mL DCM. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with EtOAc: petroleum ether (5:95) to provide the title compound (48g, 68%) as a red oil. LCMS: [M+H] + 354.2.

[0543] Step 3: (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine

[0544] Under hydrogen, a mixture of (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexane-1-amine (60.0 g, 169.7 mmol, 1 eq) and Pd(OH)2 on carbon (10.0 g, 71.2 mmol, 0.42 eq) in EtOH (600 mL) was stirred at room temperature for 14 h. The solid was filtered off. The filtrate was concentrated under vacuum to provide the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H] + 174.1.

[0545] Intermediate B2: (1r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexane-1-amine

[0546]

[0547] Step 1: tert-Butyl 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)acetate

[0548] A solution of (1r, 4r) -4- (dibenzylamino) cyclohexane-1-ol (8.85 g, 30 mmol, 1 equivalent), tert-butyl 2-bromoacetate (11.69 g, 60 mmol, 2 equivalents) and t-BuOK (6.72 g, 60 mmol, 2 equivalents) in DCM (120 mL) was stirred at room temperature for 2 h. Tert-butyl 2-bromoacetate (11.69 g, 60 mmol, 2 equivalents) and t-BuOK (6.72 g, 60 mmol, 2 equivalents) were then added to the resulting solution. The mixture was stirred for another 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 eluted with petroleum ether / EtOAc (10: 1) to provide the title compound (5.6 g, 46%) as a white solid. LCMS: [M+H] + 410.30.

[0549] Step 2: 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol

[0550] At 0 ° C, LiAlH4 (1.14 g, 30 mmol, 3 eq) was added to a solution of tert-butyl 2-(((1r, 4r)-4-(dibenzylamino)cyclohexyl)oxy)acetate (4.10 g, 10 mmol, 1 eq) in THF (40 mL). The resulting solution was stirred for 2 h. After completion, the resulting solution was quenched by adding water (1.2 mL), 15% NaOH aqueous solution (1.2 mL) and water (3.6 mL) at 0 ° C. The resulting solution was diluted with 30 mL of THF and stirred at room temperature for 1 h. The solid was filtered off and the filtrate was concentrated to provide 2.5 g of the title compound as a yellow oil. LCMS: [M+H] + 340.25.

[0551] Step 3: 2-(2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-N,N-dimethylacetamide

[0552] To a solution of 2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethan-1-ol (3.40 g, 10 mmol, 1 eq) in DMF (50 mL) was added 60% NaH (1.20 g, 30 mmol, 3 eq). The resulting solution was stirred for 10 min and 2-bromo-N,N-dimethylacetamide (5 g, 30 mmol, 3 eq) was added. The resulting solution was stirred for another 12 h at room temperature. 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 provide the title compound (3.4 g, 75%) as a colorless oil. LCMS: [M+H] + 425.35.

[0553] Step 4: (1r,4r)-N,N-dibenzyl-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexane-1-amine

[0554] To a solution of 2-(2-(((1r,4r)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-N,N-dimethylacetamide (3.10 g, 7.3 mmol, 1 eq) in THF (35 mL) was added LiAlH4 (0.83 g, 22 mmol, 3.00 eq). The resulting solution was stirred at 0 ° C for 2 h. The reaction was quenched by adding water (1 mL), 15% NaOH aqueous solution (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 solid was filtered and the filtrate was concentrated under reduced pressure to provide 2.5 g of the title compound as a colorless oil. LCMS: [M+H] + 411.30.

[0555] Step 5: (1r,4r)-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexane-1-amine

[0556] Under hydrogen, a mixture of (1r,4r)-N,N-dibenzyl-4-(2-(2-(dimethylamino)ethoxy)ethoxy)cyclohexane-1-amine (2.50 g, 6.1 mmol, 1 equiv) and Pd(OH)2 / C (1.2 g) in EtOH (30 mL) 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 by reverse phase column eluting with MeCN / H2O to provide the title compound (0.4 g, 25%) as a colorless oil. LCMS: [M+H] + 231.25.

[0557] Intermediate B3: 1-(4-aminopiperidin-1-yl)-2-morpholinoethane-1-one hydrochloride

[0558]

[0559] Step 1: tert-Butyl (1-(2-morpholinoacetyl)piperidin-4-yl)carbamate

[0560] 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 by water (50 mL) and extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product was slurried in MeOH (10 mL) and then filtered and rinsed with MeOH to provide the title compound (1 g, 43%) as a white solid. LCMS: [M+H] + 328.20.

[0561] Step 2: 1-(4-aminopiperidin-1-yl)-2-morpholinoethan-1-one hydrochloride

[0562] 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 h. The reaction was concentrated under vacuum to provide 0.96 g of the title compound as a crude white solid. LCMS: [M+H] + 228.25.

[0563] Intermediate B4: 5-chloro-6-(2-morpholinoethoxy)pyridin-3-amine

[0564]

[0565] Step 1: 4-(2-((3-chloro-5-nitropyridin-2-yl)oxy)ethyl)morpholine.

[0566] To a solution of 2-morpholinoethane-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 H2O 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 eluted with EtOAc / petroleum ether (4 / 5) to provide the title compound (0.99 g, 35%) as a yellow oil. LCMS: [M+H] + 288.05.

[0567] Step 2: 5-Chloro-6-(2-morpholinoethoxy)pyridin-3-amine.

[0568] 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by a reverse phase column eluted with H2O / ACN (1 / 3) to provide the title compound (132 mg, 16%) as a brown oil. LCMS: [M+H] + 258.15.

[0569] Intermediate B5: 3-(2-methoxyethoxy)cyclohexane-1-amine hydrochloride

[0570]

[0571] Step 1: tert-Butyl (3-(2-methoxyethoxy)cyclohexyl)carbamate

[0572] 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 ice / water (15 mL). The resulting solution was extracted with DCM (80 × 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 eluted with EtOAc / petroleum ether (20: 80) to provide the title compound (1.12 g, 18%) as a yellow oil. LCMS: [M + H] + 274.00.

[0573] Step 2: 3-(2-methoxyethoxy)cyclohexane-1-amine hydrochloride

[0574] 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 provide the title compound (615 mg, 65.57%) as a yellow solid. LCMS: [M+H] + 174.00.

[0575] Intermediate B6: 6-(4-morpholinopiperidin-1-yl)pyridin-3-amine

[0576]

[0577] Step 1: 4-(1-(5-nitropyridin-2-yl)piperidin-4-yl)morpholine

[0578] 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 by water (50 mL). The solid was collected by filtration and washed with water to provide the title compound (1.15 g, 79%) as a yellow solid. LCMS: [M+H] + 293.15.

[0579] Step 2: 6-(4-morpholinopiperidin-1-yl)pyridin-3-amine

[0580] Under H2 atmosphere, 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 h. The solid was filtered and the filtrate was concentrated under vacuum to provide the title compound (985 mg, 99%) as a black solid. LCMS: [M+H] + 263.20.

[0581] Intermediate B7: 1-Methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

[0582]

[0583] Step 1: tert-Butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate

[0584] A solution of tert-butyl (4-amino-1-methylcyclohexyl)carbamate (630 mg, 2.76 mmol, 1 eq), KCO (952 mg, 6.89 mmol, 2.5 eq), and (bromomethyl)benzene (1081 mg, 6.32 mmol, 2.29 eq) in MeCN (5 mL) was stirred at 80 ° C for 2 h. The solid was filtered off. The filtrate was concentrated and applied to a silica gel column using petroleum ether:EtOAc (13:87) to provide the title compound (80 mg, 71%) as a white solid. LCMS: [M+H] + 409.30.

[0585] Step 2: N1,N1-dibenzyl-4-methylcyclohexane-1,4-diamine

[0586] A solution of tert-butyl (4-(dibenzylamino)-1-methylcyclohexyl)carbamate (3.3 g, 8.08 mmol, 1 equiv) in HCl / 1,4-dioxane (60 mL, 4 M) was stirred at room temperature for 1 h. The solid was collected by filtration to provide the title compound (2.1 g, 84%) as a white solid. LCMS: [M+H] + 309.20.

[0587] Step 3: N4,N4-dibenzyl-1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

[0588] A solution of N1,N1-dibenzyl-4-methylcyclohexane-1,4-diamine (1 g, 3.24 mmol, 1 eq), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 6.46 mmol, 2 eq) and K2CO3 (1.34 g, 9.73 mmol, 3 eq) in ACN (50 mL) was stirred at 80 ° C for 5 h. The solid was filtered off. The filtrate was concentrated and applied to a silica gel column using ethyl acetate / petroleum ether (20:80) to provide the title compound (850 mg, 67%) as a yellow oil. LCMS: [M+H] + 391.20.

[0589] Step 4: 1-Methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

[0590] Under hydrogen, a mixture of N4,N4-dibenzyl-1-methyl-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (820 mg, 2.1 mmol, 1 eq) and Pd(OH)2 / C (29.5 mg, 0.21 mmol, 0.1 eq) in EtOH (30 mL) was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to provide the title compound (365 mg, 82%) as a yellow oil. LCMS: [M+H] + 211.10.

[0591] Intermediate B8: 4-(3,3,3-trifluoropropoxy)cyclohexane-1-amine

[0592]

[0593] Step 1: 1-Nitro-4-(3,3,3-trifluoropropoxy)benzene

[0594] At 0 ° C, NaH (60% w / w) (170 mg, 7.09 mmol, 2 equivalents) was added to a solution of 3,3,3-trifluoropropane-1-ol (1348 mg, 11.82 mmol, 3.3 equivalents) in THF (20 mL). The mixture was stirred for 15 min. 1-Fluoro-4-nitrobenzene (500 mg, 3.54 mmol, 1 equivalent) was then added to the solution at 0 ° C. The resulting solution was stirred at room temperature for 1 h. After completion, the reaction was quenched by adding 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 using ethyl acetate / petroleum ether (16: 84) to provide the title compound (320 mg, 38%).

[0595] Step 2: 4-(3,3,3-trifluoropropoxy)cyclohexane-1-amine

[0596] In a pressure vessel 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 eq), isopropanol (20 mL) and Rh / Al2O3 (1.1 g, 10.52 mmol, 10 eq) was stirred at 80°C for 3 h. After completion, the solid was filtered off. The resulting mixture was concentrated under vacuum to provide the title compound (183 mg, 82%) as a yellow oil. LCMS: [M+H] + 212.30.

[0597] Intermediate B9: (1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexane-1-amine hydrochloride

[0598]

[0599] Step 1: tert-Butyl ((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)carbamate

[0600] A solution of tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate (2 g, 8.79 mmol, 1 eq), Ti(Oi-Pr)4 (2.5 g, 8.79 mmol, 1 eq), 2,2,2-trifluoroethylamine hydrochloride (1.43 g, 10.55 mmol, 1.2 eq) and HOAc (527 mg, 8.79 mmol, 1 eq) in EtOH (20 mL) was stirred at room temperature for 1 h. NaBH3CN (828 mg, 13.19 mmol, 1.5 eq) 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 Na2SO4 and concentrated under reduced pressure. The crude product was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to provide the title compound (1 g, 37% yield) as an off-white oil. LCMS: [M+H] + 311.10.

