Quinolines and azaquinolines as inhibitors of CD38

Abstract

To provide novel compounds useful in the treatment of diseases associated with abnormal activity or expression of CD38 (e.g., cancers such as lung cancer, melanoma, and colon cancer).SOLUTION: There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X3 is CR3 or N; X4 is CR4 or N; A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S; L is a C1-4 alkylene linker; n is 0 or 1; and Q is H, C1-10 alkyl, C2-10 alkenyl, etc.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] CD38 (cluster of differentiation 38) is widely expressed on the surface of multiple cell types and binds nicotinamide adenine dinucleotide (NAD + CD38 is a member of the ADP-ribosyl cyclase family responsible for the degradation of NADPH. CD38 was first characterized as a surface antigen on immune cells as an activation marker located on the plasma membrane and membranes of intracellular organelles (Quarona, V., et al. Cytometry B Clin Cytom 84(4):207-217(2013)). Human CD38 contains 300 amino acid residues, including a short N-terminal fragment, a single transmembrane helix, and a C-terminal catalytic domain. CD38 is generally classified as a type II membrane protein, but has also been reported to exist in a type III orientation (Zhao YZ et al. Biochim Biophys Acta 1853(9):2095-2103(2012)). CD38 is a cytochrome P456 receptor agonist (CYP456) that mediates the degradation of NADPH. + NAD converts NAD to ADP-ribose (ADPR) or cyclic ADPR (cADPR) and nicotinamide (Chini EN et al. Trends Pharmacol Sci 39(4):424-436(2018)). + is recognized as the primary substrate of CD38, but nicotinamide adenine dinucleotide phosphate (NADP + ) and nicotinamide mononucleotide (NMN + It is also known that CD38 has other substrates, such as ATP, ATPase, and ATPase inhibitors. Under some conditions, CD38 can also catalyze base exchange reactions with these same substrates (Preugschat, F et al. Arch Biochem Biophys, 479:114-20 (2008)). This CD38-dependent NAD + Metabolism involves extracellular and intracellular metabolites, intracellular Ca 2+and regulates signal transduction pathways (Horenstein, AL, et al. Oncoimmunology 2(9):e26246(2013) and Chini EN et al. 2018). CD38 also functions as a receptor, regulating the development, activation, and differentiation of multiple immune cell types through its receptor-ligand activity (Quorona B et al. 2013). CD31 / PECAM-1 has been reported to be a ligand for CD38 (Deaglio S, J Immunol, 160:395-402(1998)).

[0003] CD38 exerts diverse physiological functions, and the characterization of CD38 knockout (KO) mice has revealed the various roles played by this protein. CD38KO mice are characterized by a significant reduction in endogenous cADPR levels in all tissues / organs analyzed, except the brain (Partida-Sanchez S et al. Nat Med, 7:1209-16 (2001) and Ceni C et al. J Biol Chem 278(42):40670-40678 (2003)). In pancreatic islets, loss of CD38 abolishes glucose-induced cADPR production, intracellular Ca2+ upregulation, and endothelial cell death. 2+ , and insulin secretion are impaired (Kato J et al. J Biol Chem, 274:1869-72 (1999)). CD38KO also impairs acetylcholine-induced cADPR accumulation in acinar cells, resulting in Ca 2+ This results in a marked change in signal transduction patterns (Fukushi Y et al. J Biol Chem, 276:649-55 (2001)). Similarly, cADPR production in neutrophils increases intracellular Ca during chemotaxis. 2+ Release and extracellular Ca 2+It has been shown to regulate both influx and influx and is required for bacterial clearance in vivo (Partida-Sanchez S et al. Nat Med, 7:1209-16 (2001)). CD38KO mice also exhibit other defects, such as 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)), impaired α-adrenergic receptor-stimulated contraction in the aorta (Mitsui-Saito M et al. J Vet Med Sci, 65:1325-30 (2003)), and cardiac hypertrophy (Takahashi J et al. Biochem Biophys Res Commun, 312:434-40 (2003)). These findings underscore the diverse biological roles played by CD38.

[0004] CD38 expression has also been associated with the immunosuppressive functions of regulatory T (Treg) cells, tumor-associated macrophages (TAM), and myeloid-derived suppressor cells (MDSC) (Feng X et al. Clin Cancer Res 23(15):4290-4300(2017), Krejcik J et al. Blood 128(3):384-394(2016), Chevrier S et al. Cell 169(4):736-749 e718(2017), and Levy A Neuro Oncol 14(8):1037-1049(2012)). CD38KO Treg cells are associated with the immunosuppressive functions of NAD + NAD cannot be consumed +They are significantly more susceptible to induced cell death (Chen J et al. J Immunol 176(8):4590-4599(2006) and Hubert, SB et al. J Exp Med, 207:2561-8(2010)). Conversely, Tregs with high CD38 expression are more suppressive than other subsets with low or no CD38 expression (Krejcik et al. 2016 and Patton DT et al. PLoS One 6(3):e17359(2011)). Similarly, CD38 high MDSCs have a stronger ability to suppress activated T cells. high MDSC activity promoted esophageal tumor growth in mice, an effect that could be inhibited by CD38 blockade (Karakasheva TA et al. Cancer Res 75(19):4074-4085(2015)). + The expansion of MDSCs has been reported in colorectal cancer, especially in previously treated patients (Karakasheva TA et al. JCI Insight 3(6)(2018)). A broad approach of systems immunology has revealed an association between CD38-expressing tumor-infiltrating lymphocytes (TILs) and poor prognosis in renal clear cell carcinoma (ccRCC) and early-stage lung adenocarcinoma (Chevrier S et al. 2017 and Lavin Y et al. Cell 169(4):750-765 e717(2017)). ccRCC was found to co-express CD38 with other markers associated with T cell exhaustion, while lung adenocarcinoma was found to express only CD38. highTreg cells have been enriched in the tumor microenvironment (TME) (Chevrier S et al. 2017 and Lavin Y et al. 2017). High co-expression of CD38 and CD101 on TILs in tumor tissue correlated with poor survival in pancreatic cancer patients (Zhang M et al. Immunol Invest, 48:466-79 (2019)). Studies examining exhausted T cell populations in humans with chronic infections and various cancers identified CD38 as a marker of T cell exhaustion and found that the presence of such exhausted T cells was associated with impaired TIL function in more severe HIV infection and lung cancer (Bengsch B et al. Immunity 48(5):1029-1045 e1025 (2018)). CD38 also influences the metabolic adaptability of T cells, and inhibition of CD38 expression in T cells leads to increased glutaminolysis, enhanced oxidative phosphorylation, and altered mitochondrial dynamics, resulting in decreased NAD levels. + is upregulated, activating T cells (Chatterjee S et al. 2018). This study further demonstrated that CD38 inhibition enhances the efficacy of adoptive T cell therapy by preventing T cell exhaustion (Chatterjee S et al. Cell Metab 27(1):85-100 e108(2018)).

[0005] The role of CD38 in tumorigenesis and immunosuppression is an active area of ​​research, with multiple studies linking CD38 to tumor progression. CD38 has been shown to promote cervical cancer cell proliferation by reducing reactive oxygen species levels and inhibiting apoptosis (Liao S et al. Mol Carcinog 56(10):2245-2257(2017)). Loss of CD38 in human lung adenocarcinoma cells inhibited cell proliferation, invasion, and xenograft growth in nude mice (Bu X et al. Carcinogenesis 39(2):242-251(2017)). CD38KO mice were shown to be more resistant to tumor growth and efficiently rejected B16-F10 melanoma tumors (Baruch BB et al. Oncotarget, 9:31797-811(2018)). Similarly, targeting CD38 expression or activity in the TME inhibited glioma progression and extended the lifespan of glioma-bearing mice (Blacher E et al. Int J Cancer 136(6):1422-1433(2013)). CD38 has also been identified as a biomarker for advanced localized prostate cancer (Sahoo D et al. Oncotarget,9:6550-61(2018)).

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

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

[0008] CD38 is a major NAD-dependent regulator of aging in mammals. + CD38 is one of the key enzymes involved in the decline of NAD (Hogan KA et al. Front Immunol 10:1187(2019)). CD38KO mice are consistently protected from this progressive deficiency and age-related metabolic dysfunction (Camacho-Pereira J et al. Cell Metab,23:1127-39(2016)). Similarly, inhibition of CD38 reduces age-related NAD +CD38KO mice are also protected from diet-induced obesity, fatty liver, and glucose intolerance due to their higher energy expenditure (Barbosa MT et al. FASEB J 21(13):3629-3639(2007)). Recent studies have shown that age-related NAD + The decrease in NAD associated with aging is associated with the expression of CD38 on M1-like macrophages. The induction of CD38 on M1-like macrophages by aging-associated inflammation contributes to the age-related increase in NAD. + This new understanding of CD38 regulation in age-related M1-like macrophages suggests that CD38 may be involved in the regulation of NAD during aging, particularly in tissues with a high resident macrophage population. + This establishes it as an attractive target for preventing its decline (Wu et al. Nat. Metab, 11:1186-1187 (2020)).

[0009] Optimal NAD + Consistent with its role in regulating NAD levels, NAD may be regulated via CD38 inhibition or NAD precursor supplementation. + Replenishing or boosting NAD using supplements can alter disease outcomes. + Supplementation of CD38 sensitized tumors resistant to anti-PD-L1 therapy to immunotherapy, while CD38-expressing tumors were resistant to immunotherapy (Lv et al. Cell Metab, 33: P110-127 (2021)). This further strengthens the rationale for CD38 inhibition in immunotherapy-resistant patients. Furthermore, genetic and pharmacological approaches have been used to inhibit CD38-dependent NAD +It has been demonstrated that targeting metabolism can alleviate multi-organ fibrosis (Shi et al. iScience, 24: (2021)). CD38 is elevated in skin biopsies from patients with systemic sclerosis. CD38 inhibition or supplementation can reduce NAD + Boosting levels prevented multi-organ fibrosis.

[0010] CD38 is a cell surface marker for multiple myeloma, and because these cells are particularly susceptible to CD38 depletion, CD38 provides a useful therapeutic target for this malignancy (Chini EN et al. 2018). Clinical trials have demonstrated that antibodies targeting CD38 are particularly effective in patients with relapsed / refractory multiple myeloma (Frerichs KA et al. Expert Rev Clin Immunol, 14:197-206 (2018) and van de Donk NWCJ et al. Front Immunol, 9:2134 (2018)). The anti-CD38 antibody daratumumab has been approved by the FDA for the treatment of multiple myeloma. Several other therapeutic antibodies against CD38 are currently in clinical development for multiple myeloma and other cancers (van de Donk NWCJ 2018).

[0011] There is a wealth of literature reporting the potential therapeutic effects of inhibiting aberrant CD38 expression or activity. For example, the following diseases are characterized by aberrant CD38 expression or activity: non-small cell lung cancer, melanoma, cancers treated with and / or resistant to checkpoint therapy, and adenosine-dependent tumors (Chen L et al., "CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1 / PD-L1 blockade." Cancer Discov. 8, 1156-1175 (2018)), lung cancer (adenocarcinoma) (Bu X et al., "CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells." Carcinogenesis 39, 242-251 (2018)), and cervical cancer (Liao S et al., "CD38 enhances the proliferation and inhibits the apoptosis of cervical cancer cells by affecting the mitochondria"). "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-infiltrated tumors (Lavin Y et al.「Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.」Cell 169,750-757.e15(2017)), MDSC-infiltrated tumors (Karakasheva TA et al.「CD38 +M-MDSC expansion characterizes a subset of advanced colorectal cancer patients.」JCI Insight 3,1-8(2018)), HIV / AIDS(Bengsch B et al.「Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted resource epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells.」Cell 48,1029-1045(2018)), adoptive T cell therapy(Chatterjee S et al.「CD38-NAD + axis regulates immunotherapeutic anti-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)). Age-related diseases (Wu et al. "CD38-expressing macrophages drive age-related NAD(+) decline" Nat Metab. 11 (2020)), multi-organ fibrosis, systemic sclerosis, metabolic diseases (Shi et al. "Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis" iScience, 24: (2021)), systemic lupus erythematosus (Peclat et al. "The NADase enzyme CD38: an emerging pharmacological target for systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis" Curr Opin Rheumatol. (2020)), asthma, allergic airway diseases (Deshpande et al. "CD38 in the pathogenesis of allergic airway disease: potential therapeutic targets" Pharmacol Ther., (2016)), multiple sclerosis, neurodegeneration, and neurological diseases (Langley et.al. "CD38-dependent NAD+ depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration" BioRxiv (2020)).

[0012] In summary, CD38 plays a key role in cancer progression, the generation of an immunosuppressive TME, the metabolic adaptability of T cells, and NAD during aging and other physiological conditions. + CD38 is a multifunctional enzyme and signaling receptor that plays an important role in regulating levels of CD38. Inhibition of CD38 in various disease states, including tumor growth, has already shown clinical promise, and the development of potent and selective small molecule inhibitors will generate treatment options for other conditions characterized by aberrant CD38 expression or activity. The compounds, compositions, and methods described herein will help meet these and other needs. Summary of the Invention

[0013] The present invention relates to compounds of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein the constituent members are as defined below.

