Improved NF-κB-inducing kinase (NIK) inhibitors

Abstract

The present invention provides novel compounds of formula (I) and pharmaceutical compositions containing these compounds. The compounds of formula (I) can function as NF-κB-inducing kinase (NIK) inhibitors, and in particular can induce the intracellular degradation of NIK, making these compounds highly advantageous for use in therapeutic methods, including the treatment or prevention of cancer, inflammatory diseases, and autoimmune diseases. [Case 1] TIFF2025536982000085.tif62149

Description

[Technical Field]

[0001] The present invention provides novel compounds of formula (I) and pharmaceutical compositions containing these compounds. The compounds of formula (I) can function as NF-κB-inducing kinase (NIK) inhibitors, and in particular can induce the intracellular degradation of NIK, making them highly advantageous for use in therapeutic methods, including the treatment or prevention of cancer, inflammatory diseases, and autoimmune diseases. [Background technology]

[0002] Activation of the NF-κB pathway is involved in many pathologies, including cancer and inflammatory diseases. In addition to the canonical NF-κB pathway, which is primarily induced during proinflammatory processes, the non-canonical NF-κB pathway (or NF-κB2) is also overactivated in many cancers and B cell-mediated autoimmune pathologies. This non-canonical NF-κB pathway is known to be regulated by the activity of the kinase NIK (NF-κB-inducing kinase), also known as MAP3K14. In adult tissues, NIK is not only constitutively expressed as a protein but is also constitutively degraded by the proteasome. Upon triggering of specific receptors (CD40LR, BAFFR, lymphotoxin-βR), NIK is dissociated from its protein partners, inhibiting its constitutive degradation and thus increasing its stability in the cytosol, thus enhancing its activity as a governor of the NF-κB2 cascade (reviewed in Sun SC, Nat Rev Immunol, 2017, 17(9):545-558, doi:10.1038 / nri.2017.52). NIK is overexpressed in many hematological and solid cancers and has been reported as one of the key molecules involved in cancer cell proliferation, tumorigenicity, and immune evasion (Maubach G et al., Biochim Biophys Acta Rev Cancer, 2019, 1871(1):40-49, doi:10.1016 / j.bbcan.2018.10.002). For example, in melanoma cells, NIK positively regulates the expression of EZH2, an oncogenic lysine methyltransferase that suppresses the gene expression of genes involved in immunogenicity factors and cellular senescence (De Donatis GM et al., Oncogene, 2016, 35(21):2735-45, doi:10.1038 / onc.2015.331). More recently, a pool of intracellular NIK located in the outer mitochondrial membrane of glioblastoma cells has been discovered and implicated in mitochondrial fission, a process that allows cancer cells to increase the number of mitochondria per cell and adapt to the high energy demands associated with aggressive proliferation. Interestingly, the role of NIK in mitochondrial fission is independent of its activity on the NF-κB2 pathway.Furthermore, NIK is involved in providing energy to cancer cells in nutrient-limited environments, enabling malignant cells to switch from glycolysis to oxidative phosphorylation for ATP production (Kamradt ML et al., Cell Death Dis, 2021, 12(3):271, doi:10.1038 / s41419-020-03383-z). In B cells, NIK is involved in the differentiation of naive B cells into antibody-secreting memory B cells, a key factor in autoimmune diseases caused by the pathological production of autoantibodies, such as systemic lupus erythematosus (SLE) (Brightbill HD et al., Nat Commun, 2018, 9(1):179, doi:10.1038 / s41467-017-02672-0).

[0003] Given the prominent role of NIK in the pathogenesis of cancer, inflammatory and autoimmune diseases, intense research and development efforts have been undertaken to discover small molecules capable of specifically modulating NIK kinase activity.

[0004] To date, a wide range of small molecules have been reported as NIK inhibitors. For example, the pan-kinase inhibitor staurosporine was found to inhibit kinase activity at micromolar levels (Mortier J et al., Bioorganic Med Chem Lett, 2010, 20(15):4515-4520, doi:10.1016 / j.bmcl.2010.06.027). In 2005, the first series of pyrazolo[4,3-c]isoquinoline derivatives was characterized by Sanofi (WO 2004 / 005287). Following this initial identification, virtual screening yielded 49 hits from 67,500 core structures in 2010 (Mortier J et al., op. cit.). An IC of 51 μM was obtained. 50 These 49 hits were selected and tested in the radiometric assay for identification of compounds with value.

[0005] In 2012, Genentech reported nanomolar IC50 values ​​from high-throughput screening and subsequent optimization. 50reported a new potent NIK inhibitor, yielding compounds with IC values ​​of 0.60 μM (De Leon-Boenig G et al., Structure, 2012, 20(10):1704-1714, doi:10.1016 / j.str.2012.07.013). This first identification of an NIK inhibitor by co-crystallization with the catalytic domain of NIK served as a starting point for many researchers in academia and the pharmaceutical industry. Thus, in 2013, Amgen reported a compound with IC values ​​of 0.60 μM. 50 reported another high-throughput screen with the identification of new hits of value (Li K et al., Bioorganic Med Chem Lett, 2013, 23(5):1238-1244, doi:10.1016 / j.bmcl.2013.01.012).

[0006] The first set of identified NIK inhibitors was then used to develop a molecular docking-based QSAR model, which enabled the identification and evaluation of new indole aminopyrimidine derivatives as potent NIK inhibitors with significantly improved inhibitory activity (Ye Q et al., Chem Phys Lett, 2019, 718 (October 2018): 38-45, doi:10.1016 / j.cplett.2019.01.031).

[0007] Genentech's further optimization of NIK inhibitors led to the discovery of a series of tricyclic inhibitors in 2017 by co-crystallization of the lead compound with NIK (Castanedo GM et al., J Med Chem, 2017, 60(2):627-640, doi:10.1021 / acs.jmedchem.6b01363). Following the development of these compounds, a new series of 3-hydroxypyrrolidin-2-one derivatives was identified in 2018 (Blaquiere N et al., J Med Chem, 2018, 61(15):6801-6813, doi:10.1021 / acs.jmedchem.8b00678). Aiming to improve metabolic stability, researchers further identified a new 4-methoxy-2-amidopyridine compound, also known as NIK SMI1, with the highest potency and metabolic stability (Blaquiere N et al., cited above). Based on this study and the identification of the binding mode, a new 2-amine-5H-pyrrolo[3,2-d]-pyrimidine structure was obtained by Zhao's group by replacing the 2-amidopyridine group of NIK SMI1 (Li Z et al., J Med Chem, 2020, 63(8):4388-4407, doi:10.1021 / acs.jmedchem.0c00396).

[0008] In 2018, screening of a different Prestwick library selected N-acetyl-3-aminopyrazole, whose activity was increased by further modification to an IC of 8.4 μM. 50 (Pippione AC et al., Medchemcomm, 2018, 9(6):963-968, doi:10.1039 / c8md00068a).