[0601] Step 2: (1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexane-1-amine

[0602] A solution of tert-butyl ((1r,4r)-4-(((2,2,2-trifluoroethyl)amino)methyl)cyclohexyl)carbamate (1 g, 3.22 mmol, 1 eq) in HCl(g) / 1,4-dioxane (20 mL, 548.53 mmol, 204.3 eq) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to provide the title compound (505 mg, 75%) as a white solid. LCMS: [M+H] + 211.05.

[0603] Intermediate B10: 4-(2,2,2-trifluoroethoxy)cyclohexane-1-amine

[0604]

[0605] Step 1: 1-Nitro-4-(2,2,2-trifluoroethoxy)benzene

[0606] At 0 ° C, NaH (60% w / w) (0.85 g, 0.035 mmol, 2.5 equivalents) was added portionwise to a solution of 2,2,2-trifluoroethane-1-ol (1.7 g, 0.017 mmol, 1.2 equivalents) in THF (20 mL). After stirring for 30 min, 1-fluoro-4-nitrobenzene (2 g, 14.17 mmol, 1 equivalent) was added to this solution at 0 ° C. The resulting solution was stirred at 25 ° C for 3 h. The reaction was then quenched by adding 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 using ethyl acetate / petroleum ether (1: 9) to provide the title compound (1.2 g, 38%) as a yellow solid.

[0607] Step 2: 4-(2,2,2-trifluoroethoxy)cyclohexane-1-amine

[0608] Under a hydrogen atmosphere, a solution of 1-nitro-4-(2,2,2-trifluoroethoxy)benzene (1.1 g, 4.97 mmol, 1 eq) and Rh / Al2O3 (0.39 g, 3.83 mmol, 0.77 eq) in i-PrOH (10 mL) was stirred at 80 ° C and 10 atm for 3 h. After completion, the solid was filtered off. The resulting mixture was concentrated under vacuum to provide the title compound (450 mg, 46%) as a colorless oil. LCMS: [M+H] + 198.10.

[0609] Intermediate B11: N1-(1,1-difluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride

[0610]

[0611] Step 1: tert-Butyl (4-((1,1-difluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate

[0612] A solution of tert-butyl (4-oxocyclohexyl)carbamate (938.2 mg, 4.4 mmol, 1.2 eq), 1,1-difluoro-2-methylpropane-2-amine (400 mg, 3.67 mmol, 1 eq) and Ti(Oi-Pr)4 (1250 mg, 4.4 mmol, 1.2 eq) in THF (20 mL) was stirred at room temperature for 1 h, and then NH 3- BH3 (136.4 mg, 4.4 mmol, 1.2 eq) was added and the solution was stirred at room temperature for 1.5 h. After completion, the reaction was quenched by adding 30 mL of MeOH and then concentrated. The crude product was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (3:1) to provide the title compound (350 mg, 31%) as a yellow solid. LCMS: [M+H] + 307.10.

[0613] Step 2: N1-(1,1-difluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride

[0614] 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 h. Upon completion, the resulting mixture was concentrated to provide the title compound (329 mg) as a white solid. LCMS: [M+H]+ 207.10.

[0615] Intermediate B12:N 1 -(1,1,1-trifluoro-2-methylpropan-2-yl)cyclohexane-1,4-diamine hydrochloride.

[0616]

[0617] Step 1: tert-Butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate

[0618] A solution of 1,1,1-trifluoro-2-methylpropane-2-amine (2.7 g, 21.241 mmol, 1.0 eq), tert-butyl (4-oxocyclohexyl)carbamate (5.44 g, 0.025 mmol, 1.2 eq) and Ti(Oi-Pr)4 (7.24 g, 0.025 mmol, 1.2 eq) in THF (100 mL) was stirred at 25 °C for 1 h, and then NH 3- BH3 (0.79 g, 0.025 mmol, 1.20 equiv) and the resulting solution was stirred at 25 ° C for 3 h. After completion, the reaction was quenched by adding 200 mL of MeOH. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:4) to provide the title compound (1.7 g, 25% yield) as a light yellow oil. LCMS: [M+H] + 325.

[0619] Step 2: N 1 -(1,1,1-trifluoro-2-methylpropane-2-yl)cyclohexane-1,4-diamine hydrochloride

[0620] A solution of tert-butyl (4-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)cyclohexyl)carbamate (300 mg, 0.93 mmol, 1 eq) and TFA (0.2 mL) in DCM (4 mL) was stirred at 25 °C for 1 h. After completion, the resulting mixture was concentrated under vacuum to afford the title compound (180 mg, 87% yield) as a colorless oil. LCMS: [M+H] + 225.15.

[0621] Example 1: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide

[0622]

[0623] Step 1: 6-Imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid

[0624] A mixture of methyl 6-bromo-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylate (700 mg, 1.82 mmol, 1 equivalent), imidazole (148 mg, 2.18 mmol, 1.2 equivalents), Cs2CO3 (888 mg, 2.72 mmol, 1.5 equivalents) and CuI (35 mg, 0.18 mmol, 0.1 equivalents) 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 light yellow solid. LCMS: [M+H] + 359.2.

[0625] 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

[0626] A mixture of 6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid (200 mg, 0.56 mmol, 1 eq), intermediate B1 (97 mg, 0.56 mmol, 1 eq), HATU (318 mg, 0.84 mmol, 1.5 eq) and DIPEA (108 mg, 0.84 mmol, 1.5 eq) 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.

[0627] Step 3: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-benzo[d]imidazole-7-carboxamide

[0628] 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 eq) in TFA (1 mL, 0.15 mmol, 1 eq) 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).

[0629] Example 2: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-7-carboxamide

[0630]

[0631] Step 1: 6-Bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide

[0632] At room temperature and N2 atmosphere, to a solution of intermediate A1 (160 mg, 0.43 mmol, 1 eq) in DMF (10 mL) was added [2-fluoro-6-(trifluoromethyl)phenyl]methanamine (92 mg, 0.47 mmol, 1.1 eq), DIPEA (84 mg, 0.65 mmol, 1.5 eq) and HATU (197 mg, 0.52 mmol, 1.2 eq) and the mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3), and the combined organic layers were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH, 3:1) to provide the title compound (180 mg, 0.33 mmol, 76% yield). LCMS: [M+H] + 548.1.

[0633] Step 2: N-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide

[0634] Following the procedure in Example 1-Step 1 using 6-bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide, the title compound was isolated as a solid (20 mg, 0.038 mmol, 11% yield). LCMS: [M+H] + 534.4.

[0635] Step 3: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-7-carboxamide

[0636] Following the procedure in Example 1-Step 3 using N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide, the title compound (8 mg, 0.019 mmol, 51% yield) was prepared as a solid. LCMS: [M+H] + 404.0, 1 HNMR(400MHz,DMSO-d6)δ13.3(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).

[0637] Example 3: N-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide

[0638]

[0639] Step 1: N-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide

[0640] To a solution of 6-bromo-N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide (prepared in Example 1-Step 1, 120 mg, 0.22 mmol, 1 eq) in DMF (5 mL) was added PdCl2(dppf)-CH2Cl2 (51 mg, 0.04 mmol, 0.2 eq), CuI (8 mg, 0.04 mmol, 0.2 eq) and K2CO3 (61 mg, 0.44 mmol, 2 eq). Tributyl(thiazol-5-yl)stannane (99 mg, 0.26 mmol, 1.2 eq) 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 x 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 afford the title compound (50 mg, 0.09 mmol, 41% yield). LCMS: [M+H] + 551.2.

[0641] Step 2: N-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3H-benzimidazole-4-carboxamide

[0642] Following the procedure in Example 1-Step 3 using N-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-thiazol-5-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxamide, the title compound (30 mg, 0.069 mmol, 76% yield) was prepared as a solid. LCMS: [M+H] + 421.0; 1 HNMR (400MHz, DMSO-d6) δ13.1(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).

[0643] Example 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide

[0644]

[0645] Step 1: 5-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide

[0646] To a solution of intermediate A1 (100 mg, 0.27 mmol, 1 eq), HOBt (44 mg, 0.32 mmol, 1.2 eq), EDC (50 mg, 0.32 mmol, 1.2 eq) in DMF (2 mL) was added intermediate B1 (51 mg, 0.30 mmol, 1.1 eq), 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 provide the title compound (50 mg, 0.095 mmol, 35% yield) as a brown oil. LCMS: [M+H] + 528.2.

[0647] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide

[0648] Following 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, the title compound was prepared as an oil (25 mg, 0.047 mmol, 50% yield). LCMS: [M+H] + 531.3.

[0649] Step 3: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide

[0650] Following the procedure in 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, the title compound was isolated as a yellow solid (10 mg, 0.025 mmol, 53% yield). LCMS: [M+H] + 401.1; 1HNMR(400MHz,DMSO-d6)δ13.10(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,1 H),3.90(s,1H),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).

[0651] Example 5: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxamide

[0652]

[0653] Step 1: Methyl 5-iodoindoline-7-carboxylate

[0654] To a stirred solution of 1-iodopyrrolidine-2,5-dione (21.2 g, 94.3 mmol, 3 equivalents) in ACN (100 mL) was added methyl indoline-7-carboxylate (5570 mg, 31.4 mmol, 1 equivalent) at -20 ° C. After quenching with saturated Na2S2O3 (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 light yellow solid. LCMS: [M + H] + 304.0.

[0655] Step 2: Methyl 5-iodo-1H-indole-7-carboxylate

[0656] To a solution of methyl 5-iodoindoline-7-carboxylate (910 mg, 3 mmol, 1 eq) in toluene (16 mL) was added MnO2 (1357 mg, 15.61 mmol, 5.2 eq). 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 provide the title compound (540 mg, 1.79 mmol, 60% yield) as a light yellow solid. LCMS: [M + H] + 301.9.

[0657] Step 3: 5-iodo-1H-indole-7-carboxylic acid

[0658] To a solution of methyl 5-iodo-1H-indole-7-carboxylate (540 mg, 1.79 mmol, 1 eq) in MeOH (3 mL) and THF (3 mL) was added NaOH (4.3 mL, 12.9 mmol, 7.2 eq) and the mixture was stirred at 25 ° C for 1 h. The reaction mixture was concentrated and acidified using 1M HCl solution. The resulting solid was collected by filtration to provide the title compound (467 mg, 1.63 mmol, 91% yield) as a white solid. LCMS: [M+H] + 285.9.

[0659] Step 4: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-iodo-1H-indole-7-carboxamide

[0660] A solution of 5-iodo-1H-indole-7-carboxylic acid (100 mg, 0.35 mmol, 1 eq), [2-fluoro-6-(trifluoromethyl)phenyl]methanamine (81 mg, 0.42 mmol, 1.2 eq), DIPEA (120 mg, 0.91 mmol, 2.6 eq) and HATU (160 mg, 0.42 mmol, 1.2 eq) 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc, 3: 1, v / v) to provide the title compound (150 mg, 0.33 mmol, 93% yield) as a gray solid. LCMS: [M+H] + 463.0.