[0014] The present invention is also directed to pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0015] The present invention is also directed to a method of inhibiting the function of CD38 by contacting said CD38 with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0016] The present invention is also directed to a method of treating a disease associated with aberrant activity or expression of CD38 by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0017] The present invention is further directed to a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with aberrant activity or expression of CD38.

[0018] The present invention is further directed to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy. [Brief explanation of the drawings]

[0019] [Figure 1A] 1 is a graph showing splenic NAD+ concentrations at a single time point after administration of various doses of the compound of Example 7. [Figure 1B] 1 is a graph showing liver NAD+ concentrations at a single time point after administration of various doses of the compound of Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention provides a CD38 inhibitor compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: X 3 is CR 3 or N; X 4は , C.R. 4 or N; A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S, and the 5-membered heteroaryl group of A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; L is C 1-4 is an alkylene linker; n is 0 or 1; Q is H, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, and C of said Q 1-10 Alkyl, C 2-10 Alkenyl, C2-10 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 represented by Cy. 1 , Cy 1 ~C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d and wherein said C is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 Alkynyl is Cy 1 , CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d optionally substituted with 1, 2, or 3 substituents independently selected from Cy 1 are respectively, C 6-10 Aryl, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1 is C 1-6 is alkyl; R 2 , R 3 , and R 4 are H, halo, and C, respectively. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 and R is independently selected from 2 , R 3 , and R 4 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl is halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NRc2 R d2 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 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 are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 C 1-6 Alkyl, 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 1-4Alkyl and 4- to 10-membered heterocycloalkyl-C 1-4 Alkyl, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or, R c and R d together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 Rd3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from: Or, R c1 and R d1 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R.c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from: Or, R c2 and R d2 together with the N atom to which they are attached, form halo, C 1-4 Alkyl, C 1-4 Haloalkyl, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2Rb3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , and S(O)NR c3 R d3 forming a 4- to 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 substituents independently selected from: R a3 , R b3 , R c3 , and R d3 are H and C, respectively. 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 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 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 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each selected from OH, CN, amino, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; and R e , R e1 , R e2 , and R e3 are H and C, respectively. 1‐4 alkyl, and CN; X 3 is CR 3 and X 4 is CR 4 If so, then ring A is [ka] The present invention relates to a CD38 inhibitor compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

[0021] In some embodiments, A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming N atoms, and the 5-membered heteroaryl group of A is selected from halo and C 1-4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0022] In some embodiments, A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming heteroatoms selected from N, O, and S.

[0023] In some embodiments, A is halo and C 1-4 In some embodiments, A is imidazolyl or thiazolyl optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, and C 1-4 In some embodiments, A is imidazolyl optionally substituted by 1, 2, or 3 substituents independently selected from alkyl, halo, and C 1-4 and thiazolyl optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0024] In some embodiments, A is imidazolyl or thiazolyl. In some embodiments, A is imidazolyl. In some embodiments, A is thiazolyl.

[0025] In some embodiments, A is imidazol-1-yl or thiazol-5-yl. In some embodiments, A is imidazol-1-yl. In some embodiments, A is thiazol-5-yl.

[0026] In some embodiments, A is [ka] is.

[0027] In some embodiments, A is [ka] is.

[0028] In some embodiments, X 3 is CR 3 is.

[0029] In some embodiments, X 3 is N.

[0030] In some embodiments, X 4 is CR 4 is.

[0031] In some embodiments, X 4 is N.

[0032] In some embodiments, R 1 is methyl.

[0033] In some embodiments, R 2 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NRc2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 is selected from.

[0034] In some embodiments, R 2 is H, halo, or C 1-4 It is alkyl.

[0035] In some embodiments, R 2 is H.

[0036] In some embodiments, R 3 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NRc2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 is selected from.

[0037] In some embodiments, R 3 is H, halo, or C 1-4 It is alkyl.

[0038] In some embodiments, R 3 is H.

[0039] In some embodiments, R 4 H, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 Rd2 is selected from.

[0040] In some embodiments, R 4 is H, halo, or C 1-4 It is alkyl.

[0041] In some embodiments, R 4 is H.

[0042] In some embodiments, Q is C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, and C of said Q 6-10 Aryl, C 3-14 Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each represented by Cy. 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b, N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d and wherein said C is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 1 , CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R dis optionally substituted by 1, 2, or 3 substituents independently selected from

[0043] In some embodiments, Q is phenyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and the phenyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each represented by Cy. 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c Rd and wherein said C is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 1 , CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d is optionally substituted by 1, 2, or 3 substituents independently selected from

[0044] In some embodiments, Q is C 6-10 Aryl, C 3-14 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 14-membered heterocycloalkyl, and C of said Q 6-10 Aryl, C 3-14Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl are each represented by Cy. 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein said C is optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0045] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b C optionally substituted with 1, 2, or 3 substituents independently selected from 3-14 is cycloalkyl, and the C 1-6 Alkyl is OR a is optionally replaced by

[0046] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein the C is a 5- to 14-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0047] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. cR d , and S(O)2R b C optionally substituted with 1, 2, or 3 substituents independently selected from 3-6 is cycloalkyl, and the C 1-6 Alkyl is OR a is optionally replaced by

[0048] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein the C is a 5- to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0049] In some embodiments, Q is phenyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and the phenyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each represented by Cy. 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein said C is optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0050] In some embodiments, Q is C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, and C of said Q 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are each represented by Cy 1, Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein said C is optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0051] In some embodiments, Q is phenyl or 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl of Q are each selected from Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein said C is optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0052] In some embodiments, Q is cyclohexyl, phenyl, pyridinyl, or piperidinyl, each of which is selected from the group consisting of Cy 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein the C is optionally substituted by one or two substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0053] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, OR a , and NR c R dand wherein the C is cyclohexyl optionally substituted by one or two substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0054] In some embodiments, Q is C 1-6 It is phenyl optionally substituted by haloalkyl or CN.

[0055] In some embodiments, Q is OR a is pyridinyl optionally substituted by

[0056] In some embodiments, Q is S(O)R b is piperidinyl optionally substituted by

[0057] In some embodiments, Q is Cy 1 , Haro, C 1-6 Alkyl, OR a , and NR c R d and wherein the C is cyclohexyl substituted by one or two substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by

[0058] In some embodiments, Q is C 1-6 It is phenyl substituted with haloalkyl or CN.

[0059] In some embodiments, Q is OR a is pyridinyl substituted with

[0060] In some embodiments, Q is S(O)R b and piperidinyl substituted with

[0061] In some embodiments, Q is 4-(2-methoxyethoxy)cyclohexyl, 4-(oxetan-3-ylamino)cyclohexyl, 4-(2-hydroxypropan-2-yl)cyclohexyl, 4-((2,2,2-trifluoroethyl)amino)cyclohexyl, 4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 4-(2-(pyrrolidin-1-yl)ethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 1-hydroxyethyl ... 4-(2-(2-(dimethylamino)ethoxy)pyridin-3-yl, 6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl, and 1-(methylsulfonyl)piperidin-4-yl.

[0062] In some embodiments, Q is 4-(2-methoxyethoxy)cyclohexyl, 4-(oxetan-3-ylamino)cyclohexyl, 4-(2-hydroxypropan-2-yl)cyclohexyl, 4-((2,2,2-trifluoroethyl)amino)cyclohexyl, 4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 4-(2-(pyrrolidinedione)-2-yl)cyclohexyl, 4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 4-(2-(pyrrolidinedione)-2-yl)cyclohexyl, 4-(2-(trifluoroethyl)amino ... 4-((2,2,2-trifluoroethyl)amino)cyclohexyl, 4-methoxycyclohexyl, 4,4-difluorocyclohexyl, and 4-(1-hydroxycyclopropyl)cyclohexyl.

[0063] In some embodiments, Q is chosen from 4-(trifluoromethyl)phenyl and 4-cyanophenyl.

[0064] In some embodiments, Q is selected from 6-(2-morpholinoethoxy)pyridin-3-yl, 6-(2,2,2-trifluoroethoxy)pyridin-3-yl, 6-(2-(dimethylamino)ethoxy)pyridin-3-yl, and 6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl.

[0065] In some embodiments, Q is 1-(methylsulfonyl)piperidin-4-yl.

[0066] In some embodiments, Cy 1 are OR a1 C optionally substituted by one or two substituents independently selected from 3-7 cycloalkyl.

[0067] In some embodiments, Cy 1 are OR a1 and cyclopropyl optionally substituted by one or two substituents independently selected from:

[0068] In some embodiments, Cy 1 is 1-hydroxycyclopropyl.

[0069] In some embodiments, R a are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, a C 1-6 Alkyl is OR a3 , C(O)NR c3 R d3 , and NR c3R d3 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0070] In some embodiments, R c and R d are H and C, respectively. 1-6 Alkyl, C 1-6 and independently selected from haloalkyl, and 4- to 10-membered heterocycloalkyl.

[0071] In some embodiments, R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 are H and C, respectively. 1-6 Alkyl, and C 1-6 haloalkyl.

[0072] In some embodiments, R a3 , R b3 , R c3 , and R d3 are H and C, respectively. 1-6 Alkyl, and C 1-6 haloalkyl.

[0073] In some embodiments, n is 0.

[0074] In some embodiments, compounds of formula II are provided herein. [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , X 3 , X 4 and Q are as defined herein, or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, compounds of formula III are provided herein. [ka] or a pharmaceutically acceptable salt thereof, wherein R Q Cy 1 , Cy 1 -C 1-4 Alkyl, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d C is selected from 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy1 , CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d is optionally substituted by 1, 2, or 3 substituents independently selected from

[0076] In some embodiments, R Q Cy 1 , Haro, C 1-6 Alkyl, OR a , and NR c R d C is selected from 1-6 Alkyl is OR a is optionally replaced by

[0077] In some embodiments, provided herein are compounds of formula (I), wherein X 3 is CR 3 or N; X 4 is CR 4 or N; A is a 5-membered heteroaryl group having 1, 2, or 3 ring-forming N atoms, and the 5-membered heteroaryl group of A is selected from halo and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; n is 0; Q is phenyl, C 3-6 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl, and the phenyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl are each represented by Cy. 1 , Haro, C 1-6 Alkyl, C 1-6 Haloalkyl, CN, OR a , N.R. c R d , and S(O)2R b and wherein said C is optionally substituted by 1, 2, or 3 substituents independently selected from 1-6 Alkyl is OR a is optionally replaced by; Cy 1 are OR a1 C optionally substituted by one or two substituents independently selected from 3-7 independently selected from cycloalkyl; R 1 is C 1-6 is alkyl; R 2 , R 3 , and R 4 are H, respectively; R a are H and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, a C 1-6Alkyl is OR a3 , C(O)NR c3 R d3 , and NR c3 R d3 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R b are respectively, C 1-6 independently selected from alkyl; R c and R d are H and C, respectively. 1-6 Alkyl, C 1-6 independently selected from haloalkyl, and 4- to 10-membered heterocycloalkyl; R a1 are H and C, respectively. 1-6 alkyl; and R a3 , R c3 , and R d3 are H and C, respectively. 1-6 The compound is provided wherein the alkyl is independently selected from the group consisting of aryl, aryl, aryl and alkyl.

[0078] In some embodiments, the compound is 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methylquinolin-2(1H)-one; 6-(1H-imidazol-1-yl)-1-methyl-4-(((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)amino)quinolin-2(1H)-one; 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,5-naphthyridin-2(1H)-one; 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one; 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridin-2(1H)-one; 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,7-naphthyridin-2(1H)-one; 2-(1H-imidazol-1-yl)-8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 8-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 2-(1H-imidazol-1-yl)-5-methyl-8-((4-(trifluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one; 2-(1H-imidazol-1-yl)-5-methyl-8-((6-(2-morpholinoethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one; 6-(1H-imidazol-1-yl)-1-methyl-4-(((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)amino)quinolin-2(1H)-one; 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one; 6-(1H-imidazol-1-yl)-1-methyl-4-((1-(methylsulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one; 2-(((1r,4r)-4-((6-(1H-imidazol-1-yl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)amino)cyclohexyl)oxy)-N,N-dimethylacetamide; 6-(1H-imidazol-1-yl)-1-methyl-4-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)quinolin-2(1H)-one; 4-(((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one; 4-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)amino)-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one; 6-(1H-imidazol-1-yl)-1-methyl-4-(((1r,4r)-4-(2-(pyrrolidin-1-yl)ethoxy)cyclohexyl)amino)quinolin-2(1H)-one; 8-(((1r,4r)-4-((2,2-difluoropropyl)amino)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 8-(1S,4r)-4-((S)-1-hydroxyethyl)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 2-(((1r,4r)-4-((2-(1H-imidazol-1-yl)-5-methyl-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-8-yl)amino)cyclohexyl)oxy)-N,N-dimethylacetamide; 4-((2-(1H-imidazol-1-yl)-5-methyl-6-oxo-5,6-dihydropyrido[3,2-d]pyrimidin-8-yl)amino)benzonitrile; 2-(1H-imidazol-1-yl)-5-methyl-8-(((1r,4r)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one; 2-(1H-imidazol-1-yl)-8-(((1r,4r)-4-methoxycyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 2-(1H-imidazol-1-yl)-5-methyl-8-((6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one; 8-((4,4-difluorocyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; 8-(((1r,4r)-4-(1-hydroxycyclopropyl)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one; and 8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one; or or a pharmaceutically acceptable salt of any of the foregoing.