[0009] In 2020, Chen et al. reported a series of 7H-pyrrolo[2,3-d]pyrimidin-4-amines as potent NIK inhibitors (Chen Y et al., J Med Chem, 2020, 63(13):6748-6773, doi:10.1021 / acs.jmedchem.0c00055). Two new cocrystal structures involving NIK cocrystallized with indoline and azaindoline were reported by Janssen (Jacoby E et al., Futur Drug Discov, 2020, 2(3):FDD43, doi:10.4155 / fdd-2020-0004). Genentech recently pursued the optimization of these series to obtain azabicyclo[3.1.0]hexanone-containing inhibitors (Crawford JJ et al., Synth, 2020, 52(22):3420-3426, doi:10.1055 / s-0040-1707279).

[0010] Further notable reports on 4-anilinoquinolines as NIK inhibitors and their use in the treatment of cancer, including cutaneous melanoma, lymphoma, and leukemia, include patent applications WO 2015 / 032800, WO 2018 / 007648, WO 2019 / 134969, and WO 2019 / 134975.

[0011] However, despite these intense research and development efforts, none of the previous attempts to obtain small molecules capable of specifically modulating NIK kinase activity in cancer, inflammatory diseases, or autoimmune diseases have led to the development of pharmaceuticals approved by regulatory agencies.Therefore, there remains an urgent and unmet need to provide new and improved compounds that modulate NIK for use in therapy, particularly for therapeutic intervention in cancer, inflammatory diseases, and autoimmune diseases. Summary of the Invention

[0012] The present invention addresses this need and provides novel compounds that target NIK and have highly advantageous therapeutic profiles. In particular, the present invention provides novel compounds that have been found to effectively induce the intracellular degradation of NIK. Given the profound impact of NIK on various cellular functions involved in the pathogenesis of cancer, inflammatory diseases, and autoimmune diseases, significantly reducing its intracellular concentration is an efficient way to halt NIK activity, whether in the cytosol or mitochondria, and whether or not it is dependent on the NF-κB2 pathway. Therefore, the NIK-specific degradation inducers provided in accordance with the present invention constitute a fundamentally novel and promising therapeutic approach. The clinically beneficial consequences of NIK degradation induced by these novel molecules are diverse and include the inhibition of cell proliferation and the induction of cellular senescence without cytotoxicity. Furthermore, these novel NIK degradation inducers can modulate the role of NIK in mitochondrial fission by inhibiting NIK-induced phosphorylation of DRP1 (a key player in mitochondrial fission). These effects make the compounds provided herein particularly advantageous for therapeutic uses, including the treatment of cancer, inflammatory diseases, and autoimmune diseases.

[0013] Accordingly, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0014] In formula (I), ring A is selected from the following groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7): [ka] is an aromatic group selected from Group (A-1) is substituted by group R A1 and group R A2 and is substituted with one or more groups R A3phenyl or 6-membered monocyclic heteroaryl optionally further substituted with Groups (A-2) and (A-3) each contain a group R A1 and group R A2 and is substituted with one or more groups R A3 is a 5-membered monocyclic heteroaryl optionally further substituted with Group (A-4) is substituted by group R A2 and is substituted with one or more groups R A3 an 8-membered bicyclic heteroaryl optionally further substituted with Groups (A-5) and (A-6) each have a group R A2 and is substituted with one or more groups R A3 is a 9-membered bicyclic heteroaryl optionally further substituted with Group (A-7) is a group R A2 and is substituted with one or more groups R A3 or naphthyl or a 10-membered bicyclic heteroaryl optionally further substituted with

[0015] Surprisingly in the context of the present invention, two substituents R A1 and R A2 or a second fused ring having a substituent R at a specific position shown in formulas (A-4), (A-5), (A-6), and (A-7) above. A2 It has been found that compounds of formula (I) having ring A containing and advantageously exhibit improved therapeutic properties, including significantly more potent inhibitory effect on cell proliferation and significantly enhanced senescence-inducing activity. Thus, as summarized in the table below, compounds of Examples 9 and 10 according to the present invention have ring A but contain substituents R at specific positions required by the present invention. A1 and R A2and "Compound 42" and "Compound 43" disclosed in WO 2019 / 134969 (which contain substituents R at specific positions required by the present invention). A1 and R A2 It was also demonstrated that the compound (containing both α- and β-glucan) exhibited improved activity in the proliferation and senescence assays described in Example 143, compared to a compound (containing both α- and β-glucan) but not both. [Table 1] * This reference compound, i.e., 7-chloro-N-(4-(2-methoxyethoxy)phenyl)quinolin-4-amine, corresponds to "Compound 42" disclosed on page 22 of WO 2019 / 134969. ** This reference compound, i.e., 7-chloro-N-(3-(hydroxy)-4-(methoxy)phenyl)quinolin-4-amine, corresponds to "Compound 43" disclosed on page 23 of WO 2019 / 134969.

[0016] In formula (I), R A1 is -O(C 1~5 alkyl), -O(C 2~5 alkenyl), C 1~5 Alkyl, C 2~5 Alkenyl, -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 and the cycloalkyl group in the -(C alkylene)-cycloalkyl 0~3 Each heterocycloalkyl group in the (alkylene)-heterocycloalkyl may be one or more groups R Cyc and optionally substituted with -(C 0~3 alkylene)-cycloalkyl or the -(C0~3 One or more -CH2- units contained in the alkylene in the alkylene)-heterocycloalkyl are each -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0017] R A2 is C 1~12 Alkyl, -(C 1~12 alkylene)-OH, -(C 0~5 alkylene)-O(C 1~12 alkyl), -(C 0~5 alkylene)-O(C 1~12 haloalkyl), -(C 0~5 alkylene)-O-(C 1~12 alkylene)-OH, -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 alkyl), -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl), -CO(C 1~12 alkyl), -CO(C 1~12 haloalkyl), -SO2-(C 1~12 alkyl), -SO2-(C 1~12 haloalkyl), halogen, C 1~5 Haloalkyl, -(C 0~5 alkylene)-carbocyclyl and -(C 0~5 alkylene)-heterocyclyl, wherein said C 1~12 alkyl, the -(C 1~12 alkylene)-OH, 0~5 alkylene)-O(C 1~12 alkyl), the -(C 0~5 alkylene)-O(C 1~12 haloalkyl), the -(C 0~5 alkylene)-O-(C 1~12 alkylene)-OH, 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 alkyl), the -(C0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl), the —CO(C 1~12 alkyl), the —CO(C 1~12 haloalkyl), -SO2-(C 1~12 alkyl) or -SO2-(C 1~12 One or more -CH2- units in the haloalkyl) are each -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -(C alkyl)-, -CO-, and -CH=CH-, 0~5 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~5 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Cyc and optionally substituted with -(C 0~5 alkylene)-carbocyclyl or the -(C 0~5 One or more -CH2- units contained in the alkylene in the alkylene)-heterocyclyl are each -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0018] Each R A3 If present, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more -CH2- units contained in the alkylene in the alkylene)-heterocyclyl are each -O-, -NH-, -N(C 1~5and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0019] R N is hydrogen, C 1~5 Alkyl and -CO-(C 1~5 alkyl).