[0661] Step 5: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxamide

[0662] A solution of N-(2-fluoro-6-(trifluoromethyl)benzyl)-5-iodo-1H-indole-7-carboxamide (150 mg, 0.32 mmol, 1 eq), imidazole (66 mg, 0.97 mmol, 3 eq), CuI (13 mg, 0.06 mmol, 0.2 eq) and K2CO3 (144 mg, 0.97 mmol, 3 eq) 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×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 provide the title compound (4.4 mg, 0.01 mmol, 3% yield) as a gray solid. LCMS: [M+H] + 403.0; 1 HNMR (400MHz, CD3OD) δ9.28 (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).

[0663] Example 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide

[0664]

[0665] Step 1: 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide

[0666] A solution of 5-iodo-1H-indole-7-carboxylic acid (prepared in Example 5-step 2, 844 mg, 2.94 mmol, 1 equivalent), intermediate B1 (611 mg, 3.53 mmol, 1.2 equivalents), DIPEA (1.33 mL, 7.64 mmol, 2.6 equivalents), HATU (1.34 g, 3.53 mmol, 1.2 equivalents) in DMF (15 mL) was stirred at room temperature for 6 h. 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 Na2SO4 and concentrated under reduced pressure. The residue was purified by column (petroleum ether: EtOAc, 3: 1, v / v) to provide the title compound (740 mg, 1.67 mmol, 56% yield) as a gray solid. LCMS: [M+H] + 443.2.

[0667] Step 2: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-indole-7-carboxamide

[0668] To a mixture of 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol, 1 eq), PdCl2(dppf)2 (18.4 mg, 0.02 mmol, 0.2 eq), CuI (4.3 mg, 0.02 mmol, 0.2 eq) and K2CO3 (31.2 mg, 0.23 mmol, 2 eq) in DMF (4 mL) was added tributyl(thiazol-5-yl)stannane (63 mg, 0.17 mmol, 1.5 eq). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 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) δ11.23 (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).

[0669] Example 7: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0670]

[0671] A solution of intermediate A2 (23 g, 100 mmol, 1.0 eq), intermediate B1 (19.1 g, 110 mmol, 1.1 eq), HATU (57.2 g, 150 mmol, 1.5 eq) and DIPEA (32.4 g, 250 mmol, 2.5 eq) 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC eluting with ACN / H2O to provide the title compound (24.8 g, 64 mmol, 64% yield) as a white solid. LCMS: [M+H] + 385.15; 1 H NMR(300MHz,DMSO-d6)δ12.08(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).

[0672] Example 8: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indazole-7-carboxamide

[0673]

[0674] Step 1: Methyl 2-amino-5-iodo-3-methylbenzoate

[0675] 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 eluted with EtOAc / petroleum ether (0-30%) to provide the title compound (1.2 g, 68.1% yield) as a yellow solid. LCMS: [M+H] + 292.10.

[0676] Step 2: Methyl 5-iodo-1H-indazole-7-carboxylate

[0677] 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 and the mixture was stirred at room temperature for 1 h. Continuous tert-butyl nitrite (744 mg, 7.22 mmol, 2.1 equiv) and KOAc (100 mg, 1.019 mmol, 0.30 equiv) were then added at 0 ° C and the mixture was stirred under reflux overnight. The mixture was concentrated and purified by flash chromatography on silica gel eluted with DCM / petroleum ether (0-30%) to provide the title compound (0.8 g, 77.1% yield) as a yellow solid. LCMS: [M+H] + 303.00.

[0678] Step 3: 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-7-carboxylic acid

[0679] To a solution of 5-iodo-1H-indazole-7-formic acid methyl ester (600 mg, 1.99 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (79.4 mg, 1.99 mmol, 1.0 equiv, 60%) and SEMCl (331.2 mg, 1.99 mmol, 1.0 equiv) 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 Na2SO4. After concentration, the crude product was purified by flash chromatography on silica gel eluted with EtOAc / petroleum ether (0-100%) to provide the title compound (300 mg, 36.1% yield) as a yellow oil. LCMS: [M+H] + 419.02.

[0680] Step 4: 5-iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide

[0681] A mixture of 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid (280 mg, 0.67 mmol, 1.0 equiv), Intermediate 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 eluted with MeOH / DCM (0-10%) to provide the title compound (160 mg, 41.7% yield) as a yellow oil. LCMS: [M+H] + 574.15.

[0682] Step 5: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide

[0683] Under nitrogen, 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), Cs2CO3 (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 dioxane (10 mL) was stirred at 120 ° C. overnight. The mixture was concentrated and purified by flash chromatography on silica gel eluted with MeOH / DCM (0-10%) to provide the title compound (40 mg, 31.9% yield) as a yellow oil. LCMS: [M+H] + 514.30.

[0684] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indazole-7-carboxamide

[0685] 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 using 7 M ammonia in methanol. The mixture was concentrated and purified by flash chromatography on silica gel eluted with MeOH / DCM (0-10%) to provide the title compound (15.3 mg, 57.4% yield) as an off-white solid. LCMS: [M+H] + 384.20. 1 H NMR (400MHz, DMSO-d6) δ13.26(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),3.56(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).

[0686] Example 9: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide

[0687]

[0688] Step 1: 1-(3-Bromo-4-nitrophenyl)-1H-imidazole

[0689] 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 3×30 mL EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3: 2) to provide the title compound (990 mg, 81% yield) as a yellow solid. LCMS: [M+H] + 268.00.

[0690] Step 2: 7-Bromo-5-(1H-imidazol-1-yl)-2-methyl-1H-indole

[0691] To a solution of 1-(3-bromo-4-nitrophenyl)-1H-imidazole (500 mg, 1.87 mmol, 1.0 equivalent) in THF (10 mL) was added 0.5 M prop-1-en-2-ylmagnesium bromide (15 mL, 7.46 mmol, 4.0 equivalents) under nitrogen and -40 ° C. The resulting solution was further stirred at -40 ° C for 1 h. The reaction was quenched with a saturated aqueous solution of 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 eluted with EtOAc / petroleum ether (1: 4) to provide the title compound (220 mg, 42.7%) as a light yellow solid. LCMS: [M+H] + 276.05.

[0692] Step 3: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide

[0693] A solution of 7-bromo-5-(1H-imidazol-1-yl)-2-methyl-1H-indole (200 mg, 0.72 mmol, 1.0 equiv), intermediate 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. under a CO (2 atm) atmosphere for 6 h. 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 under vacuum. The crude product (80 mg) was purified by preparative HPLC eluting with ACN / H2O to provide the title compound (20 mg, 7%) as a white solid. LCMS: [M+H] + 397.20. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.35(d,J=7.7Hz,1H),8.17(s,1H),7.75(d,J=1 0.7Hz,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).

[0694] Example 10: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide

[0695]

[0696] Step 1: 2-(1H-imidazol-1-yl)-5-nitropyridin-4-amine

[0697] A solution of 2-chloro-5-nitropyridin-4-amine (2.5 g, 14.4 mmol, 1 eq), 1H-imidazole (1.96 g, 28.81 mmol, 2 eq) and K2CO3 (3.98 g, 28.81 mmol, 2 eq) 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 provide the title compound (3 g) as a yellow crude solid. LCMS (ESI, m / z): 206.18 [M + H] + .

[0698] Step 2: 4-Bromo-2-(1H-imidazol-1-yl)-5-nitropyridine

[0699] To a solution of 2-(1H-imidazol-1-yl)-5-nitropyridin-4-amine (3 g, 14.62 mmol, 1 eq) and CuBr2 (4.9 g, 21.93 mmol, 1.5 eq) in CH3CN (10 mL) was added isoamyl nitrite (2.57 g, 21.93 mmol, 1.5 eq). 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 H2O / CH3CN to provide the title compound (1.6 g, 40.6%) as a yellow solid. LCMS (ESI, m / z): 269.06 [M + H] + .

[0700] Step 3: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine

[0701] 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) was added 1 M vinylmagnesium bromide (23.8 mL, 23.79 mmol, 4.0 equiv) under nitrogen and -78 ° C, and the resulting solution was stirred at -78 ° C for 2 h. The resulting solution was quenched with a saturated aqueous solution of NH4Cl. After concentration, the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (45:55) to provide the title compound (180 mg, 11.5%) as a yellow solid. LCMS (ESI, m / z): 263.10 [M + H] + .

[0702] Step 4: Methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate

[0703] Under carbon monoxide, 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)Cl2 (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 at 70° C. for 2 h. The resulting mixture was concentrated under vacuum and the crude product was chromatographed on a C18 reverse phase using CH3CN / H2O as the eluent to provide the title compound (50 mg, 30%) as a yellow solid. LCMS (ESI, m / z): 243.24 [M+H] + .

[0704] Step 5: 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid

[0705] 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 / H2O (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 under vacuum and the crude product was purified by C18 reverse phase elution with CH3CN / H2O to provide the title compound (10 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 229.21 [M+H] + .

[0706] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide

[0707] A solution of 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (15 mg, 0.066 mmol, 1 eq), Intermediate B1 (11.4 mg, 0.066 mmol, 1 eq), HATU (25 mg, 0.066 mmol, 1.0 eq) and DIPEA (17 mg, 0.13 mmol, 2.0 eq) in DMF (1 mL) was stirred at room temperature for 1 h. The resulting mixture was purified by C18 reverse phase elution with CH3CN / H2O to provide the title compound (5 mg, 20%) as a white solid. LCMS: 384.25 [M+H] + . 1HNMR (400MHz, CD3OD-d4) δ8.52(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).

[0708] Example 11: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide

[0709]

[0710] Step 1: Methyl 5-bromo-2-methyl-1H-indole-7-carboxylate

[0711] Under nitrogen, to a solution of methyl 5-bromo-2-nitrobenzoate (1g, 3.85mmol, 1 equivalent) in THF (15mL) was added prop-1-en-2-ylmagnesium bromide (2.23g, 15.38mmol, 4.0 equivalents), and the resulting solution was stirred at -50 ° C for 2h. The solution was quenched with NH4Cl saturated aqueous solution and extracted with 3×30mL 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 provide the title compound (160mg, 15.1% yield) in the form of a yellow solid. LCMS (ESI, m / z): 268.00[M+H] + .

[0712] Step 2: Methyl 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylate

[0713] Under nitrogen, to a solution of methyl 5-bromo-2-methyl-1H-indole-7-carboxylate (70 mg, 0.26 mmol, 1.0 equiv), Pd(dppf)Cl2 (76 mg, 0.10 mmol, 0.4 equiv), CuI (15 mg, 0.078 mmol, 0.3 equiv) and Na2CO3 (55 mg, 0.52 mmol, 2.0 equiv) in DMF (4 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (110 mg, 0.52 mmol, 2.0 equiv). The solution was stirred at 80 ° C for 2 h. The solution was quenched with H2O. The solid was filtered off. The resulting mixture was extracted with 3×10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase eluting with H2O / CH3CN to provide the title compound (30 mg, 42% yield) as a brown solid. LCMS (ESI, m / z): 273.32 [M+H] + .