[0079] It is to be further understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0080] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include any and all individual subcombinations of the members of such groups and ranges. For example, "C 1-6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0081] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described throughout this specification. Unless otherwise specified, these rings can be attached to the remainder of the molecule at any ring member allowed by valency. For example, the terms "pyridinyl," "pyridyl," or "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0082] The term "n-membered" (where "n" is an integer) typically refers to the number of atoms forming the ring in a moiety where "n" is the number of atoms forming the ring. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0083] In compounds of the invention having more than one variable, each variable may be a different moiety independently selected from the groups defining that variable. For example, if a structure is depicted as having two R groups coexisting in the same compound, the two R groups may represent different moieties independently selected from the groups defined as R.

[0084] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0085] As used herein, the term "substituted" means that a hydrogen atom has been replaced with a non-hydrogen group. It is understood that substitution at an atom is limited by valency.

[0086] As used herein, "C i-j The term "i and j" (where i and j are integers) is used in conjunction with a chemical group to specify a range of carbon atoms in that chemical group, with ij defining the range. For example, C 1-6 Alkyl means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0087] As used herein, the term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. In some embodiments, an 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, and n-heptyl. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0088] As used herein, "alkylene," employed alone or in combination with other terms, refers to a linking alkyl group.

[0089] As used herein, "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0090] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0091] As used herein, "halo" or "halogen," used alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0092] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having up to a full valence of halogen atom substituents, which may be the same or different. In some embodiments, the halogen atoms are fluorine atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.

[0093] As used herein, the term "alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0094] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-(haloalkyl). In some embodiments, the haloalkoxy group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkoxy groups include -OCF.

[0095] As used herein, "amino," used alone or in combination with other terms, refers to NH2.

[0096] As used herein, the term "alkylamino," used alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, alkylamino groups have 1 to 6 or 1 to 4 carbon atoms. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0097] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of formula -N(alkyl). Examples of alkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, the alkyl groups each independently have 1 to 6 or 1 to 4 carbon atoms.

[0098] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to non-aromatic cyclic hydrocarbons, such as cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two, three, or four fused, bridged, or spiro rings) ring systems. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to the cycloalkyl ring, such as benzo derivatives of cyclopentane, cyclohexene, cyclohexane, or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as adamantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused together through a single carbon atom, such as spiro[2.5]octane). In some embodiments, cycloalkyl groups have 3 to 10 ring members or 3 to 7 ring members. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are C 3-7Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0099] As used herein, the term "cycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the cycloalkyl portion 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 portion is monocyclic. In some embodiments, the cycloalkyl portion is C 3-7 It is a monocyclic cycloalkyl group.

[0100] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally include one or more alkenylene or alkynylene groups as part of the ring structure and has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Further included within the definition of heterocycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a common bond) to a non-aromatic heterocycloalkyl ring, such as 1,2,3,4-tetrahydroquinoline. When a heterocycloalkyl group contains a fused aromatic ring, the heterocycloalkyl group can be attached to the main structure through either an aromatic or non-aromatic ring. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-1-yl) and spiroheterocycloalkyl groups (heterocycloalkyl moieties containing at least two rings fused through a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl]). In some embodiments, heterocycloalkyl groups have 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, heterocycloalkyl groups have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms.Carbon atoms or heteroatoms in the ring(s) of a heterocycloalkyl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized. In some embodiments, the heterocycloalkyl moiety is C. 2-7 Monocyclic heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group 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.

[0101] As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is C 2-7 It is a monocyclic heterocycloalkyl group.

[0102] As used herein, the term "aryl," used 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.

[0103] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the aryl portion is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0104] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., fused ring system) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. Carbon atoms or heteroatoms in the ring(s) of a heteroaryl group can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized, as long as the aromatic character of the ring is preserved. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0105] As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkyl portion is methylene. In some embodiments, the heteroaryl portion 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 portion has 5 to 10 carbon atoms.

[0106] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Geometric isomers of olefins, 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 may be isolated as a mixture of isomers or as separated isomeric forms.

[0107] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and rings in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers, which result from the exchange of a single bond with an adjacent double bond with the concomitant migration of a methyl group. Methyltropic tautomers can include, for example, 2-methyl-2H-pyrazolo[3,4-c]pyridine and 1-methyl-1H-pyrazolo[3,4-c]pyridine.

[0108] The compounds of the present invention also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds contain at least one deuterium atom.

[0109] As used herein, the term "compound," unless otherwise specified, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0110] All compounds and pharmaceutically acceptable salts thereof may be found in or isolated together with other substances such as water and solvents (eg, in the form of hydrates and solvates).

[0111] In some embodiments, the compound of the present invention or a salt thereof is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched for the compound of the present invention. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound of the present invention or a salt thereof. Methods for isolating compounds and salts thereof are routine in the art.

[0112] 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 undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0113] 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 acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two. Lists of suitable salts are 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.

[0114] synthesis The compounds of the present invention (including their salts) may be prepared using known organic synthesis techniques, and may be synthesized according to any of a number of possible synthetic routes.

[0115] The reaction for preparing 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.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for that specific reaction step can be selected by those skilled in the art.

[0116] The preparation of compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0117] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0118] As used herein, the expressions "ambient temperature," "room temperature," and "RT" are understood in the art and generally refer to a temperature that is about the same as the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20°C to about 30°C, e.g., the reaction temperature.

[0119] The compound of formula I can be prepared according to a number of preparation routes known in the literature.The following scheme provides an exemplary synthetic method for preparing the compound of the present invention.Unless otherwise indicated, all substituents are as defined herein.

[0120] Scheme 1 [ka] Scheme 1 illustrates the synthesis of analogs following a general route utilizing well-established chemistry. Alkylated anilines can be treated with reagents such as iodosuccinimide or any N-halosuccinimide in a polar solvent such as DMF at room temperature to afford para-halogenated anilines (Step 1-1). Anilines can be acylated with a monoalkyl malonate and a base such as triethylamine in a solvent such as ethyl acetate (Step 1-2). The resulting ester can be hydrolyzed with a base such as sodium hydroxide in the presence of water to afford the carboxylic acid (Step 1-3), which can then be cyclized using phosphorus pentoxide under acidic conditions at elevated temperature (Step 1-4). The imidazole ring can be introduced by treatment with imidazole in a polar solvent such as DMSO at elevated temperature in the presence of a base such as KCO, a catalyst such as CuI, and a ligand such as L-proline (Step 1-5). The dione can be converted to a chloroquinolinone by treatment with a reagent such as phosphoryl chloride (Step 1-6). The resulting aryl chloride can be reacted with the amine NH2(L) in a non-polar solvent such as toluene at elevated temperature. n Treatment with Q and a Pd catalyst such as Pd(OAc) 2 , a ligand such as BINAP, and a base such as t-BuONa can convert to the desired analogs (steps 1-7).

[0121] Scheme 2 [ka] Scheme 2 illustrates an alternative route to the desired analogs. Heteroaryl amino acids can be treated with reagents such as iodosuccinimide or any N-halosuccinimide in a polar solvent such as acetic acid at room temperature or elevated temperature to give para-halogenated anilines (Step 2-1). The anilines can be acylated by treatment with a reagent such as acetic anhydride and a base such as triethylamine in a solvent such as THF (Step 2-2). The resulting amides can be alkylated with a reagent such as methyl iodide and a base such as cesium carbonate in a polar solvent such as DMF (Step 2-3), followed by cyclization with a strong base such as LiHMDS in a solvent such as THF (Step 2-4). The imidazole ring can be introduced by treatment with imidazole in the presence of a base such as KCO, a catalyst such as CuI, and a ligand such as L-proline in a polar solvent such as DMSO at elevated temperature (Step 2-5). The dione can be converted to a chloroquinolinone by treatment with a reagent such as phosphoryl chloride (Step 2-6). The resulting aryl chloride can be reacted with the amine NH2(L) in a non-polar solvent such as toluene at elevated temperature. n Treatment with Q and a Pd catalyst such as Pd(OAc) 2 , a ligand such as BINAP, and a base such as t-BuONa can convert to the desired analogs (steps 2-7).

[0122] Scheme 3 [ka] Scheme 3 illustrates another route to the desired analogs. Substituted haloaromatic esters can be coupled to five-membered heteroaromatic rings (Step 3-1) via several different methods known to those skilled in the art. These include, for example, coupling aromatic tributylstannanes in the presence of a Pd catalyst such as Pd(dppf)Cl2 in a polar solvent such as DMF at elevated temperatures. Alternatively, the imidazole ring can be introduced by treatment with imidazole in the presence of a base such as K2CO3, a catalyst such as CuI, and a ligand such as L-proline in a polar solvent such as DMSO at elevated temperatures. The bis-heterocycle can be converted to a dione via a one-pot reaction by treating an aryl fluoride with N-methylacetamide and a strong base such as LiHMDS in a solvent such as THF (Step 3-2). The dione can be converted to a chloroquinolinone by treatment with a reagent such as phosphoryl chloride (Step 3-3). The resulting aryl chloride can be converted to an amine NH2(L) in a nonpolar solvent such as toluene at elevated temperatures. n Treatment with Q and a Pd catalyst such as Pd(OAc) 2 , a ligand such as BINAP, and a base such as Cs 2 CO 3 can convert to the desired analogue (steps 3-4).

[0123] Scheme 4 [ka] Scheme 4 illustrates an alternative route to the desired analogs. Halofluoroheteroaryl esters can be treated with a reagent such as methylamine and a base such as DIEA in a solvent such as ACN at room temperature or elevated temperature to give methylamines (Step 4-1). Anilines can be acylated by treatment with a reagent such as an acyl chloride and a base such as triethylamine in a solvent such as DCM (Step 4-2). Cyclization can be achieved using a strong base such as LiHMDS in a solvent such as THF (Step 4-3). The imidazole ring can be introduced by treatment with imidazole in the presence of a base such as KCO, a catalyst such as CuI, and a ligand such as L-proline in a polar solvent such as DMSO at elevated temperature (Step 4-4). The dione can be converted to a chloroquinolinone by treatment with a reagent such as phosphoryl chloride (Step 4-5). The resulting aryl chloride can be converted to an amine NH(L) in a nonpolar solvent such as toluene at elevated temperature. n Treatment with Q and a Pd catalyst such as Pd(OAc) 2 , a ligand such as BINAP, and a base such as t-BuONa can convert to the desired analogs (steps 4-6).

[0124] How to use The compounds of the present invention can inhibit the activity of CD38. For example, the compounds of the present invention can be used to inhibit the activity or function of CD38 in cells or in individuals or patients in need of inhibition of the enzyme by administering an inhibitory effective amount of a compound of the present invention to the cells, individuals, or patients. As used herein, the term "intracellular" includes both within the cell membrane and on the surface of the cell membrane.

[0125] The compounds of the present invention act as CD38 inhibitors, inhibiting NAD + Thus, the present invention further provides a method for increasing the level of NAD in a sample or a patient. + 1. A method for increasing the level of NAD comprising contacting the sample with a compound of formula I or a pharmaceutically acceptable salt thereof or administering to a patient a compound of formula I or a pharmaceutically acceptable salt thereof, +The increase in the level of NAD before contact or administration + The present invention relates to a method in which the level of

[0126] The compounds of the present invention are useful for treating various diseases associated with abnormal expression or activity of CD38. For example, the compounds of the present invention are useful for treating cancer. In some embodiments, the cancer is characterized by abnormal expression or activity, e.g., increased expression or activity, of CD38 compared to normal cells. In some embodiments, cancers treatable by the present invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colon cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck (upper aerodigestive) cancer, urethral cancer, colon cancer, and the like.

[0127] The compounds of the invention are useful for treating T cell depleted tumors (see, e.g., Hashimoto M, Kamphorst AO, Im SJ, et al. CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med. 2018;69:301-318. doi:10.1146 / annurev-med-012017-043208) and tumors defined as inflammatory, altered, and non-inflammatory immune tumors based on immune scores (see, e.g., Galon J, Bruni D. Approaches to treat immune hot, altered, and cold tumors with combination immunotherapies. Nat Rev Drug Discov. 2019;18(3):197-218. doi:10.1038 / s41573-018-0007-y).

[0128] In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Examples of lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma. Examples of leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0129] In some embodiments, the cancer treatable by administration of the compounds of the invention is lung cancer.

[0130] In some embodiments, the cancer treatable by administration of the compounds of the invention is melanoma.

[0131] In some embodiments, the cancer treatable by administration of the compounds of the invention is colon cancer.

[0132] Other cancers that can be treated by administration of the compounds of the invention include cancers treated with checkpoint therapy, resistant cancers treated with checkpoint therapy, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0133] Other cancers that may be treated by administration of the compounds of the invention include bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0134] In some embodiments, cancers treatable by administration of the compounds of the invention are multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive tract cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0135] Other cancers that can be treated by administration of the compounds of the invention include cancers treated with checkpoint therapy, resistant cancers treated with checkpoint therapy, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC-infiltrated tumors.