[0020] R 1 , R 4 and R 5 are hydrogen and C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more -CH2- units contained in the alkylene in the alkylene)-heterocyclyl are each -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0021] R 2 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl and -(C 0~3 alkylene)-heterocyclyl, wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more -CH2- units contained in the alkylene in the alkylene)-heterocyclyl are each -O-, -NH-, -N(C 1~5and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, and -SO-.

[0022] R 3 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-CHF2, -(C 0~3 alkylene)-CHF, -(C 0~3 alkylene)-(C 2~5 haloalkyl), -(C 0~3 alkylene)-O-(C1~5 haloalkyl), -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl and -(C 0~3 alkylene)-heterocyclyl, wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more -CH2- units contained in the alkylene in the alkylene)-heterocyclyl are each -O-, -NH-, -N(C 1~5 optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-; 3 is not morpholin-4-yl or -NH-phenyl, and the phenyl group in said -NH-phenyl is Cyc is optionally replaced by

[0023] Each R Cyc is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -R 6 -R 7 wherein said -(C 0~3 and the cycloalkyl group in the -(C alkylene)-cycloalkyl 0~3 Each heterocycloalkyl group in the alkylene-heterocycloalkyl is 1~5 Alkyl, C2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl) and -SO-(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0024] Each R 6 is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each independently selected from halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and wherein one or more -CH2- units contained in said alkylene, said alkenylene or said alkynylene are each independently selected from -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0025] Each R 7 -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and optionally substituted with one or more groups independently selected from alkyl.

[0026] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient.Accordingly, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or any of the above entities and a pharmaceutically acceptable excipient for use as a medicament.

[0027] The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the above entities and a pharmaceutically acceptable excipient for use in the treatment or prevention of cancer, inflammatory diseases or autoimmune diseases. The present invention therefore particularly provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient for use in the treatment or prevention of cancer, inflammatory diseases or autoimmune diseases.

[0028] The present invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of cancer, an inflammatory disease or an autoimmune disease.

[0029] The present invention also relates to a method of treating or preventing cancer, inflammatory disease or autoimmune disease, comprising administering to a subject (preferably a human) in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the above entities in combination with a pharmaceutically acceptable excipient. It will be understood that a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (or pharmaceutical composition) can be administered in accordance with this method.

[0030] As explained above, diseases / disorders that can be treated or prevented with compounds of formula (I) or a pharmaceutically acceptable salt thereof (or corresponding pharmaceutical composition) in accordance with the present invention include cancer, inflammatory diseases and autoimmune diseases, among others.

[0031] The cancer that can be treated or prevented may be, for example, a solid cancer or a blood cancer. In particular, cancers that can be treated or prevented according to the present invention include breast cancer (e.g., triple-negative breast cancer), prostate cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), colon cancer, colorectal cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, kidney cancer, head cancer, neck cancer, blood cancer, Merkel cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, extranodal lymphoma or non-extranodal lymphoma), leukemia (e.g., acute lymphoblastic leukemia), and the like. Preferably, the cancer is selected from the group consisting of leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myelogenous leukemia, bone cancer, bone marrow cancer, brain cancer (e.g., glioblastoma), esophageal cancer, gum cancer, nasopharyngeal cancer, skin cancer, melanoma, stomach cancer, tongue cancer, uterine cancer, anal cancer, genitourinary cancer, bladder cancer, endometrial cancer, vaginal cancer, vulvar cancer, testicular cancer, biliary tract cancer, hepatic gallbladder cancer, neuroblastoma, epidermoid carcinoma, squamous cell carcinoma, fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, laryngeal cancer, oral cancer, thymoma, neuroendocrine carcinoma, or multiple myeloma. The cancer (including any one of the specific types of cancer listed above) may be, for example, a primary cancer or a metastatic cancer.

[0032] As explained above, the cancer that can be treated or prevented according to the present invention may be a blood cancer, particularly lymphoma or leukemia. Preferably, the blood cancer that can be treated or prevented is a Hodgkin's lymphoma (or Hodgkin's disease), including, for example, nodular sclerosing Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte-rich Hodgkin's lymphoma, lymphocyte-depleted Hodgkin's lymphoma, non-Hodgkin's lymphoma, including, for example, follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma). lymphoma, nodular lymphocyte-predominant Hodgkin's lymphoma, e.g., mycosis fungoides, Sézary's disease, T-zone lymphoma, peripheral / cutaneous T-cell lymphoma including lymphoepithelioid cell lymphoma (e.g., Lennert's lymphoma) or peripheral T-cell lymphoma, lymphosarcoma, malignant immunoproliferative disorders including, e.g., Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin disease) or immunoproliferative small intestinal disease (e.g., Mediterranean disease), e.g., multiple myeloma, including Köhler's disease or myelomatosis, plasma cell leukemia, e.g. acute lymphoblastic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g. leukemic reticuloendotheliosis) or lymphocytic leukemia, including hairy cell leukemia (e.g. leukemic reticuloendotheliosis) or adult T-cell leukemia, e.g. acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myelosarcoma (e.g. chloroma or granulocytic sarcoma), acute promyelocytic leukemia or acute myelomonocytic leukemia myeloid leukemia including myeloid leukemia, for example polycythemia vera, chronic BCR-ABL negative myeloproliferative disorders including essential thrombocythemia or idiopathic myelofibrosis, monocytic leukemia, acute erythrombocytosis or erythroleukemia, for example acute erythrocytic myelopathy or Di Guglielmo disease, chronic erythrombocytosis, for example Heilmeyer-Schonell disease, acute megakaryoblastic leukemia, mast cell leukemia, acute panmyelosis, acute myelofibrosis and Letterer-Siwe disease.