[0714] Step 3: 2-Methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylic acid

[0715] To a solution of methyl 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylate (30 mg, 0.11 mmol, 1 eq) in THF / H2O (2 mL / 0.4 mL) was added NaOH (9 mg, 0.22 mmol, 2.0 eq). The resulting solution was stirred at room temperature for 6 h. The pH was adjusted to 4 using 2M HCl. The solid was filtered off to provide the title compound (22 mg, 77% yield) as a brown solid. LCMS (ESI, m / z): 259.30 [M+H] + .

[0716] Step 4: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxamide

[0717] A solution of 2-methyl-5-(thiazol-5-yl)-1H-indole-7-carboxylic acid (22 mg, 0.085 mmol, 1 eq), (2-fluoro-6-(trifluoromethyl)phenyl)methanamine (19.7 mg, 0.10 mmol, 2.0 eq), HATU (32.4 mg, 0.085 mmol, 1.0 eq) and DIPEA (22.0 mg, 0.17 mmol, 2.0 eq) in DMF (3 mL) was stirred at room temperature for 40 min. The resulting solution was quenched with H2O and extracted with 3×10 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to provide 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)δ11.10(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).

[0718] Example 12: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

[0719]

[0720] Step 1: 6-(1H-imidazol-1-yl)-3-nitropyridin-2-amine

[0721] A solution of 6-chloro-3-nitropyridin-2-amine (10.0 g, 57.8 mmol, 1.0 equiv), K2CO3 (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 provide the title compound (12 g) as a light brown crude solid. LCMS (ESI, m / z): 206.18 [M+H] + .

[0722] Step 2: 2-Bromo-6-(1H-imidazol-1-yl)-3-nitropyridine

[0723] To a solution of 6-(1H-imidazol-1-yl)-3-nitropyridin-2-amine (8 g, 39.0 mmol, 1.0 equiv) and CuBr2 (13.1 g, 58.5 mmol, 1.5 equiv) in CH3CN (100 mL) was added isoamyl 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 by C18 reverse phase eluting with H2O / CH3CN to provide the title compound (2.4 g, 13.9%) as a light yellow solid. LCMS (ESI, m / z): 269.06 [M + H] + .

[0724] Step 3: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine

[0725] To a solution of 2-bromo-6-(1H-imidazol-1-yl)-3-nitropyridine (1.2 g, 4.46 mmol, 1 equivalent) in THF (50 mL) was added bromo(vinyl)magnesium (15.6 mL, 15.60 mmol, 3.5 equivalents) under nitrogen and -60 ° C, and the resulting solution was stirred at this temperature for 3 h. The resulting solution was quenched with a saturated aqueous solution of NH4Cl and extracted with 3×100 mL of EtOAc. The organic layers were combined and washed with 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase elution with H2O / CH3CN to provide the title compound (80 mg, 6%) as a brown solid. LCMS (ESI, m / z): 263.10 [M+H] + .

[0726] Step 4: Methyl 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate

[0727] Under carbon monoxide, 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)Cl2 (46 mg, 0.063 mmol, 0.10 equiv) in CH3OH (10 mL) was stirred at 70°C for 12 h. The resulting mixture was concentrated under vacuum and the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound (60 mg, 38%) as a brown solid. LCMS (ESI, m / z): 243.24 [M+H] + .

[0728] Step 5: 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid

[0729] 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 / H2O (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 min. The resulting solution was diluted with 3 mL of water. The pH value of the solution was adjusted to 4 using HCl (1 M). The solid was collected by filtration to provide the title compound (34 mg, 60%) as a light yellow solid. LCMS (ESI, m / z): 229.21 [M+H] + .

[0730] Step 6: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

[0731] 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), intermediate 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 EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluted with H2O / CH3CN to provide the title compound (13 mg, 23%) as a white solid. LCMS (ESI, m / z): 384.20 [M+H] + . 1 H NMR (300MHz, methanol-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=3.2,1.2Hz, 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).

[0732] Example 13: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide

[0733]

[0734] Step 1: Methyl 2-amino-5-iodo-3-nitrobenzoate

[0735] 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 h. The reaction was then quenched with a saturated aqueous solution of sodium sulfite. The pH of the solution was adjusted to 8 using a saturated aqueous solution of sodium bicarbonate. The solid was collected by filtration to provide the title compound (6 g, 91%) as a yellow solid. LCMS (ESI, m / z): 323 [M+H] + .

[0736] Step 2: Methyl 2,3-diamino-5-iodobenzoate

[0737] 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 H2O (50 mL) in EtOH (200 mL) was stirred at 80 ° C for 25 min. Insoluble solids were filtered off. The resulting mixture was concentrated, and the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound (4.2 g, 77%) as a red solid. LCMS (ESI, m / z): 293.0 [M + H] + .

[0738] Step 3: Methyl 5-iodo-2-methyl-1H-benzo[d]imidazole-7-carboxylate

[0739] 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 H2SO4 (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 applied to a silica gel column eluted with EtOAc / petroleum ether. The crude product was further purified by C18 reverse phase chromatography eluted with H2O / CH3CN to provide the title compound (2.23 g, 49%) as a white solid. LCMS (ESI, m / z): 317.0 [M+H] +.

[0740] Step 4: Methyl 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylate

[0741] 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)Cl2 (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 off. The residue was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to provide the title compound (128 mg, 49%) as a white solid. LCMS (ESI, m / z): 274.2 [M+H] + .

[0742] Step 5: 2-Methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylic acid

[0743] A solution of methyl 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylate (128 mg, 0.47 mmol, 1.0 eq), NaOH (94 mg, 2.34 mmol, 5.0 eq) and H2O (1.5 mL) in MeOH (4.5 mL) was stirred at room temperature for 3 h. The pH of the solution was adjusted to 6 using 1 M aqueous HCl. After concentration, the crude product was applied to a silica gel column using dichloromethane / methanol to provide the title compound (110 mg, 90.6%) as a white solid. LCMS (ESI, m / z): 260.1 [M+H] + .

[0744] Step 6: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide

[0745] A solution of 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylic acid (105 mg, 0.41 mmol, 1.0 equiv), intermediate 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 adding 0.1 mL of ethanolamine. The crude product was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to provide 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).

[0746] Example 14: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide

[0747]

[0748] Step 1: 2-Chloro-6-(1-ethoxyvinyl)-7H-purine

[0749] Under nitrogen, a solution of 2,6-dichloro-7H-purine (3.78 g, 20.00 mmol, 1.0 equiv), tributyl(1-ethoxyvinyl)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 a saturated aqueous solution of KF. The insoluble solid was filtered out. 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 eluted with (DCM: MeOH, 10: 1) to provide the title compound (3 g, 67% yield). LCMS: [M+H] + 225.1.

[0750] Step 2: Ethyl 2-chloro-7H-purine-6-carboxylate

[0751] A solution of 2-chloro-6-(1-ethoxyvinyl)-7H-purine (2.24 g, 9.97 mmol, 1.0 equiv), KMnO4 (315 mg, 1.99 mmol, 0.20 equiv), NaIO4 (10.7 g, 49.86 mmol, 5.0 equiv) and H2O (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 Na2SO4 and concentrated under reduced pressure to give the crude title compound (1 g, 44% yield). LCMS: [M+H] + 227.1.

[0752] Step 3: Ethyl 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate

[0753] 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 eluted with petroleum ether / EtOAc (1 / 1) to provide the title compound (400 mg, 56% yield) as a white solid. LCMS: [M+H] + 357.1.

[0754] Step 4: Ethyl 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylate

[0755] 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), Pd2(dba)3 (77 mg, 0.084 mmol, 0.15 equiv), tBuXphos (60 mg, 0.14 mmol, 0.25 equiv) and K3PO4 (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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM:MeOH, 10: 1) to provide the title compound (210 mg, 96% yield) as a white solid. LCMS: [M+H] + 389.20.

[0756] Step 5: 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylic acid

[0757] 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 of the solution was adjusted to 5 using 1 M HCl. The resulting solution was extracted with n-BuOH. The organic layer was concentrated to provide the crude title compound (160 mg, 82% yield) as a white solid. LCMS: [M+H] + 361.15.

[0758] Step 6: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide

[0759] 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), Intermediate Bl (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.

[0760] Step 7: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7H-purine-6-carboxamide

[0761] 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 afford the title compound (47 mg, 52% yield) as a white solid. LCMS: [M+H] + 386.25; 1 HNMR(300MHz,DMSO-d6)δ13.56(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=5.9,3.7 Hz,2H),3.28-3.23(m,4H),2.07(d,J=12.3Hz,2H),1.89(d,J=12.8Hz,2H),1.66(d,J =12.6Hz, 1H), 1.58 (d, J = 12.3Hz, 1H), 1.32 (d, J = 12.2Hz, 1H), 1.24 (d, J = 11.9Hz, 1H).

[0762] Example 15: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide

[0763]

[0764] Step 1: 6-(1H-imidazol-1-yl)-2-methyl-3-nitropyridine

[0765] 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 3×100 mL EtOAc. The organic layers were combined and washed with 100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue was then applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound (1.03 g, 37%). LCMS: 205.19 [M+H] + .

[0766] Step 2: 6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine

[0767] 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 h and the solid was filtered off. The resulting solution was concentrated under vacuum to provide the title compound (810 mg, 92%) as a brown solid. LCMS (ESI, m / z): 175.21 [M+H] + .

[0768] Step 3: 4-Bromo-6-(1H-imidazol-1-yl)-2-methylpyridin-3-amine

[0769] 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 using 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 under vacuum. The residue was purified by C18 reverse phase chromatography eluted with H2O / ACN to provide the title compound (460 mg, 61%) as a yellow solid. LCMS (ESI, m / z): 253.10 [M+H] + .

[0770] Step 4: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine

[0771] 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 CHCl 3 (20 mL) was stirred at 0° C. in a water / ice bath for 2 h. Isoamyl 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 under vacuum and the residue was applied to a silica gel column eluted with EtOAc to provide the title compound (350 mg 73%) as a brown solid. LCMS (ESI, m / z): 264.09 [M+H] + .

[0772] Step 5: Methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0773] Under a carbon monoxide atmosphere, 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)Cl2 (61 mg, 0.084 mmol, 0.10 equiv) in MeOH (10 mL) was stirred at 70°C for 12 h. The resulting solution was concentrated under vacuum and applied to a silica gel column eluted with EtOAc to provide the title compound (73 mg, 36%) as a light yellow solid. LCMS (ESI, m / z): 244.23 [M+H] + .