[0136] 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, leprosy, tuberculosis, leishmaniasis, cardiac hypertrophy, congestive heart failure (CHF), muscular dystrophy, stroke, organ reperfusion injury, idiopathic pulmonary fibrosis, pancreatitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), irritable bowel syndrome (IBS), colitis, gout, obesity, sarcopenic obesity, metabolic syndrome, and metabolic syndrome. Rheumatism, end-stage renal failure, dyslipidemia, hearing loss, liver disease, steatosis, non-alcoholic steatohepatitis (NASH / NAFLD), asthma, allergic airway disease, Alzheimer's disease, multiple sclerosis, neurodegeneration, neurological disorders, systemic sclerosis, multisystem fibrosis, age-related diseases, neurocognitive disorders, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnup disease, skin hyperpigmentation, diabetic neuropathy, radiation exposure, ultraviolet-induced skin damage, psoriasis, periodontal disease, chronic lymphocytic leukemia, amyotrophic lateral sclerosis, Parkinson's disease, Leber's congenital amaurosis, insulin resistance, and type 1 diabetes.

[0137] The CD38 inhibitors of the present invention may also have therapeutic utility in CD38-associated disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly those diseases characterized by overexpression of CD38 or its increased activity.

[0138] As used herein, the term "cell" refers to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living within an organism, such as a mammal.

[0139] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" CD38 with a compound of the invention or "contacting" a cell with a compound of the invention includes administering a compound of the invention to an individual or patient, such as a human, that has CD38, as well as introducing a compound of the invention into a sample containing, for example, a cell preparation or purified preparation containing CD38.

[0140] As used herein, the terms "individual" or "patient," used interchangeably, refer to a mammal, particularly a human. An individual or patient may be in need of treatment.

[0141] As used herein, the phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician.

[0142] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease (i.e., halting further progression of the symptoms and / or symptomology) in an individual experiencing or exhibiting the symptoms or symptomology of the disease, or 2) ameliorating a disease (i.e., reversing the symptoms and / or symptomology) in an individual experiencing or exhibiting the symptoms or symptomology of the disease.

[0143] As used herein, the terms "preventing" or "prevention" refer to preventing disease in an individual who may be predisposed to the disease but who has not yet experienced or exhibited the symptoms or symptomology of the disease. In some embodiments, the present invention is directed to a method of preventing disease in a patient by administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0144] Combination therapy For example, one or more additional pharmaceutical agents or therapeutic methods can be used in combination with the compounds of the invention, such as chemotherapeutic or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapy, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic inhibitors, or signal transduction inhibitors. The agents can be combined with the compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0145] Suitable drugs for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapy, targeted cancer therapy, immunotherapy, or radiation therapy.The compounds of the present invention can be effective in combination with antihormonal agents for the treatment of breast cancer and other tumors.Suitable examples include antiestrogens, including but not limited to tamoxifen and toremifene, aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane, adrenergic corticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant).Suitable antihormonal agents used in the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention. These 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).

[0146] Suitable agents for use in combination with the compounds of the invention to treat cancer further include agents that target adenosine signaling such as A2aR and A2bR, inhibitors of the adenosine production pathway and nodes 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.

[0147] In some tumors, angiogenesis inhibitors can be effective in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0148] Suitable chemotherapeutic or other anti-cancer agents include alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as, for example, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0149] Other anti-cancer agent(s) include antibody therapeutics directed against checkpoint or costimulatory molecules, such as CTLA-4, PD-1, PD-L1, or 4-1BB, respectively, or antibodies directed against cytokines (such as IL-10 or TGF-β). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Additional anti-cancer agent(s) include antibody therapeutics directed against surface molecules of hematological cancers, such as ofatumumab, rituximab, and alemtuzumab.

[0150] Methods for safely and effectively administering 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 the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0151] Pharmaceutical Preparations and Dosage Forms When used as a pharmaceutical, the compound of the present invention can be administered in the form of a pharmaceutical composition. Pharmaceutical composition refers to the combination of the compound of the present invention or its pharmaceutically acceptable salt with at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be oral, topical (including ocular and mucous membranes, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer, intratracheal, intranasal, epithelial, and transdermal), ocular, or parenteral.

[0152] The present disclosure also includes pharmaceutical compositions containing one or more of the compounds of the present invention as active ingredients, combined with one or more pharmaceutically acceptable carriers.When preparing the compositions of the present invention, the active ingredient is typically mixed with additives, diluted by additives, or enclosed in such carriers, for example, in the form of capsules, sachets, paper, or other containers.When additives function as diluents, they can be solid, semi-solid, or liquid materials that act as vehicles, carriers, or mediums for the active ingredient.Therefore, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0153] The compositions may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients.

[0154] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0155] When preparing solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can 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 to about 500 mg of the active ingredient of the present invention.

[0156] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablets or pills can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope covering the former. These two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0157] Liquid forms into which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0158] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices that deliver the formulation in an appropriate manner.

[0159] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will be determined by the judgment of the attending clinician depending on factors such as the condition being treated and the severity of the disease, the age, weight, and general condition of the patient, etc.

[0160] The composition administered to patient can be in the form of the above-mentioned pharmaceutical composition.These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered.Aqueous solution can be packaged for immediate use or can be lyophilized, and lyophilized preparation is combined with sterile aqueous carrier before administration.

[0161] Therapeutic dosages of the compounds of the invention can vary depending, for example, on the particular application for which the treatment is given, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, a compound of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage can be determined by variables such as the type of disease or disorder and its progression, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the formulation of any excipients, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0162] The compounds of the present invention can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent such as an antiviral agent, an anticancer agent, a vaccine, an antibody, an immune enhancer, an immunosuppressant, an anti-inflammatory agent, etc. [Example]

[0163] The present invention will be described in more detail by specific examples.The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to achieve essentially the same results.The compounds of the examples have been found to be inhibitors of CD38 according to one or more of the assays provided herein.

[0164] Device: 1H NMR spectra were recorded at 300 or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Bruker Topspin software to assign chemical shifts and multiplicities. When two adjacent peaks of equal or unequal height are observed, these two peaks can be labeled as either a multiplet or a doublet. In the case of a doublet, a coupling constant can be assigned using this software. In any given example, one or more protons may not be observed because they are obscured by water and / or solvent peaks. The LCMS equipment and conditions are as follows:

[0165] 1. 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: water / 6.5 mM NH4HCO3, pH = 10; B: acetonitrile. Flow rate: 1.2 mL / min at 40 °C. Detector: 190-400 nm. Gradient stop time: 3.0 min. Process flow: [Table 1]

[0166] 2. LC (basic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Shim-pack scepter C18 33 x 3.0 mm, 3.0 μm. Mobile phase: A: water / 5 mM NH4HCO3; B: acetonitrile. Flow rate: 1.5 mL / min at 40 °C. Detector: 190-400 nm. Gradient stop time: 2.0 min. Process flow: [Table 2]

[0167] 3. LC (acidic conditions): Shimadzu LC-20ADXR, binary pump, diode array detector. Column: Halo C18, 30 x 3.0 mm, 2.0 μm. Mobile phase: A: water / 0.05% TFA, B: acetonitrile / 0.05% TFA. Flow rate: 1.5 mL / min at 40°C. Detector: 190-400 nm. Gradient stop time: 2.0 min. Process flow: [Table 3]

[0168] 4. LC (acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: Halo C18, 30 x 3.0 mm, 2.0 μm. Mobile phase A: water / 0.1% FA; Mobile phase B: acetonitrile / 0.1% FA. Flow rate: 1.5 mL / min at 40°C. Detector: 190-400 nm. Gradient stop time: 3.0 min. Process flow: [Table 4]

[0169] 5. The MS detector was configured with electrospray ionization as the ionization source. Acquisition mode: scan. Nebulization gas flow rate: 1.5 L / min. Drying gas flow rate: 15 L / min. Detector voltage: 0.95-1.25 kV. DL temperature: 250°C. Heat block temperature: 250°C. Scan range: 90.00-900.00 m / z.

[0170] 6. Sample preparation: Samples were dissolved in ACN or methanol at 1-10 mg / mL, and then filtered through a 0.22 μm filter membrane. Injection volume: 1-3 μL.

[0171] Definitions: ACN (acetonitrile); Ac2O (acetic anhydride); AcOH (acetic acid); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Cs2CO3 (cesium carbonate); CuI (copper iodide); DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); eq (equivalent); Et3N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); 1 H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); H2O (water); Hz (hertz); K2CO3 (potassium carbonate); L (liter); LCMS (liquid chromatography-mass spectrometry); LiHMDS (lithium bis(trimethylsilyl)amide); M (molar concentration); MeI (methyl iodide); MeOH (methanol); mg (milligram); MHz (megahertz); mL (milliliter), mmol (millimol); NaBH3CN (sodium cyanoborohydride); Na2CO3 (sodium carbonate); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); NIS (N-iodide) succinimide); NMP (N-methyl-2-pyrrolidone); P2O5 (phosphorus pentoxide); Pd / C (palladium on carbon); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane); Pd(OAc)2 (palladium(II) acetate); PE (petroleum ether); preparative HPLC (preparative high-performance liquid chromatography); RT (room temperature); t-BuOK (potassium tert-butoxide); t-BuONa (sodium tert-butoxide); TEA (triethylamine); THF (tetrahydrofuran); Ti(Oi-Pr)4 (titanium isopropoxide); TFA (trifluoroacetic acid).

[0172] Int-B1: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine [ka]

[0173] Step 1: (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol A mixture of (1r,4r)-4-aminocyclohexan-1-ol (30.0 g, 260.5 mmol, 1.0 equiv), benzyl bromide (133 g, 777.6 mmol, 3 equiv), and K2CO3 (72.0 g, 520.9 mmol, 2 equiv) in ACN (300 mL) was stirred at 75 °C for 2 h. The reaction was quenched with water. The solid was collected by filtration to give the title compound (65 g, 85%) as a white solid. LCMS: [M+H] + 296.2.

[0174] Step 2: (1r,4r)-N,N-Dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine A mixture of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (59 g, 199.7 mmol, 1 equiv.), 1-bromo-2-methoxyethane (82.6 g, 594.3 mmol, 3 equiv.), and t-BuOK (33.6 g, 299.2 mmol, 1.5 equiv.) in DCM (1 L) was stirred at room temperature for 4 h. The reaction was quenched with water and extracted with 3 x 500 mL of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / PE (5:95) to give the title compound (48 g, 68%) as a red oil. LCMS: [M+H] + 354.2.

[0175] Step 3: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine (60.0 g, 169.7 mmol, 1 equiv.) and Pd(OH)2C (10.0 g, 71.2 mmol, 0.42 equiv.) in EtOH (600 mL) were stirred under hydrogen at room temperature for 14 hours. The solid was filtered off. The filtrate was concentrated in vacuo to give the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H] + 174.1.

[0176] Example 1: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methylquinolin-2(1H)-one [ka]

[0177] Step 1: 4-Iodo-N-methylaniline A solution of N-methylaniline (23.0 g, 215 mmol, 1 equiv.) and NIS (48.3 g, 215 mmol, 1 equiv.) in DMF (240 mL) was stirred at room temperature for 1 h. The reaction was then quenched with water (500 mL). The resulting solution was extracted with EtOAc (3×600 mL). The organic layers were combined, washed with brine, and concentrated to give the title compound (41.5 g, 83%) as a black oil. LCMS: [M+H] + 234.00.

[0178] Step 2: Ethyl 3-((4-iodophenyl)(methyl)amino)-3-oxopropanoate. A solution of 4-iodo-N-methylaniline (41.0 g, 176 mmol, 1 equiv.), EtN (23.1 g, 229 mmol, 1.3 equiv.), and ethyl 3-chloro-3-oxopropanoate (39.7 g, 264 mmol, 1.5 equiv.) in EtOAc (500 mL) was stirred at room temperature for 2 h. The resulting solution was washed with HO (3×500 mL). The organic layer was concentrated, and the residue was purified by silica gel chromatography eluting with EtOAc / PE (1 / 9) to give the title compound (50 g, 82%) as a yellow oil. LCMS: [M+H] + 348.05.

[0179] Step 3: 3-((4-iodophenyl)(methyl)amino)-3-oxopropanoic acid A solution of NaOH (23.0 g, 576 mmol, 5.0 equiv.) in HO (50 mL) was added to a solution of ethyl 3-((4-iodophenyl)(methyl)amino)-3-oxopropanoate (40.0 g, 115 mmol, 1 equiv.) in MeOH (150 mL) at 0° C. The resulting solution was stirred at room temperature for 2 h. MeOH was removed by concentration, and then the pH value of the solution was adjusted to 4 with concentrated HCl. The solid was collected by filtration to give the title compound (20 g, 54%) as a black solid. LCMS: [M+H] + 319.95.

[0180] Step 4: 6-iodo-1-methylquinoline-2,4(1H,3H)-dione A solution of 3-((4-iodophenyl)(methyl)amino)-3-oxopropanoic acid (11.6 g, 36 mmol, 1.0 equiv) and P2O5 (10.3 g, 72 mmol, 2.0 equiv) in methanesulfonic acid (100 mL) was stirred at 100 °C for 5 h. Upon completion, the reaction was quenched with water. The insoluble solid was collected by filtration to give the title compound (9.87 g, 91%) as a black solid. LCMS: [M+H] + 301.15.