[0033] Further, cancers include, for example, malignant tumors, carcinomas, undifferentiated carcinomas, giant cell carcinomas, spindle cell carcinomas, small cell carcinomas, papillary carcinomas, squamous cell carcinomas, lymphoepithelial carcinomas, basal cell carcinomas, pilomatricomas, transitional cell carcinomas, papillary transitional cell carcinomas, adenocarcinomas, malignant gastrinomas, biliary tract carcinomas, hepatocellular carcinomas, mixed hepatocellular and cholangiocarcinomas, trabecular adenocarcinomas, adenoid cystic carcinomas, adenomatous intrapolypoid adenocarcinomas, familial adenomatous polyposis, solid tumors, malignant carcinoid tumors, bronchioloalveolar carcinomas, papillary adenocarcinomas, chromophobe carcinomas, acidophilic carcinomas, acidophilic adenocarcinomas, basophilic carcinomas, clear cell adenocarcinomas, granular cell tumors, follicular adenocarcinomas, papillary adenocarcinomas, follicular adenocarcinomas, nonencapsulated sclerosing carcinomas, adrenocortical carcinomas, and anaplastic lymphomas. Endometrial carcinoma, skin adnexal carcinoma, apocrine gland carcinoma, sebaceous gland carcinoma, cerumen gland carcinoma, adenocarcinoma, mucoepidermoid carcinoma, cystadenocarcinoma, papillary cystadenocarcinoma, papillary serous cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, invasive ductal carcinoma, medullary carcinoma, lobular carcinoma, inflammatory carcinoma, Paget's disease, acinic cell carcinoma, adenosquamous carcinoma, adenocarcinoma with squamous metaplasia, malignant thymoma, malignant ovarian stromal tumor, malignant thecoma, malignant granulosa cell tumor, malignant neuroblastoma, Sertoli cell tumor, malignant Leydig cell tumor, malignant lipid cell tumor, malignant paraganglioma, malignant extramammary paraganglioma, pheochromocytoma, malignant glomus tumor, malignant melanoma, Pigmented melanoma, superficial spreading melanoma, malignant melanoma in giant pigmented nevi, epithelioid cell melanoma, malignant blue nevi, sarcoma, fibrosarcoma, malignant fibrous histiocytoma, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, stromal sarcoma, malignant mixed tumor, mixed Müllerian tumor, nephroblastoma, hepatoblastoma, carcinosarcoma, malignant mesenchymoma, malignant Brenner tumor, malignant phyllodes tumor, synovial sarcoma, malignant mesothelioma, dysgerminoma, embryonal carcinoma, malignant teratoma, malignant ovarian stromal tumor, choriocarcinoma, malignant mesonephroma, angiosarcoma, malignant hemangioendothelioma, Kaposi's sarcoma, malignant hemangiopericytoma, lymphatic vessels Sarcoma, osteosarcoma, parosteal osteosarcoma, chondrosarcoma, malignant chondroblastoma, mesenchymal chondrosarcoma, giant cell tumor of bone, Ewing's sarcoma, malignant odontogenic tumor, ameloblastic sarcoma, malignant ameloblastoma, ameloblastic fibrosarcoma, malignant pinealoma, chordoma, malignant glioma, ependymoma, astrocytoma, protoplasmic astrocytoma, fibrillary astrocytoma, astroblastoma, glioblastoma, oligodendroglioma, oligodendroglioma, primitive neuroectodermal tumor, cerebellar sarcoma, ganglioneuroblastoma, neuroblastoma, retinoblastoma, olfactory neurogenic tumor, malignant meningioma, neurofibrosarcoma, malignant neurilemmoma, malignant granular cell tumor, malignant lymphoma, natural killer (NK) leukemia,The tumor may be an NK lymphoma (e.g., extranodal or non-extranodal natural killer / T-cell (NK / T) lymphoma), an NK cell-derived malignancy, acute NK leukemia, Hodgkin's disease, Hodgkin's lymphoma, granulomatous granulomatosis, malignant small lymphocytic lymphoma, malignant large cell diffuse lymphoma, malignant follicular lymphoma, mycosis fungoides, non-Hodgkin's lymphoma, malignant histiocytosis, multiple myeloma, mast cell sarcoma, immunoproliferative small intestinal disease, leukemia, lymphocytic leukemia, plasma cell leukemia, erythroleukemia, lymphosarcoma cell leukemia, myeloid leukemia, basophilic leukemia, eosinophilic leukemia, monocytic leukemia, mast cell leukemia, megakaryoblastic leukemia, myeloid sarcoma, or hairy cell leukemia.

[0034] Preferably, inflammatory diseases that can be treated or prevented according to the present invention are arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, uric acid arthritis, gout, chronic polyarthritis, shoulder periarthritis, cervical arthritis, lumbosacral arthritis, enteropathic arthritis, ankylosing spondylitis, asthma, dermatitis, psoriasis, scleroderma, polymyositis, dermatomyositis, juvenile dermatomyositis, primary biliary cirrhosis, fibrosis, cystic fibrosis. , pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, renal fibrosis, keloids, scleroderma, arthrofibrosis, delayed and / or chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, pemphigus, pemphigus vulgaris, pemphigus herpetiformis, pemphigus vegetans, IgA pemphigus, pemphigus erythematosus, bullous pemphigoid, pemphigoid gestationis, mucodermatoses, nodular pemphigoid, linear IgA bullous dermatosis Dermatitis, bullous lichen planus, epidermolysis bullosa acquisita, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vascular disease, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves' disease, gastrointestinal allergy, conjunctivitis, atherosclerosis, coronary artery disease, angina pectoris, small artery disease, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, systemic sclerosis, antiphospholipid syndrome syndrome, Sjogren's syndrome, autoimmune hemolytic anemia, colitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), embolism, pulmonary embolism, arterial embolism, venous embolism, allergic inflammation, cardiovascular disease, transplant-related disease, graft-versus-host disease (GVHD), disorders associated with graft rejection, post-traumatic degeneration, stroke, transplant rejection, allergic conditions, hypersensitivity, allergic rhinitis, allergic eczema, and inflammatory diseases of the skin.

[0035] Additionally, autoimmune diseases that can be treated or prevented in accordance with the present invention include lupus (e.g., lupus erythematosus or lupus nephritis), Hashimoto's thyroiditis, Wegener's disease, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes (e.g., insulin-dependent diabetes mellitus, type 1 diabetes, or type 2 diabetes), Goodpasture's syndrome, myasthenia gravis, pemphigus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sympathetic nervous system disorders, and the like. Preferably, the disease is selected from: inflammatory bowel disease, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis, Sjogren's syndrome, arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, polymyositis, scleroderma, psoriasis, primary sclerosing cholangitis, asthma, transplant rejection, host-versus-graft disease, graft-versus-host disease, and mixed connective tissue disease.

[0036] Further diseases that can be treated or prevented with the compounds of the present invention include, for example, any of the diseases / disorders mentioned in Thu YM et al., Cytokine Growth Factor Rev, 2010, 21(4):213-226, doi:10.1016 / j.cytogfr.2010.06.002 or Pflug KM et al., Int J Mol Sci, 2020, 21:8470, doi:10.3390 / ijms21228470.