[0774] Step 6: 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid

[0775] 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 min and then concentrated under vacuum and diluted with 1 mL of water. The pH was adjusted to 4 using 1 M HCl, and the solid was then collected by filtration to provide the title compound (40 mg, 58%) as a light yellow solid. LCMS (ESI, m / z): 230.20 [M+H] + .

[0776] Step 7: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide

[0777] 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 min. 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 under vacuum, and the residue was then purified by C18 reverse phase eluting with H 2 O / CH 3 CN to provide 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).

[0778] Example 16: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0779]

[0780] Step 1: 2-(1H-imidazol-1-yl)-4-methyl-5-nitropyridine

[0781] A solution of 2-chloro-4-methyl-5-nitropyridine (5.0 g, 28.98 mmol, 1.0 equiv), K2CO3 (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 EtOAc. The organic layers were combined, dried over sodium sulfate, washed with 100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc to provide the title compound (1.3 g, 22%) as a brown solid. LCMS (ESI, m / z): 205.19 [M + H] + .

[0782] Step 2: 6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine

[0783] Under a hydrogen atmosphere, 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 h. The solid was filtered off and the resulting mixture was then concentrated under vacuum to provide the title compound (1.17 g) as a crude brown solid. LCMS (ESI, m / z): 175.21 [M+H] + .

[0784] Step 3: 2-Bromo-6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine

[0785] 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 by NaOH (15% in water). The resulting solution was extracted with 3×30 mL EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase elution with H2O / ACN to provide the title compound (360 mg, 45%) as a light yellow solid. LCMS (ESI, m / z): 253.10 [M+H] + .

[0786] Step 4: 7-Bromo-5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine

[0787] A solution of 2-bromo-6-(1H-imidazol-1-yl)-4-methylpyridin-3-amine (360 mg, 1.42 mmol, 1.0 eq) and Ac2O (728 mg, 7.13 mmol, 5.0 eq) in CHCl3 (15 mL) was stirred at 0 ° C for 2 h. KOAc (42 mg, 0.43 mmol, 0.30 eq) and isoamyl nitrite (418.0 mg, 3.57 mmol, 2.5 eq) 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 under vacuum and the residue was then applied to a silica gel column eluted with EtOAc to provide the title compound (340 mg, 91%) as a brown solid. LCMS (ESI, m / z): 264.09 [M + H] + .

[0788] Step 5: Methyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[3.4-c]pyridine-7-carboxylate

[0789] Under a carbon monoxide atmosphere, 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)Cl2 (64 mg, 0.087 mmol, 0.10 equiv) in MeOH (10 mL) was stirred at 70°C for 12 h. The resulting mixture was concentrated under vacuum, and the crude mixture was applied to a silica gel column eluted with EtOAc to provide the title compound (100 mg, 47%) as a light yellow solid. LCMS (ESI, m / z): 244.23 [M+H] + .

[0790] Step 6: 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid

[0791] 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 / H2O (4.0 mL / 0.8 mL) was added NaOH (49 mg, 1.23 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 30 min. The resulting solution was diluted with 3 mL of water. The pH was adjusted to 4 using 1 M HCl, and the solid was collected by filtration to provide the title compound (64 mg, 68%) as a yellow solid. LCMS (ESI, m / z): 230.20 [M+H] + .

[0792] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0793] 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 intermediate 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 EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase elution with H2O / ACN to provide 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).

[0794] Example 17: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide

[0795]

[0796] Step 1: 5-Nitro-2-(thiazol-5-yl)isonicotinic acid.

[0797] 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)Cl2 (362 mg, 0.50 mmol, 0.10 equiv), CuI (190 mg, 1.0 mmol, 0.20 equiv) and K2CO3 (1.4 g, 9.91 mmol, 2.0 equiv) in DMF (20 mL) was stirred at 80°C for 5 h. After the reaction was complete and the reaction mixture was cooled to room temperature, the solid was collected by filtration to provide the title compound (700 mg, 56%) as a gray solid. LCMS (ESI, m / z): 252.22 [M+H] + .

[0798] Step 2: Methyl 5-nitro-2-(thiazol-5-yl)isonicotinate

[0799] A solution of 5-nitro-2-(thiazol-5-yl)isonicotinic acid and SOCl2 (10 mL) in CH3OH (30 mL) was stirred at 70°C for 12 h, the resulting solution was concentrated under vacuum, and the residue was applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound (343 mg, 68%) as a light yellow solid. LCMS (ESI, m / z): 266.24 [M+H] + .

[0800] Step 3: 5-amino-2-(thiazol-5-yl)isonicotinate

[0801] Under a hydrogen atmosphere, 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 CH3OH (10 mL) was stirred at room temperature for 10 h. The solid was filtered and the resulting solution was concentrated under vacuum to provide the title compound (300 mg, 94%) as a light brown solid. LCMS (ESI, m / z): 236.26 [M+H] + .

[0802] Step 4: 3-amino-2-bromo-6-(thiazol-5-yl)isonicotinate

[0803] A solution of 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 by NaOH (15% in water). The resulting mixture was extracted with 3×20 mL EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 reverse phase elution using H2O / ACN to provide the title compound (80 mg, 20%) as a light yellow solid. LCMS (ESI, m / z): 314.16 [M+H] + .

[0804] Step 5: Methyl 3-amino-2-methyl-6-(thiazol-5-yl)isonicotinate

[0805] 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 H0 (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 provide the title compound (56 mg, 82%) as a light brown solid. LCMS (ESI, m / z): 250.29 [M+H] + .

[0806] Step 6: Methyl 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylate

[0807] 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 CHCl 3 (5.0 mL) was stirred at 0 ° C for 1.5 h, and then isoamyl 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 another 2 h. The resulting solution was concentrated under vacuum, and the residue was applied to a silica gel column using EtOAc / petroleum ether to provide the title compound (60 mg) as a light yellow solid. The crude solid was used further without additional purification. LCMS (ESI, m / z): 261.27 [M + H] + .

[0808] Step 7: 5-(Thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid

[0809] 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 CH3OH / H2O (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 min, and then diluted with 2 mL of water. The pH of the resulting solution was adjusted to 4 using 1 M HCl, and the solid was collected by filtration to provide the title compound (25 mg, 44%) as a light yellow solid. LCMS (ESI, m / z): 247.24 [M+H] + .

[0810] Step 8: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide

[0811] A solution of 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (20 mg, 0.08 mmol, 1.0 equiv), intermediate 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 by C18 reverse phase elution with H2O / ACN to provide 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) δ9.11(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).

[0812] Example 18: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide

[0813]

[0814] Step 1: 2-Chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine

[0815] 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-ethoxyvinyl)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 a saturated aqueous solution of KF. The insoluble solid was filtered out. The resulting solution was extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with (DCM:MeOH, 10:1) to provide the title compound (3.5 g, 73% yield). LCMS: [M+H] + 241.1.

[0816] Step 2: Ethyl 2-chlorothieno[3,2-d]pyrimidine-4-carboxylate

[0817] A solution of 2-chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine (2.40 g, 9.97 mmol, 1.0 equiv), KMnO4 (630.3 mg, 3.99 mmol, 0.40 equiv) and NaIO4 (10.66 g, 49.85 mmol, 5.0 equiv) in H2O (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 Na2SO4 and concentrated under reduced pressure. The crude product was applied to a silica gel column eluted with EtOAc: petroleum ether (2:3) to provide the title compound (500 mg, 21% yield). LCMS: [M+H] + 243.1.

[0818] Step 3: Ethyl 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylate

[0819] 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), Pd2(dba)3 (136 mg, 0.15 mmol, 0.15 equiv), tBuXphos (85 mg, 0.20 mmol, 0.20 equiv), K3PO4 (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 Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with (DCM:MeOH, 10: 1) to provide the title compound (220 mg, 81% yield) as a white solid. LCMS: [M+H] + 275.1.

[0820] Step 4: 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylic acid

[0821] A mixture of ethyl 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylate (220 mg, 0.80 mmol, 1.0 equiv), NaOH (96 mg, 2.41 mmol, 3.0 equiv) in H2O (4 mL) and MeOH (4 mL) was stirred at room temperature for 2 h. The pH of the solution was adjusted to 5 using 1 M HCl. The resulting solution was extracted with 10 mL of n-BuOH. The organic layer was concentrated to provide the crude title compound (200 mg) as a white solid. [M+H] + 247.1.

[0822] Step 5: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-d]pyrimidine-4-carboxamide

[0823] A solution of 2-(1H-imidazol-1-yl)thieno[3,2-d]pyrimidine-4-carboxylic acid (123 mg, 0.50 mmol, 1.0 equiv), intermediate 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 under vacuum. The crude product was purified by preparative HPLC eluting with ACN / H2O to provide the title compound (43.1 mg, 21% yield) as a white solid. LCMS: [M+H] + 402.05; 1 HNMR(300MHz,DMSO-d6)δ9.21(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).

[0824] Example 19: 2-(Aminomethyl)-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide

[0825]

[0826] Step 1: 1-(3-Bromo-4-nitrophenyl)-1H-imidazole

[0827] 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 provide the title compound (12.9 g, 96% yield) as a light yellow solid. LCMS: [M+H] + 268.00.

[0828] Step 2: 2-Bromo-4-(1H-imidazol-1-yl)aniline

[0829] A mixture of 1-(3-bromo-4-nitrophenyl)-1H-imidazole (1.60 g, 5.97 mmol, 1.0 equiv), NH2NH2.H2O (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 eluted with EtOAc / petroleum ether (4 / 1) to provide the title compound (1.0 g, 70% yield) as a white solid. LCMS: [M+H] + 237.99.

[0830] Step 3: 2-Bromo-4-(1H-imidazol-1-yl)-6-iodoaniline

[0831] 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 EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with EtOAc / petroleum ether (1 / 1) to provide the title compound (14.0 g, 83% yield) as a yellow oil. LCMS: [M+H] + 363.89.

[0832] Step 4: tert-Butyl (3-(2-amino-3-bromo-5-(1H-imidazol-1-yl)phenyl)prop-2-yn-1-yl)carbamate

[0833] Under nitrogen, a mixture of 2-bromo-4-(1H-imidazol-1-yl)-6-iodoaniline (7.28 g, 20.00 mmol, 1.0 equivalent), tert-butyl propan-2-yn-1-ylcarbamate (3.11 g, 20.04 mmol, 1.0 equivalent), Pd(PPh ) Cl (1.40 g, 1.99 mmol, 0.10 equivalent), CuI (0.38 g, 2.00 mmol, 0.10 equivalent) 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 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 afford the title compound (4.5 g, 58% yield) as a yellow oil. LCMS: [M+H] + 391.07.

[0834] Step 5: tert-Butyl ((7-bromo-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate

[0835] 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 NaAuCl4.2H2O (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 eluted with EtOAc / petroleum ether (1 / 1) to provide the title compound (700 mg, 38% yield) as a yellow solid. LCMS: [M+H] + 391.07.