[0181] Step 5: 6-(1H-imidazol-1-yl)-1-methylquinoline-2,4(1H,3H)-dione A solution of 6-iodo-1-methylquinoline-2,4(1H,3H)-dione (2.00 g, 6.64 mmol, 1.0 equiv), 1H-imidazole (3.62 g, 53.1 mmol, 8 equiv), KCO (1.84 g, 13.3 mmol, 2 equiv), CuI (1.27 g, 6.64 mmol, 1.0 equiv), and L-proline (382 mg, 3.32 mmol, 0.50 equiv) in DMSO (25 ml) was stirred at 120 °C for 1.5 h. The reaction was concentrated, and the crude product was purified by reverse-phase column eluting with HO / ACN to give the title compound (800 mg, 50%) as a green solid. LCMS: [M+H] + 242.25

[0182] Step 6: 4-chloro-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one A solution of 6-(1H-imidazol-1-yl)-1-methylquinoline-2,4(1H,3H)-dione (5.5 g, 22.8 mmol, 1.0 equiv) in phosphoryl trichloride (40 mL) was stirred at 120° C. for 2 hours. The resulting mixture was concentrated to remove most of the phosphoryl trichloride. The crude product was dissolved in 100 mL of DCM. The pH value of the solution was adjusted to 8 with saturated aqueous Na2CO3 solution. The solid was filtered, the filtrate was extracted with DCM (3×500 mL), and the organic layers were combined and concentrated under vacuum to give the title compound (3.4 g, 57%) as a green solid. LCMS: [M+H] + 260.15.

[0183] Step 7: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methylquinolin-2(1H)-one A solution of 4-chloro-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one (200 mg, 0.77 mmol, 1.0 equiv), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (Int-B1, 200 mg, 1.16 mmol, 1.5 equiv), Pd(OAc) (17 mg, 0.077 mmol, 0.10 equiv), BINAP (48 mg, 0.077 mmol, 0.10 equiv), and t-BuONa (148 mg, 1.54 mmol, 2.0 equiv) in toluene (5 mL) was stirred at 60 °C under a nitrogen atmosphere for 3 h. The reaction was then concentrated in vacuo. The crude product was purified by reverse phase column eluting with H2O / ACN (2 / 1) to give the title compound (64.7 mg, 21%) as a white solid. LCMS: [M+H] + 397.20. 1 H NMR(300 MHz, DMSO-d6) δ 8.26(d, J=0.9 Hz,1H), 8.25(s,1H), 7.84(dd, J=2.4, 9.0 Hz, 1H), 7.78(t, J=1.5, 1.2 Hz, 1H), 7.53(d, J=9.3 Hz, 1H), 7.14(s, 1H), 6.55(d, J=7.2 Hz, 1H), 5.57(s, 1H), 3.60-3.51(m, 1H), 3.50(s, 3H), 3.50-3.43(m, 3H), 3.32-3.29(m, 2H), 3.20(s, 3H), 2.13-2.03(m, 4H), 1.50-1.20(m, 4H).

[0184] Example 2: 6-(1H-imidazol-1-yl)-1-methyl-4-(((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)amino)quinolin-2(1H)-one [ka]

[0185] Step 1: tert-butyl ((1r,4r)-4-((6-(1H-imidazol-1-yl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)amino)cyclohexyl)carbamate A solution of 4-chloro-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one (300 mg, 1.16 mmol, 1.0 equiv), tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (371 mg, 1.73 mmol, 1.5 equiv), Pd(OAc) (25.9 mg, 0.12 mmol, 0.10 equiv), BINAP (71.9 mg, 0.12 mmol, 0.10 equiv), and t-BuONa (222 mg, 2.31 mmol, 2.0 equiv) in toluene (6 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. The resulting solution was concentrated and purified by reverse phase column eluting with H2O / ACN (1 / 1) to give the title compound (296 mg, 59%) as a pale yellow solid. LCMS: [M+H] + 437.25

[0186] Step 2: 4-(((1r,4r)-4-aminocyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one dihydrochloride A solution of tert-butyl ((1r,4r)-4-((6-(1H-imidazol-1-yl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)amino)cyclohexyl)carbamate (276 mg, 0.63 mmol, 1.0 equiv) in HCl / 1,4-dioxane (10 mL, 4 M) was stirred at room temperature for 1 h. The reaction was then concentrated to remove most of the solvent. The solid was collected by filtration to give the crude title compound (261 mg) as a white solid. LCMS: [M+H] + 338.15.

[0187] Step 3: 6-(1H-imidazol-1-yl)-1-methyl-4-(((1r,4r)-4-(oxetan-3-ylamino)cyclohexyl)amino)quinolin-2(1H)-one A solution of 4-(((1r,4r)-4-aminocyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methylquinolin-2(1H)-one (130 mg, 0.39 mmol, 1.0 equiv), oxetan-3-one (83.3 mg, 1.16 mmol, 3.0 equiv), AcOH (23.1 mg, 0.39 mmol, 1.0 equiv), and Ti(Oi-Pr) (109.5 mg, 0.39 mmol, 1.0 equiv) in EtOH (5 mL) was stirred at 60 °C for 3 h. NaBHCN (36.3 mg, 0.58 mmol, 1.5 equiv) was then added, and the resulting solution was stirred at 80 °C for 1 h. Upon completion, the reaction was concentrated in vacuo. The crude product was purified by reverse phase column eluting with H2O / ACN (1 / 1) to give the title compound (14 mg, 9.2%) as a white solid. LCMS: [M+H] + 394.25. 1 H NMR(300 MHz, DMSO-d6) δ 8.29(s, 1H) , 8.26(d, J =4.8 Hz, 1H), 7.85(d, J=2.4 Hz, 1H), 7.83(s, 1H), 7.53(d, J=9.0 Hz, 1H), 7.14(d, J=0.9 Hz, 1H), 6.56(d, J=7.2 Hz, 1H), 5.52(s, 1H), 4.70- 4.60(m, 2H), 4.33- 4.20(m, 2H), 4.02-3.85(m, 1H), 3.52(s, 3H), 2.75-2.62(m, 1H), 2.46-2.30(m, 2H), 2.05-1.92(m, 2H), 1.83-1.70(m, 2H), 1.50-1.10(m, 4H).

[0188] Example 3: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,5-naphthyridin-2(1H)-one [ka]

[0189] Step 1: Ethyl 3-amino-6-iodopicolinate A solution of ethyl 3-aminopicolinate (10 g, 60.2 mmol, 1.0 equiv) and NIS (14.2 g, 63.2 mmol, 1.05 equiv) in acetic acid (35 mL) was stirred at room temperature for 3 hours and then heated at 50° C. for 12 hours. Upon completion, the reaction was concentrated and then diluted with 500 mL of water. The solid was collected by filtration to give the title compound (14.84 g, 84%) as a brown solid. LCMS: [M+H] + 292.15.

[0190] Step 2: Ethyl 3-acetamido-6-iodopicolinate A solution of ethyl 3-amino-6-iodopicolinate (7008 mg, 24 mmol, 1.0 equiv), AcO (9798 mg, 96 mmol, 4.0 equiv), TEA (4856 mg, 48 mmol, 2.0 equiv), and DMAP (2931 mg, 24 mmol, 1.0 equiv) in THF (30 mL) was stirred at 75 °C for 3 h. After completion, the solid was filtered. The filtrate was diluted with 100 mL of water and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / PE (3 / 7) to afford the title compound (4300 mg, 53%) as a pale yellow solid. LCMS: [M+H] + 335.15.

[0191] Step 3: Ethyl 6-iodo-3-(N-methylacetamido)picolinate A solution of ethyl 3-acetamido-6-iodopicolinate (4250 mg, 12.7 mmol, 1.0 equiv), iodomethane (2708 mg, 19.1 mmol, 1.5 equiv), and CsCO (6216 mg, 19.1 mmol, 1.5 equiv) in DMF (15 mL) was stirred at room temperature for 1 h. The resulting solution was quenched with water (250 mL) and extracted with ethyl acetate (3×250 mL). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (4.00 g, 90%) as a yellow oil. LCMS: [M+H] + 349.15.

[0192] Step 4: 6-Iodo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione Under a nitrogen atmosphere, to a solution of ethyl 6-iodo-3-(N-methylacetamido)picolinate (3900 mg, 11.2 mmol, 1.0 equiv) in THF (10 ml) was added LiHMDS in THF (13 mL, 1 M, 1.2 equiv) at 0° C. The reaction was stirred at room temperature for 0.5 h. Upon completion, the reaction was quenched with water (200 mL) and concentrated under reduced pressure to remove THF. The solid was collected by filtration to give the title compound (2.34 g, 70%) as a white solid. LCMS: [M+H] + 303.15.

[0193] Step 5: 6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione A solution of 6-iodo-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione (1000 mg, 3.31 mmol, 1.0 equiv.), 1H-imidazole (1803 mg, 26.5 mmol, 8.0 equiv.), KCO (915 mg, 6.62 mmol, 2.0 equiv.), CuI (631 mg, 3.31 mmol, 1.0 equiv.), and L-proline (191 mg, 1.66 mmol, 0.50 equiv.) in DMSO (6 mL) was stirred at 120 °C under a nitrogen atmosphere for 3 h. The solid was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with MeOH / DCM (17 / 83) to give the title compound (617 mg, 77%) as a brown solid. LCMS: [M+H] + 243.15

[0194] Step 6: 4-chloro-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one A solution of 6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridine-2,4(1H,3H)-dione (563.0 mg, 2.32 mmol, 1.0 equiv) in phosphoryl trichloride (8.0 mL) was stirred at 95° C. for 2 hours. The reaction was concentrated to remove most of the phosphoryl trichloride. The residue was dissolved in water at 0° C. The pH value of the solution was adjusted to 8 with saturated aqueous Na2CO3 solution. The solid was collected by filtration to give the title compound (287 mg, 47%) as a brown solid. LCMS: [M+H] + 261.25

[0195] Step 7: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,5-naphthyridin-2(1H)-one A solution of 4-chloro-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one (236 mg, 0.91 mmol, 1.0 equiv), 2-((1r,4r)-4-aminocyclohexyl)propan-2-ol (235 mg, 1.36 mmol, 1.5 equiv), Pd(OAc) (20.3 mg, 0.091 mmol, 0.10 equiv), BINAP (56.4 mg, 0.091 mmol, 0.10 equiv), and t-BuONa (174.0 mg, 1.81 mmol, 2.0 equiv) in toluene (5 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. The reaction was concentrated in vacuo and purified by reverse phase chromatography eluting with H2O / ACN (7 / 3) to give the title compound (31.1 mg, 8.6%) as a pale yellow solid. LCMS: [M+H] + 398.25. 1H NMR(400 MHz, DMSO-d6) δ 8.89(s, 1H), 8.25(t, J=1.2, 1.2 Hz, 1H), 8.11- 8.01(dd, J =1.2, 0.9 Hz, 2H), 7.14(s, 1H), 6.71(d, J=4.8 Hz, 1H), 5.71(s, 1H), 3.50-3.42(m, 5H), 3.43-3.33(m, 3H), 3.30-3.20(m, 4H), 2.07- 1.85(m, 4H), 1.59-1.42(m, 2H), 1.40- 1.28(m, 2H).

[0196] Example 4: 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one [ka]

[0197] Step 1: 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one A solution of 4-chloro-6-(1H-imidazol-1-yl)-1-methyl-1,5-naphthyridin-2(1H)-one (601 mg, 2.31 mmol, 1.0 equiv), 2-((1r,4r)-4-aminocyclohexyl)propan-2-ol (544 mg, 3.46 mmol, 1.50 equiv), Pd(OAc) (51.8 mg, 0.23 mmol, 0.10 equiv), BINAP (144 mg, 0.23 mmol, 0.10 equiv), and t-BuONa (443 mg, 4.61 mmol, 2.0 equiv) in toluene (5 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. Upon completion, the reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by reverse phase chromatography eluting with H2O / ACN (1 / 1) to give the title compound (125.2 mg, 14% yield) as a pale yellow solid. LCMS: [M+H] + 382.20. 1 H NMR(400 MHz, DMSO-d6) δ 8.89(s, 1H), 8.25(s, 1H), 8.06(dd, J=9.2, 13.2 Hz,2H), 7.15(s, 1H), 6.72(d, J=8.4 Hz, 1H), 5.66(s, 1H), 4.09(s, 1H), 3.53(s, 3H), 3.33-3.26(m, 1H), 2.10- 1.99(m, 2H), 1.90-1.80(m, 2H), 1.50-1.38(m, 2H), 1.32-1.12(m, 3H), 1.10-1.06(s, 6H).

[0198] Example 5: 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridin-2(1H)-one [ka]

[0199] Step 1: 5-acetamido-2-chloroisonicotinic acid A solution of 5-amino-2-chloroisonicotinic acid (10 g, 57.9 mmol, 1 equiv.), acetic anhydride (11.8 g, 116 mmol, 2.0 equiv.), and TEA (11.7 g, 116 mmol, 2.0 equiv.) in THF (30 mL) was stirred at room temperature for 6 hours. The reaction was quenched with water (30 mL), and the pH value of the solution was adjusted to 3 with HCl (2 M). The solid was collected by filtration to give the title compound (11 g, 88%) as a white solid. LCMS: [M+H] + 215.00.