[0037] The present invention further relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an NF-κB-inducing kinase (NIK) inhibitor in research, i.e., as a research tool compound for inhibiting NIK. In particular, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an intracellular NIK degradation inducer in research, i.e., as a research tool compound for inducing NIK degradation. Thus, the present invention refers to the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an NIK inhibitor, particularly the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound that functions as an NIK inhibitor. The present invention further relates to a method of inhibiting NIK (particularly an in vitro method), which comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The present invention also relates to the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an NIK degradation inducer, particularly the in vitro use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound that functions as an NIK degradation inducer. Furthermore, the present invention relates to a method (particularly an in vitro method) for inducing intracellular degradation of NIK, which comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The terms "sample," "test sample," and "biological sample" include, but are not limited to, cells, cell cultures, cellular or intracellular extracts, biopsies or extracts thereof obtained from animals (e.g., humans), or blood, serum, plasma, saliva, urine, feces, or any other body fluid or extract thereof. The term "in vitro" is used in this particular context to mean "outside a living human or animal body" and is understood to include experiments carried out with cells, cellular or subcellular extracts and / or biological molecules in an artificial environment, such as an aqueous solution or culture medium, which may be provided in a flask, test tube, petri dish, microtiter plate, etc. DETAILED DESCRIPTION OF THE INVENTION

[0038] Compounds of formula (I): [ka] and pharmaceutically acceptable salts thereof are described in more detail below

[0039] In formula (I), ring A may be selected from the following groups: (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7): [ka] is an aromatic group selected from Group (A-1) is substituted by group R A1 and group R A2 and one or more (e.g., one or two) groups R A3 phenyl or 6-membered monocyclic heteroaryl optionally further substituted with Groups (A-2) and (A-3) each contain a group R A1 and group R A2 and is substituted with one or more groups R A3 is a 5-membered monocyclic heteroaryl optionally further substituted with Group (A-4) is a group R A2 and one or more (e.g., one, two, or three) groups R A3 an 8-membered bicyclic heteroaryl optionally further substituted with Groups (A-5) and (A-6) each have a group R A2 and one or more (e.g., one, two, or three) groups R A3 is a 9-membered bicyclic heteroaryl optionally further substituted with Group (A-7) is a group R A2 and one or more (e.g., one, two, or three) groups R A3or naphthyl or a 10-membered bicyclic heteroaryl optionally further substituted with

[0040] It will be understood that each of the ring atoms of groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), and (A-7) may be carbon atoms or heteroatoms selected from oxygen, sulfur, and nitrogen, as reflected by the symbol "x" in the formulae shown above these ring groups. It will be further understood that, depending on the size of the monocyclic or bicyclic ring system, certain ring atoms may be selected only from carbon and nitrogen, and certain ring atoms may be only carbon atoms. Furthermore, when group (A-1) is phenyl or group (A-7) is naphthyl, it will be understood that all ring atoms are carbon atoms. Also, as shown in the formulae of groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), and (A-7), these groups may have one group R at a specific position. A1 and one group R A2 (in the case of A-1, A-2 and A-3) or one group R A2 (in the case of A-4, A-5, A-6 and A-7), the group (A-1) which is, for example, phenyl or a 6-membered monocyclic heteroaryl is substituted at the 2-position with a group R A1 and at the 4-position is substituted with a group R A2 wherein position 1 refers to the point of attachment of said phenyl or said heteroaryl to the remainder of the compound of formula (I) [i.e., the nitrogen atom N(R N ) is shown as the 1-position. In other words, when ring A is group (A-1), the substituent R A1 is bonded to the group (A-1) at the ortho position, and the substituent R A2 is bonded to group (A-1) at the para position. Group (A-2), a five-membered monocyclic heteroaryl, is bonded to group R at the 2-position. A1 and at the 3-position is substituted with a group R A2where position 1 refers to the point of attachment of said heteroaryl to the remainder of the compound of formula (I). The five-membered monocyclic heteroaryl group (A-3) is substituted at position 2 with a group R A1 and at the 4-position is substituted with a group R A2 where position 1 refers to the point of attachment of said heteroaryl to the remainder of the compound of formula (I).

[0041] When group (A-1) is a 6-membered monocyclic heteroaryl, the heteroaryl may, for example, contain one or more (e.g., 1, 2, or 3) nitrogen ring atoms, where the remaining ring atoms are carbon atoms. Thus, group (A-1) may, for example, be pyridinyl (e.g., 3-R A1 -5-R A2 -pyridin-2-yl, 2-R A1 -6-R A2 -pyridin-3-yl or 4-R A1 -6-R A2 -pyridin-3-yl, etc.), pyridazinyl (e.g., 4-R A1 -6-R A2 -pyridazin-3-yl, etc.), pyrimidinyl (e.g., 4-R A1 -2-R A2 -pyrimidin-5-yl, etc.), pyrazinyl (e.g., 3-R A1 -5-R A2 -pyrazin-2-yl) or 1,2,4-triazinyl (e.g., 5-R A1 -3-R A2 -1,2,4-triazin-6-yl, etc.), where each of the above groups can be one or more R A3 may be optionally substituted with

[0042] The five-membered monocyclic heteroaryl group (A-2) or (A-3) may contain one or more (e.g., one, two, or three) heteroatoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon atoms. Thus, group (A-2) may be, for example, 1H-pyrrolyl (e.g., 2-R A1 -3-R A2 -1H-pyrrol-1-yl, 1-R A1 -5-RA2 -1H-pyrrol-2-yl, 3-R A1 -4-R A2 -1H-pyrrol-2-yl, 2-R A1 -1-R A2 -1H-pyrrol-3-yl or 4-R A1 -5-R A2 -1H-pyrrol-3-yl, etc.), furanyl (e.g., 3-R A1 -4-R A2 -Furan-2-yl or 4-R A1 -5-R A2 -furan-3-yl, etc.), thiophenyl (e.g., 3-R A1 -4-R A2 -thiophen-2-yl or 4-R A1 -5-R A2 -thiophen-3-yl, etc.), pyrazolyl (e.g., 5-R A1 -4-R A2 -pyrazol-1-yl, 4-R A1 -5-R A2 -pyrazol-3-yl or 4-R A1 -3-R A2 -pyrazol-5-yl, etc.), imidazolyl (e.g., 5-R A1 -4-R A2 -imidazol-1-yl, 1-R A1 -5-R A2 -imidazol-2-yl or 1-R A1 -2-R A2 -imidazol-5-yl, etc.), 1,2,3-triazolyl (e.g., 5-R A1 -4-R A2 -1,2,3-triazol-1-yl, etc.), isoxazolyl (e.g., 4-R A1 -5-R A2 -isoxazol-3-yl or 4-R A1 -3-R A2 -isoxazol-5-yl) or isothiazolyl (e.g., 4-R A1 -5-R A2 -isothiazol-3-yl or 4-R A1 -3-R A2 -isothiazol-5-yl, etc.), where each of the above groups can be one or more RA3 Similarly, the group (A-3) may be, for example, 1H-pyrrolyl (e.g., 2-R A1 -4-R A2 -1H-pyrrol-1-yl, 1-R A1 -4-R A2 -1H-pyrrol-2-yl, 3-R A1 -5-R A2 -1H-pyrrol-2-yl or 4-R A1 -1-R A2 -1H-pyrrol-3-yl, etc.), furanyl (e.g., 3-R A1 -5-R A2 -furan-2-yl, etc.), thiophenyl (e.g., 3-R A1 -5-R A2 -thiophen-2-yl, etc.), pyrazolyl (e.g., 5-R A1 -3-R A2 -pyrazol-1-yl, 4-R A1 -1-R A2 -pyrazol-3-yl, 3-R A1 -1-R A2 -pyrazol-4-yl or 1-R A1 -3-R A2 -pyrazol-5-yl, etc.), imidazolyl (e.g., 2-R A1 -4-R A2 -imidazol-1-yl, 1-R A1 -4-R A2 -imidazol-2-yl or 4-R A1 -2-R A2 -imidazol-5-yl, etc.), 1,2,4-triazolyl (e.g., 5-R A1 -3-R A2 -1,2,4-triazol-1-yl or 1-R A1 -3-R A2 -1,2,4-triazol-5-yl, etc.), oxazolyl (e.g., 5-R A1 -2-R A2 -oxazol-4-yl or 4-R A1 -2-R A2 -oxazol-5-yl) or thiazolyl (e.g., 5-R A1 -2-R A2 -thiazol-4-yl or 4-RA1 -2-R A2 -thiazol-5-yl, etc.), where each of the above groups can be one or more R A3 may be optionally substituted with