[0836] Step 6: tert-Butyl ((7-cyano-5-(1H-imidazol-1-yl)-1H-indol-2-yl)methyl)carbamate

[0837] Under nitrogen, 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) was stirred at 90 ° C for 2 h. The reaction was quenched with water and extracted with 3×50 mL EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with EtOAc / petroleum ether (1 / 1) to provide the title compound (360 mg, 75%) as a yellow solid. LCMS: [M+H] + 338.15.

[0838] Step 7: 2-((tert-Butoxycarbonylamino)methyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxylic acid

[0839] 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 H2O (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 using 2M HCl and extracted with 3×50 mL EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to provide the title compound (100 mg, 28%) as a yellow solid. LCMS: [M+H] + 357.15.

[0840] Step 8: tert-Butyl ((5-(1H-imidazol-1-yl)-7-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate

[0841] 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 Intermediate 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 H2O / CH3CN to provide the title compound (120 mg, 84%) as a white solid. LCMS: [M+H] + 512.28.

[0842] Step 9: 2-(Aminomethyl)-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide

[0843] 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 H2O / CH3CN to provide the title compound (26.5 mg, 28%) as a white solid. LCMS: [M+H] + 412.10. 1 H-NMR (400MHz, methanol-d4) δ8.12(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),4.04-3.93(m,1H),3.70-3.64(m,2H),3.59-3.52(m,2H),3.39( s,3H),3.44-3.33(m,1H),2.17(d,J=11.6Hz,2H),2.09(d,J=12.4Hz,2H),1.54 -1.45(m,4H).

[0844] Example 20: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide

[0845]

[0846] Step 1: 2-Chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine

[0847] Under nitrogen, a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (10.0 g, 48.77 mmol, 1.0 equivalent), tributyl(1-ethoxyvinyl)stannane (21.1 g, 58.52 mmol, 1.2 equivalents) and Pd(PPh3)2Cl2 (3.42 g, 4.88 mmol, 0.1 equivalents) in DMF (150 mL) was stirred at 80 ° C for 1 h. The solid was filtered out. The reaction was quenched with water, and the resulting solution was extracted with 2 × 100 mL EtOAc and the organic layers were combined and concentrated under vacuum. The resulting solid was washed with 2 × 10 mL EtOH to provide the title compound (2.5 g, 21% yield) as a white solid. LCMS: [M+H]+241.01.

[0848] Step 2: 4-(1-ethoxyvinyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine

[0849] A solution of 2-chloro-4-(1-ethoxyvinyl)thieno[3,2-d]pyrimidine (2.40 g, 9.97 mmol, 1.0 equiv), 5-(tributyltinyl)-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 EtOAc, and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1:3) to provide the title compound (900 mg, 31% yield) as a white solid. LCMS: [M+H]+290.03.

[0850] Step 3: Ethyl 2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxylate

[0851] A solution of 4-(1-ethoxyvinyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine (1.10 g, 3.80 mmol, 1.0 equiv), KMnO4 (0.24 g, 1.52 mmol, 0.4 equiv), NaIO4 (4.07 g, 19.01 mmol, 5 equiv) in H2O (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 EtOAc, and the organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The resulting solid was washed with 2 × 10 mL EtOH to provide the title compound (400 mg, 36.1% yield) as a white solid. LCMS: [M+H]+292.01.

[0852] Step 4: N-(2-Fluoro-6-(trifluoromethyl)benzyl)-2-(thiazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide

[0853] 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), 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 EtOAc, and the organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC eluting with ACN / H2O to provide the title compound (74 mg, 33% yield) as a white solid. LCMS: [M+H] + 439.10. 1 H NMR(300MHz,DMSO-d6)δ9.41(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).

[0854] Example 21: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0855]

[0856] Step 1: 5-(4-methyl-5-nitropyridin-2-yl)thiazole

[0857] 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)Cl2 (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 under vacuum. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound as a brown solid (1.46 g, 60%). LCMS (ESI, m / z): 222.23 [M+H] + .

[0858] Step 2: 4-Methyl-6-(thiazol-5-yl)pyridin-3-amine

[0859] Under hydrogen, 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 at room temperature for 10 h. The solid was filtered off and the filtrate was concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluting with CH3CN / H2O to provide the title compound (697 mg, 75%) as a yellow solid. LCMS (ESI, m / z): 192.25 [M+H] + .

[0860] Step 3: 2-Bromo-4-methyl-6-(thiazol-5-yl)pyridin-3-amine

[0861] 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 under vacuum, and the crude product was purified by C18 reverse phase chromatography eluting with CH 3 CN / H 2 O to provide the title compound (655 mg, 58%) as a brown solid. LCMS (ESI, m / z): 270.15 [M + H] + .

[0862] Step 4: 5-(7-Bromo-1H-pyrazolo[3,4-c]pyridin-5-yl)thiazole

[0863] 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 CHCl 3 (10 mL) was stirred at 0 ° C for 2 h. KOAc (55 mg, 0.56 mmol, 0.30 equiv) and isoamyl 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 another 1.5 h. The resulting mixture was concentrated under vacuum and the crude product was applied to a silica gel column eluted with EtOAc / petroleum ether to provide the title compound (433 mg, 82%) as a yellow solid. LCMS (ESI, m / z): 281.13 [M + H] + .

[0864] Step 5: tert-Butyl 7-bromo-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

[0865] 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 under vacuum to provide the title compound (338 mg, 71%) as a yellow solid. LCMS (ESI, m / z): 381.25 [M+H] + .

[0866] Step 6: tert-Butyl 7-(1-ethoxyvinyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-1-carboxylate

[0867] Under nitrogen, 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) was added tributyl(1-ethoxyvinyl)stannane (426 mg, 1.18 mmol, 1.50 equiv). The resulting solution was stirred at 80 ° C for 1 h. The resulting solution was quenched with 40 mL of KF saturated aqueous solution and extracted with 3×40 mL of EtOAc. The organic layers were combined and washed with 30 mL of brine, 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 provide the title compound (100 mg, 85%) as a yellow solid. LCMS (ESI, m / z): 373.44 [M+H] + .

[0868] Step 7: Ethyl 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylate

[0869] 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 NaIO4 (236 mg, 1.10 mmol, 3.00 equiv) in H2O (2 mL). KMnO4 (17.41 mg, 0.110 mmol, 0.30 equiv) in H2O (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 H2O and extracted with 3×30 mL of EtOAc. The organic fractions were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to provide the title compound (80 mg, 79%) as a yellow solid. LCMS (ESI, m / z): 275.30 [M+H] + .

[0870] Step 8: 5-(Thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid

[0871] 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 / H2O (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 h. After completion, the pH value was adjusted to 4 using 1M HCl and the resulting solution was concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluting with CH3CN / H2O to provide the title compound (14 mg, 90%) as a yellow solid. LCMS (ESI, m / z): 247.24 [M+H] + .

[0872] Step 9: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide

[0873] 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 intermediate 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 H2O and extracted with 3×10 mL EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluted with CH3CN / H2O to provide the title compound (6 mg, 25%) as a white solid. LCMS (ESI, m / z): 402.10 [M+H] + . 1 H NMR (400MHz, CD3OD-d4) δ9.03(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 ),3.71-3.64(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).

[0874] Example 22: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0875]

[0876] Step 1: 2-(1H-imidazol-1-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid

[0877] 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 under vacuum. The crude product was purified by preparative HPLC to provide the title compound (100 mg, 41%) as a white solid. LCMS: [M+H] + 244.08.

[0878] Step 2: 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0879] 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), intermediate 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 to provide the title compound (11 mg, 11% yield) as a white solid. LCMS: [M+H] 399.20. 1H NMR (300MHz, methanol-d4) δ8.77(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).

[0880] Example 23: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide

[0881]

[0882] Step 1: 5-Chloro-7-(1-ethoxyvinyl)-1H-pyrazolo[4,3-d]pyrimidine

[0883] Under nitrogen, tributyl (1-ethoxyvinyl) stannane (2.29 g, 6.35 mmol, 1.2 equiv) and Pd (PPh 3 ) 2 Cl 2 (0.37 g, 0.53 mmol, 0.1 equiv) were added 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). The resulting solution was stirred at 60 ° C for 1.5 h. The reaction was quenched with a saturated aqueous solution of KF. The solid was filtered out. 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 eluted with EtOAc / petroleum ether (4 / 1) to provide the title compound (620 mg, 40% yield) as a yellow solid. LCMS: [M + H] + 225.65.

[0884] Step 2: 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine

[0885] 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) was added 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) under nitrogen 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 H O. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (54 / 46) to afford the title compound (80 mg, 9% yield) as a yellow oil. LCMS: [M+H] + 257.26.

[0886] Step 3: Ethyl 5-(1H-imidazol-1-yl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxylate

[0887] 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 H2O (4 mL) was added NaIO4 (250 mg, 1.17 mmol, 4 equiv) and KMnO4 (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 EtOAc and washed with 2×10 mL water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc to provide the title compound (35 mg, 37% yield) as a white solid. LCMS: [M+H] + 259.24.

[0888] Step 4: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[4,3-d]pyrimidine-7-carboxamide

[0889] 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 intermediate B1 (20 mg, 0.12 mmol, 1 equiv) and 1 M AlMe3 / toluene solution (0.17 mL, 1.5 equiv) 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 and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluted with H2O / CH3CN (58:42) to provide the title compound (8.5 mg, 19% yield) as a white solid. LCMS: [M+H] + 386.25. 1 H NMR (300MHz, DMSO-d6) δ9.13-9.00(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=1 0.8Hz, 2H), 1.92 (d, J = 10.5Hz, 2H), 1.70-1.58 (m, 2H), 1.36-1.24 (m, 2H).

[0890] Example 24: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-b]pyridine-7-carboxamide

[0891]

[0892] Step 1: Methyl 3-(3-methoxy-3-oxopropionamido)thiophene-2-carboxylate

[0893] 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 H2O. The organic layer was concentrated under vacuum to provide the title compound (12 g, 89% yield) as a yellow oil. LCMS: [M+H] + 258.10.

[0894] Step 2: Methyl 5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate

[0895] A mixture of methyl 3-(3-ethoxy-3-oxopropionamido)thiophene-2-carboxylate (9.6 g) and t-BuOK (11.9 g) in t-BuOH (200 mL) was stirred at 70° C. for 1 h. After concentration, the resulting mixture was concentrated to provide the title compound (9.5 g, crude) as a yellow solid. LCMS: [M+H] + 226.10.

[0896] Step 3: 5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylic acid

[0897] 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 H 2 O (200 mL) was stirred at 60° C. overnight. After concentration, the resulting mixture was concentrated to provide the title compound (20 g, crude) as a yellow solid. LCMS: [M+H] + 212.10.

[0898] Step 4: Thieno[3,2-b]pyridine-5,7(4H,6H)-dione

[0899] 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 6M HCl (100 mL) was stirred at room temperature for 1 h. After concentration, the solid was collected by filtration to provide the title compound as a yellow solid (4 g, 32% yield). LCMS: [M+H] + 167.95.