[0200] Step 2: 2-chloro-5-(N-methylacetamido)isonicotinic acid methyl ester To a solution of 5-acetamido-2-chloroisonicotinic acid (28.0 g, 130 mmol, 1.0 equiv) in DMF (250 mL) was slowly added NaH (6.26 g, 261 mmol, 2.0 equiv) at 0 °C, and the mixture was stirred at 0 °C for 1 h. MeI (55.56 g, 391 mmol, 3.0 equiv) was then added to the reaction, and the mixture was stirred at room temperature for an additional 5 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was washed with brine (2 × 300 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / PE (1:1) to give the title compound (27 g, 85%) as a pale yellow solid. LCMS: [M+H] + 243.10.

[0201] Step 3: 6-chloro-1-methyl-1,7-naphthyridine-2,4(1H,3H)-dione To a solution of methyl 2-chloro-5-(N-methylacetamido)isonicotinate (26.0 g, 107 mmol, 1.0 equiv.) in THF (30 mL), LiHMDS (26.9 g, 161 mmol, 1.5 equiv.) was added slowly at 0° C., and the mixture was stirred at room temperature for 2 h. After completion, the reaction was quenched with water (100 mL), and the pH value of the solution was adjusted to 3 with HCl (2 M). The solid was collected by filtration to give the title compound (19 g, 84%) as a yellow solid. LCMS: [M+H] + 211.10.

[0202] Step 4: 6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridine-2,4(1H,3H)-dione A solution of 6-chloro-1-methyl-1,7-naphthyridine-2,4(1H,3H)-dione (18.0 g, 85.5 mmol, 1.0 equiv), 1H-imidazole (46.6 g, 684 mmol, 8.0 equiv), KCO (23.6 g, 171 mmol, 2.0 equiv), and CuI (16.3 g, 85.5 mmol, 1.0 equiv) in DMSO (200 mL) was stirred at 120 °C for 24 h. Upon completion, the reaction was concentrated and purified by silica gel chromatography eluting with DCM / MeOH (65 / 35) to afford the title compound (10 g, 48%) as a yellow solid. LCMS: [M+H] + 243.05.

[0203] Step 5: 4-chloro-6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridin-2(1H)-one A solution of 6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridine-2,4(1H,3H)-dione (9.00 g, 37.2 mmol, 1.0 equiv) in phosphoryl trichloride (50 mL) was stirred at 90° C. for 2 hours. After completion, the reaction was concentrated to remove most of the phosphoryl trichloride, and the residue was dissolved in water (100 mL) at 0° C. The pH value of the solution was adjusted to 6 with saturated aqueous NaHCO3 solution. The solid was collected by filtration. The solid was washed with ACN (2×30 mL) and dried in an oven to give the title compound (3.1 g, 32%) as a brown solid. LCMS: [M+H] + 261.05. 1 H NMR (300 MHz, DMSO-d6) δ 8.81(s, 1H), 8.50(s, 1H), 7.95(d, J=2.2 Hz, 2H), 7.19(s, 1H), 7.04(s, 1H), 3.59(s, 3H).

[0204] Step 6: 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridin-2(1H)-one A solution of 4-chloro-6-(1H-imidazol-1-yl)-1-methyl-1,7-naphthyridin-2(1H)-one (398 mg, 1.53 mmol, 1.0 equiv), 2-((1r,4r)-4-aminocyclohexyl)propan-2-ol (360 mg, 2.29 mmol, 1.5 equiv), Pd(OAc) (34.3 mg, 0.15 mmol, 0.10 equiv), BINAP (95.1 mg, 0.15 mmol, 0.10 equiv), and t-BuONa (293 mg, 3.05 mmol, 2.0 equiv) in toluene (3 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. After completion, the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with DCM / MeOH (95 / 5). The crude product was concentrated and further purified by reverse phase chromatography eluting with H2O / ACN (1 / 1) to give the title compound (93.1 mg, 24%) as a white solid. LCMS: [M+H] + 382.25. 1 H NMR(400 MHz, DMSO-d6) δ 8.72(s, 1H), 8.50(d, J=1.1 Hz, 1H), 8.32(s, 1H), 7.95(t, J=1.4 Hz, 1H), 7.18(t, J=1.2 Hz, 1H), 6.71(d, J=7.5 Hz, 1H), 5.68(s, 1H), 4.11(s, 1H), 3.59(s, 3H), 2.15- 2.06(m, 2H), 1.88- 1.81(m, 2H), 1.33-1.21(m, 6H), 1.07(s, 6H).

[0205] Example 6: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,7-naphthyridin-2(1H)-one [ka]

[0206] Step 1: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,7-naphthyridin-2(1H)-one A solution of 4-chloro-6-(imidazol-1-yl)-1-methyl-1,7-naphthyridin-2-one (156 mg, 0.59 mmol, 1.0 equiv.), (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (Int-B1, 156 mg, 0.89 mmol, 1.5 equiv.), Pd(OAc) (13.4 mg, 0.060 mmol, 0.10 equiv.), BINAP (37.3 mg, 0.060 mmol, 0.10 equiv.), and t-BuONa (115 mg, 1.19 mmol, 2.0 equiv.) in toluene (2 mL) was stirred at 75 °C under a nitrogen atmosphere for 2 h. The crude product was concentrated in vacuo and purified by reverse-phase chromatography eluting with HO / ACN (65 / 35). The product was further purified by preparative HPLC to give the title compound (44.8 mg, 19%) as a pale yellow solid. LCMS: [M+H] + 398.10. 1 H NMR(400 MHz, DMSO-d6) δ 8.72(s, 1H), 8.48(s, 1H), 8.29(s, 1H), 7.93(d, J=1.4 Hz, 1H), 7.18(d, J=1.2 Hz, 1H), 6.67(d, J=7.4 Hz, 1H), 5.72(s, 1H), 3.60-3.50(m, 5H), 3.48-3.38(m, 3H), 3.30-3.23(m, 4H), 2.08- 2.01(m, 4H), 1.45-1.30(m, 4H).

[0207] Example 7: 2-(1H-imidazol-1-yl)-8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one [ka]

[0208] Step 1: Ethyl 2-chloro-5-(methylamino)pyrimidine-4-carboxylate A solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (30.0 g, 147 mmol, 1.0 equiv), methanamine hydrochloride (9.90 g, 147 mmol, 1.0 equiv), and DIEA (56.9 g, 440 mmol, 3.0 equiv) in ACN (300 mL) was stirred at room temperature for 1 h. The reaction was diluted with EtOAc (200 mL) and washed with water (3 x 200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was diluted with 200 mL of PE. The solid was collected by filtration and dried to give the title compound (20 g, 63%) as a yellow solid. LCMS: [M+H] + 216.20.

[0209] Step 2: Ethyl 2-chloro-5-(N-methylacetamido)pyrimidine-4-carboxylate A solution of ethyl 2-chloro-5-(methylamino)pyrimidine-4-carboxylate (18.0 g, 83 mmol, 1.0 equiv), acetyl chloride (19.7 g, 250 mmol, 3.0 equiv), and TEA (16.9 g, 166 mmol, 2.0 equiv) in DCM (160 mL) was stirred at room temperature for 2 days. After completion, the reaction was quenched with water (200 mL), and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was passed through a silica gel column with EtOAc / PE (1:3) to afford the title compound (7.3 g, 34%) as a yellow solid. LCMS: [M+H] + 257.95.

[0210] Step 3: 2-chloro-5-methylpyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione To a solution of ethyl 2-chloro-5-(N-methylacetamido)pyrimidine-4-carboxylate (7.2 g, 28 mmol, 1.0 equiv.) in anhydrous THF (60 mL) was added LiHMDS (5.61 g, 33.5 mmol, 1.2 equiv.) slowly at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was concentrated in vacuo to remove THF and then poured into 30 mL of water. The pH value of the solution was adjusted to 5 with HCl (2 M), and then the solid was collected by filtration to give the title compound (4.2 g, 71%) as a purple solid. LCMS: [M+H] + 212.00.

[0211] Step 4: 2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione A solution of 2-chloro-5-methylpyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione (4.00 g, 18.9 mmol, 1.0 equiv), imidazole (10.3 g, 151 mmol, 8.0 equiv), KCO (5.22 g, 37.8 mmol, 2.0 equiv), CuI (3.60 g, 18.9 mmol, 1.0 equiv), and L-proline (0.05 g, 0.47 mmol, 0.02 equiv) in NMP (40 mL) was stirred at 130 °C for 5 h. Upon completion, the reaction was diluted with 300 mL of MeOH, the solids were filtered, and the filtrate was concentrated in vacuo to remove MeOH. The crude product was purified by silica gel chromatography eluting with DCM / MeOH (4:1) to afford the title compound (3.3 g, 72%) as a yellow solid. LCMS: [M+H] + 244.05.

[0212] Step 5: 8-chloro-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one A solution of 2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione (3.10 g, 12.8 mmol, 1.0 equiv) in phosphoryl trichloride (20 mL) was stirred at 90° C. for 1 hour. After completion, the reaction was concentrated in vacuo and then diluted with 100 mL of DCM. The resulting solution was quenched with ice water. The pH value of the solution was adjusted to 8 with saturated aqueous NaCO solution and extracted with DCM (3×200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (2.3 g, 69%) as a brown solid. LCMS: [M+H] + 262.05.

[0213] Step 6: 2-(1H-imidazol-1-yl)-8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one A solution of 8-chloro-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one (1000 mg, 3.82 mmol, 1.0 equiv.), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (Int-B1, 1324 mg, 7.64 mmol, 2.0 equiv.), Pd(OAc) (85.8 mg, 0.38 mmol, 0.10 equiv.), BINAP (238 mg, 0.38 mmol, 0.10 equiv.), and CsCO (2490 mg, 7.64 mmol, 2.0 equiv.) in toluene (8 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. After completion, the resulting mixture was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with HO / ACN (3:7). The collected fractions were concentrated in vacuo to remove ACN. The solid was collected by filtration to give the title compound (567.9 mg, 37%) as a white solid. LCMS: [M+H] + 399.20. 1H NMR(300 MHz, DMSO-d6) δ 9.07(s, 1H), 8.90(m,1H), 8.21(t, J=1.4 Hz, 1H), 7.14(t, J=1.2 Hz, 1H), 6.90(d, J=8.6 Hz, 1H), 5.86(s, 1H), 3.59- 3.49(m, 5H), 3.47-3.36(m, 3H), 3.33-3.20(m, 4H), 2.08-1.89(m, 4H), 1.55-1.39(m, 2H), 1.38-1.22(m, 2H).

[0214] Example 8: 8-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one [ka]

[0215] Step 1: 8-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one A solution of 8-chloro-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one (900 mg, 3.44 mmol, 1.0 equiv), 2-((1r,4r)-4-aminocyclohexyl)propan-2-ol (1082 mg, 6.88 mmol, 2.0 equiv), Pd(OAc) (77.2 mg, 0.34 mmol, 0.10 equiv), BINAP (214 mg, 0.34 mmol, 0.10 equiv), and CsCO (2241 mg, 6.88 mmol, 2.0 equiv) in toluene (7 mL) was stirred at 75 °C under a nitrogen atmosphere for 3 h. After completion, the reaction was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with HO / ACN (32:68). The collected fractions were concentrated in vacuo to remove ACN. The solid was collected by filtration to give the title compound (682 mg, 52%) as a white solid. LCMS: [M+H] + 383.25. 1 H NMR(400 MHz, DMSO-d6) δ 9.07(s, 1H), 8.92(t, J=1.1 Hz, 1H), 8.23(t, J=1.4 Hz, 1H), 7.15(t, J=1.3 Hz, 1H), 6.93(d, J=8.5 Hz, 1H), 5.82(s, 1H), 4.09(s, 1H), 3.55(s, 3H), 3.40-3.33(m, 1H), 2.05-1.98(m, 2H), 1.89-1.79(m, 2H), 1.51-1.38(m, 2H), 1.30- 1.12(m, 3H), 1.06(s, 6H).

[0216] Example 9: 2-(1H-imidazol-1-yl)-5-methyl-8-((4-(trifluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one [ka]

[0217] Step 1: 2-(1H-imidazol-1-yl)-5-methyl-8-((4-(trifluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one A solution of 8-chloro-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one (150 mg, 0.57 mmol, 1.0 equiv.), 4-(trifluoromethyl)aniline (185 mg, 1.15 mmol, 2.0 equiv.), Pd(OAc) (12.9 mg, 0.057 mmol, 0.10 equiv.), BINAP (35.7 mg, 0.057 mmol, 0.10 equiv.), and CsCO (373 mg, 1.15 mmol, 2.0 equiv.) in toluene (3 mL) was stirred at 80 °C under a nitrogen atmosphere for 4 h. The reaction was concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography eluting with HO / ACN (57:43). The collected fractions were combined and the ACN was removed by concentration. The solid was collected by filtration to give the title compound (48.4 mg, 22%) as a white solid. LCMS: [M+H] + 387.15. 1 H NMR(300 MHz, DMSO-d6) δ 9.30(s, 1H), 9.22(s, 1H), 9.00(s, 1H), 8.32(t, J=1.4 Hz, 1H), 7.84(d, J=8.6 Hz, 2H), 7.69(d, J=8.4 Hz, 2H), 7.19(t, J=1.2 Hz, 1H), 6.43(s, 1H), 3.63(s, 3H).