[0043] In the bicyclic aromatic groups (A-4), (A-5), (A-6) and (A-7), it will be understood that at least one ring of the bicyclic fused ring system is aromatic, and preferably both rings of the bicyclic fused ring system are aromatic. Furthermore, in the bicyclic heteroaryl groups (A-4), (A-5) and (A-6), it will be understood that at least one ring of the bicyclic fused ring system contains one or more (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, and the remaining ring atoms are carbon atoms, and in particular both rings of the bicyclic fused ring system may each contain one or more (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, and the remaining ring atoms are carbon atoms. Similarly, when group (A-7) is a bicyclic heteroaryl group, at least one ring of the bicyclic fused ring system contains one or more (e.g., one, two, or three) heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon atoms; in particular, both rings of the bicyclic fused ring system may each contain one or more (e.g., one, two, or three) heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon atoms.

[0044] Thus, the group (A-4) can be, for example, 1,4-dihydropyrrolo[3,2-b]pyrrolyl (e.g., 3-R A2 -1,4-dihydropyrrolo[3,2-b]pyrrol-1-yl or 1-R A2 -1,4-dihydropyrrolo[3,2-b]pyrrol-3-yl, etc.), 1,6-dihydropyrrolo[2,3-b]pyrrolyl (e.g., 3-R A2 -1,6-dihydropyrrolo[2,3-b]pyrrol-1-yl or 1-R A2 -1,6-dihydropyrrolo[2,3-b]pyrrol-3-yl, 6H-furo[2,3-b]pyrrolyl (e.g., 6-R A2-6H-furo[2,3-b]pyrrol-4-yl or 4-R A2 -6H-furo[2,3-b]pyrrol-6-yl, 4H-furo[3,2-b]pyrrolyl (e.g., 6-R A2 -4H-furo[3,2-b]pyrrol-4-yl or 4-R A2 -4H-furo[3,2-b]pyrrol-6-yl, 4H-thieno[3,2-b]pyrrolyl (e.g., 6-R A2 -4H-thieno[3,2-b]pyrrol-4-yl or 4-R A2 -4H-thieno[3,2-b]pyrrol-6-yl, etc.), 6H-thieno[2,3-b]pyrrolyl (e.g., 6-R A2 -6H-thieno[2,3-b]pyrrol-4-yl or 4-R A2 -6H-thieno[2,3-b]pyrrol-6-yl, etc.), imidazo[5,1-b]oxazolyl (e.g., 7-R A2 -imidazo[5,1-b]oxazol-5-yl or 5-R A2 -imidazo[5,1-b]oxazol-7-yl) or imidazo[5,1-b]thiazolyl (e.g., 7-R A2 -imidazo[5,1-b]thiazol-5-yl or 5-R A2 -imidazo[5,1-b]thiazol-7-yl, etc.), where each of the above groups can be one or more R A3 may be optionally substituted with

[0045] The group (A-5) is, for example, 1-R A2 -indol-3-yl, 1-R A2 -1H-pyrrolo[2,3-b]pyridin-3-yl, 1-R A2 -1H-pyrrolo[3,2-b]pyridin-3-yl, 1-R A2 -1H-pyrrolo[2,3-c]pyridin-3-yl, 1-R A2 -1H-pyrrolo[3,2-c]pyridin-3-yl, 3-R A2 -indolizin-1-yl, 1-R A2 -indolizin-3-yl, 8-R A2 -pyrrolo[1,2-a]pyrimidin-6-yl, 6-R A2-pyrrolo[1,2-a]pyrimidin-8-yl, 5-R A2 -pyrrolo[1,2-c]pyrimidin-7-yl, 7-R A2 -pyrrolo[1,2-c]pyrimidin-5-yl, 1-R A2 -imidazo[1,5-a]pyridin-3-yl or 3-R A2 -imidazo[1,5-a]pyridin-1-yl.

[0046] The group (A-6) is, for example, indolyl (e.g., 7-R A2 -1H-indol-4-yl or 4-R A2 -1H-indol-7-yl, etc.), indolizinyl (e.g., 8-R A2 -indolizin-5-yl or 5-R A2 -indolizin-8-yl, etc.), pyrrolo[2,3-c]pyridinyl (e.g., 7-R A2 -1H-pyrrolo[2,3-c]pyridin-4-yl or 4-R A2 -1H-pyrrolo[2,3-c]pyridin-7-yl, etc.), imidazo[1,5-a]pyridinyl (e.g., 8-R A2 -imidazo[1,5-a]pyridin-5-yl or 5-R A2 -imidazo[1,5-a]pyridin-8-yl, etc.) or benzodioxolyl (e.g., 7-R A2 -benzodioxol-4-yl or 4-R A2 -benzodioxol-7-yl, etc.), where each of the above groups can be one or more R A3 may be optionally substituted with

[0047] The group (A-7) is, for example, 8-R A2 -quinolin-5-yl, 5-R A2 -Quinolin-8-yl, 8-R A2 -isoquinolin-5-yl, 5-R A2 -isoquinolin-8-yl, 4-R A2 -isoquinolin-1-yl, 1-R A2 -isoquinolin-4-yl, 8-R A2 -quinoxalin-5-yl, 8-R A2-phthalazin-5-yl, 4-R A2 -phthalazin-1-yl, 8-R A2 -Cinnolin-5-yl, 5-R A2 -Cinnoline-8-yl, 8-R A2 -quinazolin-5-yl, 5-R A2 -Quinazolin-8-yl, 8-R A2 -1,7-naphthyridin-5-yl, 5-R A2 -1,7-naphthyridin-8-yl, 5-R A2 -pyrido[3,4-d]pyrimidin-8-yl, 8-R A2 -pyrido[3,4-d]pyrimidin-5-yl, 5-R A2 -pyrido[4,3-d]pyrimidin-8-yl, 8-R A2 -pyrido[4,3-d]pyrimidin-5-yl, 8-R A2 -benzodioxan-5-yl or 4-R A2 -naphthalen-1-yl (or 4-R A2 -naphth-1-yl).