[0900] Step 5: 5,7-Dichlorothieno[3,2-b]pyridine

[0901] 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 x 50 H2O. The organic layers were combined and concentrated to provide the title compound (2.5 g, 51% yield) as a white solid. LCMS: [M+H] + 203.95.

[0902] Step 6: 7-Chloro-5-(1H-imidazol-1-yl)thieno[3,2-b]pyridine

[0903] Under nitrogen, 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), Pd2(dba)3·CHCl3 (0.87 g, 0.84 mmol, 0.10 equiv), tBuXPhos (0.35 g, 0.84 mmol, 0.10 equiv) and K3PO4 (3.57 g, 16.82 mmol, 2.00 equiv) in dioxane (15 mL) was stirred at 80 ° C overnight. The insoluble solid was filtered. The filtrate was concentrated and purified by C18 reverse phase chromatography eluting with H2O / CH3CN to provide the title compound (150 mg, 28% yield) as a yellow solid. LCMS: [M+H] + 236.05.

[0904] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[3,2-b]pyridine-7-carboxamide

[0905] Under CO, a mixture of 7-chloro-5-(1H-imidazol-1-yl)thieno[3,2-b]pyridine (100 mg, 0.42 mmol, 1.00 equiv), intermediate 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 for 2.5 h. The resulting solution was concentrated. The crude product was purified by C18 reverse phase chromatography eluting with H2O / CH3CN to give the compound as a light green solid (36 mg, 21%). LCMS: [M+H] + 401.10; 1H NMR (400MHz, DMSO-d6) δ8.78(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).

[0906] Example 25: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo[4,5-d]pyrimidine-7-carboxamide

[0907]

[0908] Step 1: 7-Chloro-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine

[0909] Under nitrogen, a solution of 5,7-dichlorothiazolo[4,5-d]pyrimidine (1.80 g, 8.74 mmol, 1.00 equiv), 1H-imidazole (0.59 g, 8.67 mmol, 0.99 equiv), Pd2(dba)3 (0.80 g, 0.87 mmol, 0.1 equiv), tBuXPhos (0.93 g, 2.18 mmol, 0.25 equiv) and K3PO4 (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 EtOAc. The organic layers were combined and concentrated. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (40:60) to provide the title compound (1.1 g, 53% yield) as a yellow solid. LCMS: [M+H]+237.99.

[0910] Step 2: 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine

[0911] 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-ethoxyvinyl)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 solution. Insoluble solids were filtered off. The resulting solution was diluted 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 to provide the title compound (600 mg, 47% yield) as a yellow solid. LCMS: [M+H]+274.07.

[0912] Step 3: Ethyl 5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine-7-carboxylate

[0913] A solution of 7-(1-ethoxyvinyl)-5-(1H-imidazol-1-yl)thiazolo[4,5-d]pyrimidine (600 mg, 2.20 mmol, 1.00 equiv), KMnO4 (139 mg, 0.88 mmol, 0.40 equiv), NaIO4 (1.88 g, 8.78 mmol, 4 equiv) in H2O (10 mL) and dioxane (10 mL) was stirred at room temperature for 30 min. The resulting solution was extracted with 3×10 mL DCM. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was purified by reverse phase column to provide the title compound (220 mg, 36% yield) as a white solid. LCMS: [M+H]+276.05.

[0914] Step 4: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thiazolo[4,5-d]pyrimidine-7-carboxamide

[0915] Under nitrogen, a solution of ethyl 5-(1H-imidazol-1-yl)thiazole[4,5-d]pyrimidine-7-carboxylate (200 mg, 0.78 mmol, 1.00 equiv), intermediate B1 (404 mg, 2.33 mmol, 3 equiv) and 1M AlMe3 / toluene solution (3.1 mL, 4.0 equiv) in toluene (10.0 mL) was stirred at 75 ° C for 2 h. The reaction was quenched with water and extracted with 3×150 mL dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by reverse phase column to provide the title compound (14 mg, 5% yield) as a white solid. LCMS: [M+H] + 403.15.

[0916] 1H NMR (300MHz, DMSO-d6) δ9.85(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=5.9,3.8H z,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).

[0917] Example 26: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[0918]

[0919] Step 1: 2,6-Dichloropyridine-3,4-diamine

[0920] Under nitrogen, a solution of 2,6-dichloro-3-nitropyridin-4-amine (7.50 g, 0.036 mmol, 1.00 equiv) and 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 under vacuum. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (3: 1) to provide the title compound (5.5 g, 86% yield) as a yellow solid. LCMS: [M+H] + 177.99.

[0921] Step 2: 4,6-Dichloro-3H-imidazo[4,5-c]pyridine

[0922] A solution of 2,6-dichloropyridine-3,4-diamine (5.50 g, 30.90 mmol, 1.00 equiv) and 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 under vacuum. The residue was applied to a silica gel column eluted with EtOAc / petroleum ether (1:4) to provide the title compound (5.5 g, 95% yield) as a yellow solid. LCMS: [M+H] + 187.97.

[0923] Step 3: 6-chloro-4-(1-ethoxyvinyl)-3H-imidazo[4,5-d]pyridine

[0924] Under nitrogen, a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (5.50 g, 29.25 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)stannane (15.85 g, 43.88 mmol, 1.50 equivalent) and Pd(PPh 3 ) 2Cl 2 (2.05 g, 2.92 mmol, 0.1 equivalent) in DMF (93 mL) was stirred at 100 ° C for 1 h. The reaction was quenched with water, the resulting solution was extracted with 2×100 mL EtOAc and the organic layers were combined, dried over sodium sulfate and concentrated. The crude product (5 mL) was purified by preparative HPLC using a gradient elution from 5 / 95 H2O / ACN to 50 / 50 H2O / ACN to provide the title compound (3 g, 45.85% yield) as a white solid after concentration. LCMS: [M+H] + 224.05.

[0925] Step 4: 4-(1-ethoxyvinyl)-6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine

[0926] 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 K2CO3 (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 H2O / ACN to provide the title compound (120 mg, 4% yield) as a white solid after concentration. LCMS: [M+H] + 256.11.

[0927] Step 5: Ethyl 6-(1H-imidazol-1-yl)-3H-imidazo[4,5-c]pyridine-4-carboxylate

[0928] 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), KMnO4 (32 mg, 0.20 mmol, 0.4 equiv) and NaIO4 (436 mg, 2.04 mmol, 4 equiv) in H2O (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 EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum to provide the title compound (60 mg, 46% yield) as a yellow solid. LCMS: [M+H] + 258.09.

[0929] Step 6: 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-3H-imidazo[4,5-c]pyridine-4-carboxamide

[0930] 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), intermediate B1 (101 mg, 0.58 mmol, 3 equiv) and 1M AlMe3 / toluene solution (0.78 mL, 4 equiv) in toluene (1 mL) was stirred at 80°C for 1 h. The crude product (5 mL) was purified by preparative HPLC to provide the title compound (14 mg, 19% yield) as a white solid. LCMS: [M+H] + 385.20. 1 HNMR(400MHz,DMSO-d6)δ13.05(s,1H),8.93(s,1H),8.72(s,1H),8.53(s,1 H),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=12.0 Hz, 2H), 1.89 (d, J = 12.2Hz, 2H), 1.63 (q, J = 12.7, 12.2Hz, 2H), 1.31 (m, 2H).

[0931] Example 27: 2-(1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide

[0932]

[0933] To a solution of intermediate A2 (150 mg, 0.65 mmol, 1.00 eq) in DMF (2 mL) was added DIPEA (508 mg, 3.93 mmol, 6 eq), HATU (348 mg, 0.92 mmol, 1.4 eq) and tetrahydro-2H-pyran-3-amine hydrochloride (126 mg, 0.92 mmol, 1.4 eq) and the mixture was stirred at room temperature for 0.5 h. The mixture was purified by C18 reverse phase chromatography eluting with H2O / CH3CN (55:45) to provide the title compound (83 mg, 41% yield) as a white solid. LCMS: [M+H] + 313.10. 1 H NMR (300MHz, DMSO-d6) δ12.15(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).

[0934] 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

[0935]

[0936] The compound of Example 27 (58 mg) was further purified by chiral HPLC using the following conditions (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: hexane: DCM = 3: 1 (10 M NH 3 -MeOH), mobile phase B: EtOH; flow rate: 16 mL / min; gradient: maintain 20% B 13 min; 220 / 254 nm) to provide the title compound with retention times of 2.39 minutes (Example 28a) and 2.87 minutes (Example 28b). The absolute stereochemistry of Examples 28a and 28b was not confirmed.

[0937] Example 28a:

[0938] Isolated as a white solid (19.8 mg, 34% yield). LCMS: [M+H] + 313.20.1 HNMR (300MHz, methanol-d4) δ8.94(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).

[0939] Example 28b:

[0940] Isolated as a white solid (18.4 mg, 32% yield). LCMS: [M+H] + 313.20. 1 HNMR (300MHz, methanol-d4) δ8.94(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).

[0941] Example 29: 4-Fluoro-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide

[0942]

[0943] Step 1: 1-(5-Bromo-2-fluoro-4-nitrophenyl)-1H-imidazole

[0944] 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 provide the title compound (3.6 g, 91%) as a yellow solid. LCMS: [M+H] + 285.95.

[0945] Step 2: 7-Bromo-4-fluoro-5-(imidazol-1-yl)-1H-indole

[0946] 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) was added dropwise bromo(vinyl)magnesium (46.2 mL, 0.030 mol, 4 equiv) in THF under nitrogen and -45 ° C. The resulting solution was stirred at -45 ° C for 2 h. The reaction was quenched with NH4Cl / H2O and extracted with 3×100 mL EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (1 / 1) to give the title compound (550 mg, 17% yield) as a white solid. LCMS: [M+H] + 279.98.

[0947] Step 3: 4-Fluoro-5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide

[0948] Under CO, a mixture of 7-bromo-4-fluoro-5-(imidazol-1-yl)-1H-indole (286 mg, 1.02 mmol, 1.00 equiv), intermediate 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. The reaction was quenched with water and extracted with 3×50 mL EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by C18 reverse phase chromatography eluted with H2O / CH3CN to provide the title compound (71 mg, 17%) as a dark yellow solid. LCMS: [M+H] + 401.10. 1H NMR (400MHz, DMSO-d6) δ11.62(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 ),3.26-3.21(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).

[0949] Example 30: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide

[0950]

[0951] Step 1: Methyl 5-(1H-imidazol-1-yl)-2-nitrobenzoate

[0952] A mixture of methyl 5-fluoro-2-nitrobenzoate (5 g, 25.1 mmol, 1 eq), 1H-imidazole (1.88 g, 27.62 mmol, 1.10 eq), K2CO3 (5.21 g, 37.66 mmol, 1.5 eq) in DMF (80 mL) was stirred at 120 ° C for 2 h. The reaction was quenched with water / ice and extracted with 3×100 mL EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluted with EtOAc / petroleum ether (9 / 1) to provide the title compound (4.4 g, 71%) as a yellow solid. LCMS: [M+H] + 248.10.