[0218] Example 10: 2-(1H-imidazol-1-yl)-5-methyl-8-((6-(2-morpholinoethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one [ka]

[0219] Step 1: 4-(2-((5-nitropyridin-2-yl)oxy)ethyl)morpholine A solution of 2-fluoro-5-nitropyridine (724 mg, 5.10 mmol, 1.0 equiv), 4-morpholineethanol (1003 mg, 7.64 mmol, 1.5 equiv), and t-BuOK (1144 mg, 10.2 mmol, 2.0 equiv) in DCM (15 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction was diluted with 30 mL of DCM and washed with water (3×50 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc / PE (3:7) to afford the title compound (1.1 g, 85%) as a yellow solid. LCMS: [M+H] + 254.15.

[0220] Step 2: 6-(2-morpholinoethoxy)pyridin-3-amine A solution of 4-(2-((5-nitropyridin-2-yl)oxy)ethyl)morpholine (600 mg, 2.37 mmol, 1.0 equiv) and Pd / C (252 mg, 2.37 mmol, 1.0 equiv) in EtOH (6 mL) was stirred under a hydrogen atmosphere at room temperature for 1 h. After completion, the solid was filtered and the filtrate was concentrated in vacuo to give the title compound (502 mg, 93%) as a black oil. LCMS: [M+H] + 224.15.

[0221] Step 3: 2-(1H-imidazol-1-yl)-5-methyl-8-((6-(2-morpholinoethoxy)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-6(5H)-one A solution of 8-chloro-2-(1H-imidazol-1-yl)-5-methylpyrido[3,2-d]pyrimidin-6(5H)-one (130 mg, 0.50 mmol, 1.0 equiv), 6-(2-morpholinoethoxy)pyridin-3-amine (222 mg, 0.99 mmol, 2.0 equiv), Pd(OAc) (11.2 mg, 0.050 mmol, 0.10 equiv), BINAP (30.9 mg, 0.050 mmol, 0.10 equiv), and CsCO (324 mg, 0.99 mmol, 2.0 equiv) in toluene (3 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. After completion, the reaction was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with HO / ACN (33:67). The collected fractions were concentrated in vacuo to remove ACN. The solid was collected by filtration to give the title compound (79.8 mg, 35%) as a yellow solid. LCMS: [M+H] + 449.20. 1 H NMR(400 MHz, DMSO-d6) δ 9.16(s, 1H), 9.08(s, 1H), 8.94(d, J=1.2 Hz, 1H), 8.29(t, J=1.4 Hz, 1H), 8.19(d, J=2.7 Hz, 1H), 7.78(dd, J=8.8, 2.8 Hz, 1H), 7.17(t, J=1.3 Hz, 1H), 6.96(d, J=8.8 Hz, 1H), 5.80(s, 1H), 4.41(t, J=5.8 Hz, 2H), 3.65-3.49(m, 7H), 2.71(t, J=5.8 Hz, 2H), 2.55-2.40(m, 4H).

[0222] The examples in Table 1 below were prepared according to the methods described in the previous examples. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0223] Example 28: 8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one [ka]

[0224] Step 1: Ethyl 5-fluoro-2-(thiazol-5-yl)pyrimidine-4-carboxylate Under a nitrogen atmosphere, a solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (4.0 g, 19.5 mmol, 1.0 equiv.), 5-(tributylstannyl)thiazole (7.7 g, 20.5 mmol, 1.05 equiv.), and Pd(dppf)Cl (1.4 g, 1.9 mmol, 0.1 equiv.) in DMF (40 mL) was stirred at 80° C. for 2 h. After concentration, the crude product was purified by reverse-phase column eluting with HO / ACN (7 / 3) to give the title compound (2.7 g, 53%) as a brown solid. LCMS: [M+H] + 254.10.

[0225] Step 2: 5-Methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione LiHMDS (7.9 mL, 7.9 mmol, 2.0 equiv, 1 M) in THF was slowly added to a solution of N-methylacetamide (577 mg, 7.9 mmol, 2.0 equiv) in THF (6 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred at room temperature for 1 hour. Then, a solution of ethyl 5-fluoro-2-(thiazol-5-yl)pyrimidine-4-carboxylate (1.0 g, 3.9 mmol, 1.0 equiv) in THF (5.0 mL) was added to the above mixture and stirred at room temperature for 1.5 hours. The reaction was quenched with water (15 mL). The pH value of the solution was adjusted to 5 with aqueous HCl (1.5 M). The solid was collected by filtration and dried in an oven to give the title compound (361 mg, 30%) as a brown solid. LCMS: [M+H] + 260.15.

[0226] Step 3: 8-chloro-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one A solution of 5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidine-6,8(5H,7H)-dione (400 mg, 1.5 mmol, 1.0 equiv) in phosphoryl trichloride (7 mL) was stirred at 90° C. for 2 hours. The resulting mixture was concentrated to remove most of the phosphoryl trichloride. The crude product was dissolved in 50 mL of DCM. The pH value of the solution was adjusted to 8 with saturated aqueous Na2CO3 solution. The resulting mixture was concentrated to remove DCM. The solid was collected by filtration and dried in an oven to give the title compound (266 mg, 62%) as a brown solid. LCMS: [M+H] + 279.25.

[0227] Step 4: 8-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one 8-chloro-5-methyl-2-(thiazol-5-yl)pyrido[3,2-d]pyrimidin-6(5H)-one (100 mg, 0.36 mmol, 1.0 equiv.), (1r,4r)-4-(2-methoxyethoxy)cyclohexane-1-amine (Int-B1, 93.2 mg, 0.54 mmol, 1.5 equiv.), Pd(OAc)2 (8.06 mg, 0.036 mmol, 0.1 equiv.), BINA in toluene (6 mL). A solution of P (22.3 mg, 0.036 mmol, 0.1 equiv) and CsCO (234 mg, 0.72 mmol, 2.0 equiv) was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting solution was concentrated in vacuo. The crude product was dissolved in 3 mL of DMF and purified by reverse-phase column eluting with HO / ACN (43 / 57) to give the title compound (75 mg, 50%) as a pale brown solid. LCMS: [M+H] + 416.20; 1 H NMR(400 MHz, DMSO-d6) δ 9.21(s, 1H), 9.07(s, 1H), 8.96(s, 1H), 6.75(d, J=8.4 Hz, 1H), 5.86(s, 1H), 3.62-3.50(m, 5H), 3.48-3.42(m, 3H), 3.30-3.25(m, 4H), 2.07- 1.96(m, 4H), 1.60-1.46(m, 2H), 1.45-1.31(m, 2H).

[0228] Example A CD38 enzyme assay The CD38 enzyme assay was performed as previously described (Becherer, JD, et al. J. Med. Chem. 2015, 58, 7021-7056). Briefly, 200 nL dose-response titrations of each test compound dissolved in 100% DMSO were spotted onto clear polystyrene 384-well plates (Thermo Product No. 264704) using a Mosquito (TTP Labtech). A 10 μL solution of 2 nM CD38 (BPS Biosciences, product number 71227) suspended in 100 mM HEPES ((4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, pH = 7.5), 4 mM EDTA (2,2',2'',2''''-(ethane-1,2-diyldinitrilo)tetraacetic acid), and 1 mM CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) was incubated with test compound for 30 min at 25°C. 400 μM nicotinamide adenine dinucleotide (NAD + The enzymatic reaction was initiated by adding 10 μL of 1000 μM (E)-2-(2-(pyridin-4-ylmethylene)hydrazinyl)pyridine in a buffer (pH = 5.2) containing 5 mM sodium acetate, 1 mM CHAPS, and 5 mM HCl. The reaction was incubated at 25°C, and the absorbance at 405 nm was measured after 60 minutes on an Envision plate reader (Perkin Elmer).

[0229] The compound 4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1H)-one was synthesized as previously described (Haffner CD, et al. J. Med. Chem. 2015, 58, 3548-3571). Control wells containing a negative control of 1% DMSO vehicle or a positive control of 100 μM 4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-6-(thiazol-5-yl)quinolin-2(1H)-one were used to calculate percent inhibition as follows:

number

[0230] The % inhibition values ​​were plotted as a function of compound concentration and the following four-parameter fit was applied to determine the IC 50 The value of is derived:

number

[0231] Compounds of the invention IC in this assay 50 The data are provided in Table A-1 below ("+" is <0.01 μM; "++" is ≧0.01 and <0.1 μM; "+++" is ≧0.1 μM and <1 μM, and "++++" is ≧1 μM). [Table 6]

[0232] Example B. Treatment with CD38 inhibitors in a dose-response in vivo PD study. NAD + Quantification of NAD + A bioanalytical method for the quantification of α-glucan was developed and utilized in PK / PD studies. The method utilized protein precipitation (PP) extraction of samples followed by LC / MS / MS analysis. It utilized a sample volume of 0.02 mL and demonstrated a linear assay range of 10 to 10,000 ng / mL. This assay was successfully applied to the analysis of samples such as spleen and liver.

[0233] Dexamethasone was used to prepare the internal standard (IS) solution as shown in the table below. [Table 7]

[0234] The LC-MS / MS system consisted of a degasser DGU-20A5R, C, a liquid chromatograph LC-30AD, a communication bus module CBM-20A, an autosampler SIL-30AC, a rack changer II, and an AB Sciex Triple Quads 5500 LC-MS / MS mass spectrometer.

[0235] Positive mode electrospray ionization (ESI) was performed on a Turbo V ion source to obtain NAD + The protonated ions of NAD and dexamethasone (IS) were obtained. Multiple reaction monitoring (MRM) was selected for quantitative analysis. + The optimized transitions for HCl and dexamethasone were 664.038→136.2 and 393.40→373.3, respectively. The instrument parameters were set as follows: ion spray voltage: 5500 V; curtain gas: 40 psi; nebulizer gas: 50 psi; turbo gas: 50 psi; collision gas: 10 psi; temperature: 400° C. The compound-dependent parameters are listed in the table below: [Table 8]

[0236] NAD +As a standard stock solution, IS was prepared at 1 mg / mL (free form) in 0.5 N perchloric acid by vortexing. Calibration standard working solutions were prepared at concentrations of 10, 20, 50, 100, 500, 1000, 2000, 5000, and 10,000 ng / mL by serial dilution of the standard stock solution with 50% methanol in water (0.1% formic acid). Quality control working solutions at concentrations of 20, 50, 500, 4000, and 8000 ng / mL were prepared by serial dilution of the standard stock solution with water. These QC samples were prepared on the day of analysis in the same manner as the calibration standards. Dexamethasone was prepared as a standard stock solution at 50 mg / mL (free form) in DMSO by vortexing. A final IS concentration of 50 ng / mL was then prepared by dilution of the IS stock solution with methanol (0.1% formic acid).

[0237] Twenty microliters of working solution (10, 20, 50, 100, 500, 1000, 2000, 5000, and 10,000 ng / mL) was added to 20 μL of blank 0.5 N perchloric acid to achieve calibration standards ranging from 10 to 10,000 ng / mL (10, 20, 50, 100, 500, 1000, 2000, 5000, and 10,000 ng / mL) in a total volume of 40 μL. Five quality control samples at 20 ng / mL, 50 ng / mL, 500 ng / mL, 4000 ng / mL, and 8000 ng / mL in 0.5 N perchloric acid were prepared separately from those used for the calibration curve. These QC samples were prepared on the day of analysis using the same method as the calibration standards.

[0238] The LC-MS / MS system consisted of a degasser DGU-20A5R, C, a liquid chromatograph LC-30AD, a communication bus module CBM-20A, an autosampler SIL-30AC, a rack changer II, and an AB Sciex Triple Quads 5500 LC / MS / MS mass spectrometer.

[0239] Chromatographic separation was performed on a Waters Atlantis T3 3um 4.6 x 100mm at room temperature. The mobile phase consisted of A: 5mM ammonium acetate (0.1% formic acid); B: methanol. The flow rate was 0.6mL / min. The injection volume was 15µL. The elution gradient is listed in the table below: [Table 9]

[0240] In vivo PD studies C57BL / 6 mice were administered 10, 30, 100, 300, or 1000 mg / kg of the compound of Example 7 in a vehicle formulation of 0.5% hydroxypropylmethylcellulose (HPMC) + 0.1% Tween 80 adjusted to pH 3.5 with citrate buffer. Plasma PK samples were collected at endpoint. Approximately 500 μL of whole blood was collected into a 1.5 mL tube containing 8 μL of 15% ethylenediaminetetraacetic acid dipotassium salt (EDTA-2K) solution. Samples were centrifuged at 6000 rpm for 5 minutes at 4°C, and approximately 200 μL of plasma was isolated and sent for bioanalysis. Samples of the whole spleen, left lobe of the liver, and whole adrenal-free left kidney were collected at endpoint to measure NAD. + Measurements were performed. Spleen, liver, and kidney samples were cut into 100-400 mg portions, their wet weights recorded, and then placed in tubes containing 0.5 N perchloric acid (1:4 ratio, (mg / μL)) within 30 seconds. Samples were flash-frozen in dry ice and stored at -80°C.