[0048] Additionally, as explained above, groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), and (A-7) each contain one or more (e.g., one, two, or three) groups R A3 Optionally substituted with the optional substituent R A3 It will be understood that the maximum number of substituents R is determined by the number of hydrogen atoms available on the particular group (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), or (A-7). For example, if group (A-1) is phenyl, said phenyl may have 0, 1, 2, or 3 substituents R A3 However, when group (A-1) is pyridinyl, said pyridinyl may have 0, 1 or 2 (but at most 2) substituents R A3 and when group (A-1) is for example pyrazinyl or pyridazinyl, said pyrazinyl or said pyridazinyl may have zero or one (but at most one) substituent R A3Unless otherwise specified, each of groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) may have one or two R A3 , more preferably one R A3 and each of said groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) is optionally substituted with any of the optional substituents R A3 Even more preferably, it is not substituted with

[0049] Preferably, ring A is group (A-1), (A-6) or (A-7). More preferably, ring A is group (A-1). Even more preferably, ring A is phenyl (i.e., 2-R A1 -4-R A2 -phenyl), pyridinyl (e.g., 3-R A1 -5-R A2 -pyridin-2-yl, 2-R A1 -6-R A2 -pyridin-3-yl or 4-R A1 -6-R A2 -pyridin-3-yl), pyridazinyl (e.g., 4-R A1 -6-R A2 -pyridazin-3-yl), pyrimidinyl (e.g., 4-R A1 -2-R A2 -pyrimidin-5-yl) or pyrazinyl (e.g., 3-R A1 -5-R A2 -pyrazin-2-yl), wherein said phenyl, said pyridinyl, said pyridazinyl, said pyrimidinyl and said pyrazinyl each represent one or more R A3 Even more preferably, ring A is phenyl (i.e., 2-R A1 -4-R A2 -phenyl) or pyridinyl (e.g., 3-R A1 -5-R A2 -pyridin-2-yl, 2-R A1 -6-R A2 -pyridin-3-yl or 4-R A1 -6-R A2-pyridin-3-yl), wherein said phenyl or said pyridinyl is one or more R A3 Even more preferably, ring A is optionally substituted with one or more (e.g., one, two, or three) groups R A3 2-R optionally substituted with A1 -4-R A2 -phenyl.

[0050] base R A1 is -O(C 1~5 alkyl), -O(C 2~5 alkenyl), C 1~5 Alkyl, C 2~5 Alkenyl, -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 and the cycloalkyl group in the -(C alkylene)-cycloalkyl 0~3 Each heterocycloalkyl group in the alkylene-heterocycloalkyl group may contain one or more (e.g., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-cycloalkyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units in the alkylene in the alkylene)-heterocycloalkyl may be replaced by -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0051] Preferably R A1 is -O(C 1~5 alkyl), -O(C 2~5 alkenyl), C 1~5 Alkyl, C 2~5 Alkenyl, -N(C 1~5 Alkyl)(C1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -(C 0~3 alkylene)-cycloalkyl and -(C 0~3 alkylene)-heterocycloalkyl, wherein said -(C 0~3 alkylene)-cycloalkyl or the -(C 0~3 The two -CH2- units contained in the alkylene in the alkylene)-heterocycloalkyl are -O-, -NH-, and -N(C 1~5 Optionally substituted with groups independently selected from alkyl), -CO-, -S-, -SO-, and -SO2-. More preferably, R A1 is -O(C 1~5 alkyl), -O(C 2~5 alkenyl), C 1~5 Alkyl, C 2~5 Alkenyl, -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, cycloalkyl, -O-cycloalkyl, heterocycloalkyl and -O-heterocycloalkyl. Even more preferably, R A1 is -O(C 1~5 alkyl) (e.g., methoxy, ethoxy, n-propoxy, or isopropoxy), C 1~5 alkyl (e.g., methyl, ethyl, n-propyl, or isopropyl), -N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., dimethylamino or diethylamino), halogen (e.g., —F, —Cl, or —Br), C 1~5 Haloalkyl (e.g., -CF3), -O-(C 1~5haloalkyl) (e.g., —OCF), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), —O-cycloalkyl (e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexoxy), and heterocycloalkyl (e.g., monocyclic heterocycloalkyl attached to the remainder of the compound of formula (I) via a nitrogen ring atom, such as pyrrolidin-1-yl, piperidin-1-yl, or morpholin-4-yl). Even more preferably, R A1 is -O(C 1~5 alkyl), halogen (e.g., -F, -Cl, or -Br), -O-(C 1~5 Even more preferably, R is selected from -O-haloalkyl and -O-cycloalkyl. A1 is -O(C 1~5 alkyl) (e.g., —OCH3) or halogen (e.g., —F or —Br). Thus, the group R A1 Particularly preferred examples include methoxy (-OCH3), -F or -Br.

[0052] Also, as explained further below, R A1 (the above preferred group R A1 or an exemplary group R A1 One or more (or all) hydrogen atoms in the 2 H). Therefore, R A1 may for example be the group -OCD3.

[0053] base R A2 is C 1~12 Alkyl, -(C 1~12 alkylene)-OH, -(C 0~5 alkylene)-O(C 1~12 alkyl), -(C 0~5 alkylene)-O(C 1~12 haloalkyl), -(C 0~5 alkylene)-O-(C 1~12 alkylene)-OH, -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C1~12 alkyl), -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl), -CO(C 1~12 alkyl), -CO(C 1~12 haloalkyl), -SO2-(C 1~12 alkyl), -SO2-(C 1~12 haloalkyl), halogen, C 1~5 Haloalkyl, -(C 0~5 alkylene)-carbocyclyl and -(C 0~5 alkylene)-heterocyclyl, wherein said C 1~12 alkyl, the -(C 1~12 alkylene)-OH, 0~5 alkylene)-O(C 1~12 alkyl), the -(C 0~5 alkylene)-O(C 1~12 haloalkyl), the -(C 0~5 alkylene)-O-(C 1~12 alkylene)-OH, 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 alkyl), the -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl), the —CO(C 1~12 alkyl), the —CO(C 1~12 haloalkyl), -SO2-(C 1~12 alkyl) or -SO2-(C 1~12 One or more (e.g., one, two, or three) -CH2- units in the alkyl group (haloalkyl) are each selected from -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -(C alkyl)-, -CO-, and -CH=CH-, 0~5 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~5 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (e.g., one, two, or three) groups R Cycand optionally substituted with -(C 0~5 alkylene)-carbocyclyl or the -(C 0~5 One or more (e.g., one, two, or three) -CH2- units in the alkylene of the alkylene)-heterocyclyl are each selected from -O-, -NH-, -N(C 1~5 The C is optionally substituted with a group independently selected from alkyl)-, -CO-, -S-, -SO- and -SO2-. 1~12 Alkyl is preferably -(CH2) 0~11 Linear C such as -CH3 1~12 alkyl, and the -(C 1~12 Alkylene)-OH is preferably -(CH 1~12 -OH and other linear -(C 1~12 alkylene)-OH, 0~5 alkylene)-O(C 1~12 alkyl) is preferably -(CH2) 0~5 -O-(CH2) 0~11 -CH3 and other linear -(C 0~5 alkylene)-O(C 1~12 alkyl), and the -(C 0~5 alkylene)-O(C 1~12 haloalkyl) is preferably a linear -(C 0~5 alkylene)-O(C 1~12 haloalkyl), and 0~5 alkylene)-O-(C 1~12 Alkylene)-OH is preferably -(CH 0~5 -O-(CH2) 1~12 -OH and other linear -(C 0~5 alkylene)-O-(C 1~12 alkylene)-OH, 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 alkyl) is preferably -(CH2) 0~5 -O-(CH2) 1~5 -O-(CH2) 0~11 -CH3 and other linear -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12alkyl), and the -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl) is preferably a linear -(C 0~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~12 haloalkyl), and the —CO(C 1~12 alkyl) is preferably -CO-(CH2) 0~11 -CH3 and other linear -CO(C 1~12 alkyl), and the —CO(C 1~12 haloalkyl) is preferably a linear -CO(C 1~12 haloalkyl), and the -SO2-(C 1~12 alkyl) is preferably -SO2-(CH2) 0~11 -CH3 and other linear -SO2-(C 1~12 alkyl), and the —SO—(C 1~12 haloalkyl) is preferably a linear -SO2-(C 1~12 haloalkyl). In particular, R A2 represents a particular group R contained in any of the compounds of formula (I) described in the Examples section. A2 It may be one of the following.