[0953] Step 2: Methyl 2-amino-5-(1H-imidazol-1-yl)benzoate

[0954] Under hydrogen, a mixture of methyl 5-(1H-imidazol-1-yl)-2-nitrobenzoate (29.6 g, 119.74 mmol, 1 eq) and Pd / C (2 g, 18.79 mmol, 0.16 eq) in MeOH (800 mL) was stirred at room temperature for 24 h. The insoluble solid was filtered off and rinsed with MeOH. The filtrate was concentrated to provide the title compound (22.77 g, 82%) as a yellow solid. LCMS: [M+H] + 218.10.

[0955] Step 3: Methyl 2-amino-5-(1H-imidazol-1-yl)-3-nitrobenzoate

[0956] A mixture of methyl 2-amino-5-(1H-imidazol-1-yl)benzoate (1.00 g, 4.60 mmol, 1.00 equiv) and 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 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to provide the title compound (960 mg) as a solid. LCMS: [M+H] + 263.10.

[0957] Step 4: Methyl 2,3-diamino-5-(1H-imidazol-1-yl)benzoate

[0958] 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 h. The insoluble solid was filtered and washed with MeOH. The filtrate was concentrated to provide the title compound (450 mg) as a solid. LCMS: [M+H] + 233.10.

[0959] Step 5: Methyl 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylate

[0960] 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), NaHSO3 (134 mg, 1.29 mmol, 1.50 equiv) in EtOH (2 mL) and H2O (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 eluted with EtOAc / petroleum ether (1 / 9) to provide the title compound (80 mg, 36%) as a solid. LCMS: [M+H] + 257.10.

[0961] Step 6: 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylic acid

[0962] 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 H O (0.20 mL) was stirred at room temperature for 2 h. The pH was adjusted to 3 using 1 M HCl. The mixture was concentrated to provide the title compound (50 mg) as a crude solid, which was carried forward without additional purification. LCMS: [M+H] + 243.10.

[0963] Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-benzo[d]imidazole-7-carboxamide

[0964] A solution of 5-(1H-imidazol-1-yl)-2-methyl-1H-benzo[d]imidazole-7-carboxylic acid (50 mg, 0.21 m...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: V is N or CR V , where R V is H, halogen or C 1-4 alkyl; W is N or CR W , where R W is H, halogen or C 1-4 alkyl; The part represented by the formula: 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 optionally substituted by 1, 2 or 3 independently selected from halogen and C 1-4 Substitution of alkyl groups; Each R N Independently selected from H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, wherein R N The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; R A , R B and R C are each independently selected from H, halogen, 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 or 4- to 10-membered heterocycloalkyl, wherein R A , R B and R C The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; L is C 1-4 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, wherein the 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, and 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents, wherein the C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from Cy 1 、CN、NO2、OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; When n is 0, Q is not H; Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents are substituted; 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c and R d Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c1 and R d1 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c2 and R d2 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; R a3 , R b3 , R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from 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 Substitution of haloalkoxy substituents; R e , R e1 , R e2 and R e3 Each independently selected from 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 oxo (═O); 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); and The condition is when: V is CH; W is CH; The moiety represented by the formula: yes n is 0; and Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; Then ring A is not 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: V is N or CR V , where R V is H, halogen or C 1-4 alkyl; W is N or CR W , where R W is H, halogen or C 1-4 alkyl; The moiety represented by the formula: 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 optionally substituted by 1, 2 or 3 independently selected from halogen and C 1-4 Substitution of alkyl groups; Each R N Independently selected from H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, wherein R N The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; R A , R B and R C are each independently selected from H, halogen, 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 or 4- to 10-membered heterocycloalkyl, wherein R A , R B and R C The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; L is C 1-4 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, wherein the 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, and 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 Substituents are substituted; When n is 0, Q is not H; Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents are substituted; 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c and R d Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c1 and R d1 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c2 and R d2 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; R a3 , R b3 , R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from 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 Substitution of haloalkoxy substituents; R e , R e1 , R e2 and R e3 Each independently selected from 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 oxo (═O); 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); and The condition is when: V is CH; W is CH; The moiety represented by the formula: yes n is 0; and Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; Then ring A is not 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: V is N or CR V , where R V is H, halogen or C 1-4 alkyl; W is N or CR W , where R W is H, halogen or C 1-4 alkyl; The moiety represented by the formula: 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 optionally substituted by 1, 2 or 3 independently selected from halogen and C 1-4 Substitution of alkyl groups; Each R N Independently selected from H, C 1-4 Alkyl, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, wherein R N The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; R A , R B and R C are each independently selected from H, halogen, 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 or 4- to 10-membered heterocycloalkyl, wherein R A , R B and R C The 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 each optionally substituted by 1, 2, 3, 4, or 5 independently selected from Cy, Cy-C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; L is C 1-4 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, wherein the 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, and 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4, or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; Where Q is not H when n is 0; Each Cy is independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , SR 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 NR c C(=NR e )NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d Substituents are substituted; Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents are substituted; 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 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where 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 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c and R d Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c1 and R d1 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c2 and R d2 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; R a3 , R b3 , R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Substitution of haloalkoxy substituents; R e , R e1 , R e2 and R e3 Each independently selected from 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 oxo (═O); 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); and The condition is when: V is CH; W is CH; The moiety represented by the formula: yes n is 0; and Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; Then ring A is not 4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the moiety represented by the following formula: Selected from:

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the moiety represented by the following formula: yes 6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the moiety represented by the following formula: yes 7. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R A , R B and R C Each independently selected from H and C 1-4 alkyl.

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

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

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

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

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

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

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 1 , R 2 and R 3 Each independently selected from H and C 1-4 alkyl.

15. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 and 4 to 14, wherein 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, wherein the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl or 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents, wherein the C 1-6 Alkyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

16. A compound as claimed in any one of claims 1, 2 and 4 to 14 or a pharmaceutically acceptable salt thereof, wherein 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, wherein the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl or 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

17. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted with C 1-10 Alkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

18. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14, wherein Q is C 1-4 alkyl.

19. A compound as claimed in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Q is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl.

20. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 A phenyl group substituted with a substituent, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

21. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1 or 2 independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, CN and OR a1 A phenyl group substituted with a substituent, wherein the C 1-6 The alkyl group is optionally substituted with CN.

22. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted with C 3-14 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

23. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted with C 4-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

24. A compound as described in any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents substituted with C 4-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

25. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 and NR c1 C(O)R b1 Substituents substituted with C 4-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

26. A compound as described in any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a1 NR c1 R d1 、C(O)NR c1 R d1 NR c1 C(O)R b1 and S(O)2R b1 Substituents substituted with C 4-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy, C(O)NR c1 R d1 NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

27. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 A 5- to 14-membered heteroaryl group substituted with a substituent, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

28. A compound as described in any one of claims 1 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 A 5- to 14-membered heteroaryl group substituted with a substituent, wherein the C 1-6 Alkyl and C 2-6 Alkynyl is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy, NR c1 R d1 and NR c1 C(O)R b1 substituted by a substituent.

29. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally replaced by Cy 1 , halogen, C 1-6 Alkyl or OR a1 substituted 5- or 6-membered heteroaryl, wherein the C 1-6 The alkyl group is optionally composed of C 1-6 Alkoxy substitution.

30. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally replaced by Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or OR a1 substituted 5- or 6-membered heteroaryl, wherein the C 1-6 Alkyl and C 2-6 The alkynyl group is optionally composed of C 1-6 Alkoxy or NR c1 R d1 replace.

31. A compound as described in any one of claims 1, 2 and 4 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 A 4- to 14-membered heterocycloalkyl substituted with a substituent, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 substituted by a substituent.

32. A compound as described in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 A 5- to 10-membered heterocycloalkyl group substituted with a substituent.

33. A compound as described in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is optionally substituted by 1 or 2 independently selected from Cy 1 , halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R b1 and S(O)2R b1 A 5- or 6-membered heterocycloalkyl group substituted with a substituent.

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

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

37. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: V is N or CR V , where R V is H, halogen or C 1-4 alkyl; W is N or CR W , where R W is H, halogen or C 1-4 alkyl; The moiety represented by the formula: Selected from: Each R N Independently selected from H and C 1-4 alkyl; R A , R B and R C Each independently selected from H and C 1-4 alkyl; Ring A is selected from: R 1 , R 2 and R 3 Each independently selected from H and C 1-4 alkyl; L is a methylene group; n is 0 or 1; Q is for C 1-10 Alkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 14-membered heterocycloalkyl, wherein the C 1-10 Alkyl, C 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl or 4- to 14-membered heterocycloalkyl are each optionally substituted by 1, 2, 3, 4 or 5 independently selected 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents, wherein the C 1-6 The alkyl group is optionally composed of 1, 2 or 3 independently selected from OH, CN, C 1-6 Alkoxy and NR c1 C(O)R b1 Substituents are substituted; Where Q is not H when n is 0; Each Cy 1 Independently selected from C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , SR 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 NR c2 C(=NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 Substituents are substituted; R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, where R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 and R d2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from Cy 2 , Cy 2 -C 1-4 Alkyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c1 and R d1 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; or R c2 and R d2 Together with the N atom to which it is attached, it forms a 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; Each Cy 2 It is C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , SR 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 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)NR c3 R d3 NR c3 C(O)OR a3 、C(=NR e3 )NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 Substituents are substituted; R a3 , R b3 , R c3 and R d3 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Alkyl, wherein the 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- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl and 4 to 10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted by 1, 2 or 3 groups independently selected from 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 Substitution of haloalkoxy substituents; R e1 , R e 2 and R e3 Each independently selected from 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 oxo (═O); 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); and The condition is when: V is CH; W is CH; The moiety represented by the formula: yes n is 0; and Q is cyclohexyl, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from Cy 1 , Cy 1 -C 1-4 Alkyl, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a1 , SR 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 NR c1 C(=NR e1 )NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 Substituents are substituted; Then ring A is not 38. A compound as described in any one of claims 1 to 3, selected from: 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-dioxidotetrahydro-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 a pharmaceutically acceptable salt of any of the above.

39. The compound of claim 1 or 2, selected from: 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-methylbutyloxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1S,4r)-4-((S)-2-hydroxy-3-methylbutyloxy)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-dimethylbutyloxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide; N-((1R,4r)-4-((S)-2-hydroxy-2,3-dimethylbutyloxy)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-methylpropionamido)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-methylpropionamido)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]heptane-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 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 above.

40. The compound of claim 1 selected from: 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]heptane-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-methylpropane-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 above.

41. The compound of claim 1 selected from: 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-methylpropane-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 above.

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

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

44. The method of claim 43, wherein the CD38 is located in a cell.

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

46. ​​The method of claim 43, wherein the contacting occurs in vivo.

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

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

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

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

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

Images