[0241] In room temperature matrices, NAD +Due to the instability of ATP, samples were stored in 0.5N perchloric acid immediately after collection and then homogenized at -80°C. A medallion bead lysis matrix containing a CD38 inhibitor and dexamethasone was added to each tube along with a 4-fold dilution of the sample in 0.5N perchloric acid. The sample was homogenized in a RETSCH MM40 at 20 m / s for 60 seconds. The homogenate was diluted 100-fold with 0.5N perchloric acid, and then 20 μL of the diluted sample was mixed with 20 μL of 50% methanol in water (0.1% formic acid) and 200 μL of methanol (0.1% formic acid) containing the internal standard (dexamethasone) for protein precipitation. The sample was then vortexed for 30 seconds. The sample was centrifuged at 4000 rpm for 5 minutes at 4°C, and the supernatant was diluted 5-fold with 5 mM ammonium formate. For quantitative analysis, 15 μL of diluted supernatant was injected into the LC / MS / MS system.

[0242] FIG. 1A shows the NAD levels in the spleen at a single time point after administration of various doses of the compound of Example 7. + Figure 1B is a graph of NAD concentration in the liver at a single time point after administration of various doses of the compound of Example 7. + 1 is a graph showing the concentration of

[0243] Various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each of the references mentioned in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X 3 CR 3 And, X 4 is N; or X3 is N, and X4 is CR4; A is a five-membered heteroaryl group having one, two, or three ring-forming heteroatoms selected from N, O, and S, wherein the five-membered heteroaryl group of A is a halo and C 1-4 Optionally substituted with one, two, or three substituents independently selected from the alkyl group; L is C 1-4 It is an alkylene linker; n is either 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, and the C of said Q 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, Cy 1 、Cy 1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 、OR 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) 2 R b 、NR c S(O) 2 NR c R d 、S(O)R b 、S(O)NR c R d 、S(O) 2 R b 、及びS(O) 2 NR c R d independently selected from 1, 2, 3, 4, or 5 substituents optionally substituted by, said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are Cy 1 、CN、NO 2 、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) 2 R b 、NR c S(O) 2 NR c R d 、S(O)R b 、S(O)NR c R d 、S(O) 2 R b 、及びS(O) 2 NR c R d Optionally substituted by one, two, or three substituents independently selected from; Cy 1 These are C 6-10 Ariel, C 3-7 A cycloalkyl, a 5-10 member heteroaryl, and a 4-10 member heterocycloalkyl are independently selected, each of which is a halo, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , 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) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 S(O)R b1 S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 Optionally substituted by one, two, three, or four substituents independently selected from; R 1 C 1-6 It is alkyl; R 2 , R 3 , and R 4 These are H, Haro, and C respectively. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 6-10 Ariel, C 3-7 Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl, 4-10 member heterocycloalkyl-C 1-4 Alkyl, CN, NO 2 , 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 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 ) R b2 , C(=NR e2 ) NR c2 R d2 , NR c2 C (=NR e2 ) NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 Selected independently from, the R 2 , R 3 , and R 4 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 6-10 Ariel, C 3-7 Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Alkyl are represented by Halo and C respectively. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, CN, NO 2 , 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 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 ) R b2 , C(=NR e2 ) NR c2 R d2 , NR c2 C (=NR e2 ) NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 S(O)R b2 S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 Optionally substituted by one, two, three, four, or five substituents independently selected from; 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 H and C are respectively 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, C 3-7 Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Selected independently from alkyl, and R a , R b , R c , R d , R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , and R d2 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, C 3-7 Cycloalkyl, 5-10 member heteroaryl, 4-10 member heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 member heteroaryl-C 1-4 Alkyl and 4-10 member heterocycloalkyl-C 1-4 Alkyl is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, 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) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 Optionally substituted by one, two, three, four, or five substituents independently selected from; Or, R c and R d Together with the N atom to which they are bonded, they form a halo, 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) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 Forms a 4- to 7-membered heterocycloalkyl group which is optionally substituted by one, two, or three substituents independently selected from; Or, R c1 and R d1 Together with the N atom to which they are bonded, they form a halo, 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) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 Forms a 4- to 7-membered heterocycloalkyl group which is optionally substituted by one, two, or three substituents independently selected from; Or, R c2 and R d2 Together with the N atom to which they are bonded, they form a halo, 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) 2 R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , and S(O) 2 NR c3 R d3 Forms a 4- to 7-membered heterocycloalkyl group which is optionally substituted by one, two, or three substituents independently selected from; R a3 , R b3 , R c3 , and R d3 H and C are respectively 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, C 3-7 A cycloalkyl, a 5-6 member heteroaryl, and a 4-7 member heterocycloalkyl are independently selected, and the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 6-10 Ariel, C 3-7 Cycloalkyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl are, respectively, OH, CN, amino, halo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Optionally substituted with one, two, or three substituents independently selected from the haloalkoxy; and R e , R e1 , R e2 , and R e3 H and C are respectively 1-4 A component independently selected from alkyl and CN. The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is imidazolyl or thiazolyl, each of which is optionally substituted with one, two, or three substituents independently selected from halo and C1-4 alkyl groups.

3. A is, 【Chemistry 2】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X3 is CR3.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X3 is N.

6. The compound according to any one of claims 1 to 3 and 5 or a pharmaceutically acceptable salt thereof, wherein X4 is CR4.

7. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein X4 is N.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.

9. R 2 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , 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 , 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) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 Selected from S(O)R b2, S(O)NR c2R d2, S(O) 2R b2, and S(O) 2NR c2R d2, or R² is H. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R 3 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , 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 , 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) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 Selected from S(O)R b2, S(O)NR c2R d2, S(O) 2R b2, and S(O) 2NR c2R d2, or R3 is H. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. R 4 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , 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 , 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) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 Selected from S(O)R b2, S(O)NR c2R d2, S(O) 2R b2, and S(O) 2NR c2R d2, or R4 is H. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. Q is a C6-10 aryl, a C3-14 cycloalkyl, a 5-14 member heteroaryl, or a 4-14 member heterocycloalkyl, where the C6-10 aryl, C3-14 cycloalkyl, 5-14 member heteroaryl, and 4-14 member heterocycloalkyl of Q are, respectively, Cy1, Cy1-C1-4 alkyl, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, 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 ) are optionally substituted with one, two, three, four, or five substituents independently selected from 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)2 R b, NR c S(O)2 NR c R d, S(O)R b, S(O)NR c R d, S(O)2 R b, and S(O)2 NR c R d, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are Cy1, 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) 2 R b , NR c S(O) 2 NR c R d , S(O) R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, optionally substituted by one, two, or three substituents independently selected from the compound.

13. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is phenyl, C3-6 cycloalkyl, 5-6 member heteroaryl, or 4-6 member heterocycloalkyl, and the phenyl, C3-6 cycloalkyl, 5-6 member heteroaryl, and 4-6 member heterocycloalkyl of Q are optionally substituted with one, two, or three substituents independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, OR a, NR c R d, and S(O)2 R b, and the C1-6 alkyl is optionally substituted with OR a.

14. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is cyclohexyl, phenyl, pyridinyl, or piperidinyl, each of which is optionally substituted with one or two substituents independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, OR a, NR c R d, and S(O)2 R b, wherein the C1-6 alkyl is optionally substituted with OR a.

15. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is a cyclohexyl substituted with one or two substituents independently selected from Cy1, halo, C1-6 alkyl, ORa, and NRcRd, wherein the C1-6 alkyl is optionally substituted with ORa.

16. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is a phenyl substituted with C1-6 haloalkyl or CN.

17. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is a pyridinyl substituted with OR a.

18. Q is 4-(2-methoxyethoxy)cyclohexyl, 4-(oxetane-3-ylamino)cyclohexyl, 4-(2-hydroxypropane-2-yl)cyclohexyl, 4-((2,2,2-trifluoroethyl)amino)cyclohexyl, 4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 4-(2-(pyrrolidine-1-yl)ethoxy)cyclohexyl, 4-((2,2-difluoropropyl)amino)cyclohexyl, 1-hydroxyethyl)cyclohexyl, 4-(2-(dimethylamino)-2-oxoethoxy)cyclohexyl, 4-((2,2, A compound according to any one of claims 1 to 12, selected from 2-trifluoroethyl)amino)cyclohexyl, 4-methoxycyclohexyl, 4,4-difluorocyclohexyl, 4-(1-hydroxycyclopropyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 4-cyanophenyl, 6-(2-morpholinoethoxy)pyridine-3-yl, 6-(2,2,2-trifluoroethoxy)pyridine-3-yl, 6-(2-(dimethylamino)ethoxy)pyridine-3-yl, 6-(2-(pyrrolidine-1-yl)ethoxy)pyridine-3-yl, and 1-(methylsulfonyl)piperidine-4-yl, or a pharmaceutically acceptable salt thereof.

19. Each Cy 1 is independently selected from C3-7 cycloalkyls, which are optionally substituted by one or two substituents independently selected from OR a1, or The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein Cy 1 is 1-hydroxycyclopropyl.

20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and 4-10 member heterocycloalkyl-C1-4 alkyl, and the C1-6 alkyl of Ra is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OR a3, C(O)NR c3 R d3, and NR c3 R d3.

21. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Rc and Rd are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and 4- to 10-membered heterocycloalkyl.

22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein n is 0.

23. Formula II 【Transformation 3】 A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, having the above.

24. Formula III 【Chemistry 4】 The compound according to any one of claims 1 to 22 having formula III, wherein R Q is selected from Cy 1, halo, C 1-6 alkyl, OR a, and NR c R d, and the C 1-6 alkyl is optionally substituted with OR a.

25. X3 is CR3 and X4 is N; or X3 is N, and X4 is CR4; A is a five-membered heteroaryl group having one, two, or three ring-forming N atoms, wherein the five-membered heteroaryl group A is optionally substituted with one, two, or three substituents independently selected from halo and C1-4 alkyl groups; n is 0; Q is phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycloalkyl, wherein the phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl of Q are optionally substituted with one, two, or three substituents independently selected from Cy1, halo, C1-6 alkyl, C1-6 haloalkyl, CN, OR a, NR c R d, and S(O)2 R b, and the C1-6 alkyl is optionally substituted with OR a; Each Cy 1 is independently selected from C3-7 cycloalkyl groups, which are optionally substituted with one or two substituents independently selected from OR a1; R1 is a C1-6 alkyl group; R2, R3, and R4 are each H; Each of Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and 4-10 member heterocycloalkyl-C1-4 alkyl, and the C1-6 alkyl of Ra is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OR a3, C(O)NR c3 R d3, and NR c3 R d3; Rb is independently selected from C1-6 alkyl groups; Rc and Rd are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and 4- to 10-membered heterocycloalkyl; R a1 is independently selected from H and C 1-6 alkyl groups; and R a3, R c3, and R d3 are each independently selected from H and C 1-6 alkyl groups. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

26. The compound is 6-(1H-imidazole-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,5-naphthyridine-2(1H)-one; 4-(((1r,4r)-4-(2-hydroxypropane-2-yl)cyclohexyl)amino)-6-(1H-imidazole-1-yl)-1-methyl-1,5-naphthyridine-2(1H)-one; 4-(((1r,4r)-4-(2-hydroxypropane-2-yl)cyclohexyl)amino)-6-(1H-imidazole-1-yl)-1-methyl-1,7-naphthyridine-2(1H)-one; 6-(1H-imidazole-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,7-naphthyridine-2(1H)-one; The compound according to claim 1, which is selected from or a pharmaceutically acceptable salt of any of the above.

27. ​​A compound which is 6-(1H-imidazole-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,5-naphthyridine-2(1H)-one, or a pharmaceutically acceptable salt thereof.

28. A compound that is 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazole-1-yl)-1-methyl-1,5-naphthyrizine-2(1H)-one, or a pharmaceutically acceptable salt thereof.

29. A compound that is 4-(((1r,4r)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)-6-(1H-imidazole-1-yl)-1-methyl-1,7-naphthyrizine-2(1H)-one, or a pharmaceutically acceptable salt thereof.

30. A compound which is 6-(1H-imidazole-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl-1,7-naphthyridine-2(1H)-one, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable additive.

32. A pharmaceutical composition containing a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting the function of CD38, comprising contacting CD38 with a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to claim 32, wherein the CD38 is located inside a cell.

34. The pharmaceutical composition according to claim 32, wherein the contact occurs in vitro or in vivo.

35. A pharmaceutical composition for use in a method of treating cancer in a patient requiring cancer treatment, comprising administering to the patient a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30.

36. The pharmaceutical composition according to claim 35, wherein the cancer is selected from cancer treated with checkpoint therapy, cancer resistant to checkpoint therapy, adenosine-dependent tumor, Treg-invasive tumor, and MDSC-invasive tumor.

37. The pharmaceutical composition according to claim 35, wherein the cancer is lung cancer, melanoma, or colon cancer.

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