[0054] Preferably R A2 is C 1~5 Alkyl, -(C 1~5 alkylene)-OH, -O(C 1~5 alkyl) (e.g., -OCH3), -O-(C 1~5 alkylene)-OH, -O-(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O-(C 1~5 alkylene)-OH, -(C 1~5 alkylene)-O-(C 1~5 alkylene)-O(C 1~5 alkyl), -O(C 1~5 alkylene)-O(C 1~5 alkyl) (e.g., -OCH2CH2OCH3 or -OCH2CH2OCH(-CH3)CH3), -O(C 1~3alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -O(C 2~5 alkenyl) (e.g., -OCH=CH2), -(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -O-(C 1~5 haloalkyl) (e.g., -OCF3), -O(C 1~5 alkylene)-O-(C 1~5 haloalkyl) (e.g., -OCH2CH2OCF3 or -OCH2CH2OCF2H), -O(C 1~3 alkylene)-O(C 1~3 alkylene)-O-(C 1~3 haloalkyl), -(C 1~5 alkylene)-O-(C 1~5 haloalkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O-(C 1~5 haloalkyl), -(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkylene)-O-(C 1~3 haloalkyl), -O(C 1~5 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., -OCH2CH2N(CH3)2), -(C 1~5 alkylene)-O(C 1~5 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -CO-NH-(C 1~5 alkyl) (e.g., -CO-NH-CH(CH3)-CH3), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~12alkyl) (e.g., -SO2-CH3), -SO2-(C 1~12 haloalkyl), halogen (e.g., -F, -Cl, or -Br), C 1~5 Haloalkyl (e.g., -CF3), -(C 0~5 alkylene)-carbocyclyl (e.g., -(C 0~5 alkylene)-cycloalkyl or -(C 0~5 alkylene)-aryl), -(C 0~5 alkylene)-heterocyclyl (e.g., -(C 0~5 alkylene)-heteroaryl or -(C 0~5 alkylene)-heterocycloalkyl, pyrazolyl [e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl], imidazolyl [e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl], isoxazolyl [e.g., isoxazol-3-yl, isoxazol-4-yl, or isoxazol-5-yl], 1,2,4-triazolyl [e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl], -yl or 1,2,4-triazol-5-yl], 1H-pyrrolyl [e.g., 1H-pyrrol-1-yl, 1H-pyrrol-2-yl or 1H-pyrrol-3-yl], furanyl [e.g., furan-2-yl or furan-3-yl], thiophenyl [e.g., thiophen-2-yl or thiophen-3-yl], pyridinyl [e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl] or pyrimidinyl [e.g., pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl], etc.), —O—(C 0~4 alkylene)-carbocyclyl (e.g., -O-(C 0~4 alkylene)-aryl or -O-(C 0~4 alkylene)-cycloalkyl, -O-cyclopentyl, etc.), -O-(C 0~4 alkylene)-heterocyclyl (e.g., -O-(C 0~4 alkylene)-heteroaryl or -O-(C 0~4alkylene)-heterocycloalkyl, such as -OCH2CH2-(morpholin-4-yl) or -OCH2CH2-(6-oxa-3-aza-bicyclo[2.1.2]heptan-3-yl), -(C 0~4 alkylene)-O-carbocyclyl (e.g., -(C 0~4 alkylene)-O-aryl or -(C 0~4 alkylene)-O-cycloalkyl), -(C 0~4 alkylene)-O-heterocyclyl (e.g., -(C 0~4 alkylene)-O-heteroaryl or -(C 0~4 alkylene)-O-heterocycloalkyl), -CO-(C 0~4 alkylene)-carbocyclyl (e.g., -CO-(C 0~4 alkylene)-aryl or -CO-(C 0~4 alkylene)-cycloalkyl) and -CO-(C 0~4 alkylene)-heterocyclyl (e.g., -CO-(C 0~4 alkylene)-heteroaryl or -CO-(C 0~4 alkylene)-heterocycloalkyl, -CO-(4-morpholinyl) or -CO-azetidinyl [e.g., -CO-(azetidin-1-yl)], etc.), wherein said -(C 0~5 carbocyclyl in the -(C alkylene)-carbocyclyl 0~5 heterocyclyl in the -O-(C alkylene)-heterocyclyl 0~4 carbocyclyl in the -O-(C alkylene)-carbocyclyl 0~4 heterocyclyl in the -(C alkylene)-heterocyclyl 0~4 carbocyclyl in the -(C alkylene)-O-carbocyclyl 0~4 heterocyclyl in the -CO-(C alkylene)-O-heterocyclyl 0~4 carbocyclyl in the -CO-(C alkylene)-carbocyclyl 0~4 Each heterocyclyl in alkylene-heterocyclyl may have one or more (e.g., one, two, or three) groups R Cyc More preferably, R A2is C 1~5 Alkyl, -(C 1~5 alkylene)-OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-O(C 1~5 alkyl), -O(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -O(C 2~5 alkenyl), -(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -O-(C 1~5 haloalkyl), -O(C 1~5 alkylene)-O-(C 1~5 haloalkyl), -O(C 1~3 alkylene)-O(C 1~3 alkylene)-O-(C 1~3 haloalkyl), -(C 1~5 alkylene)-O-(C 1~5 haloalkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O-(C 1~5 haloalkyl), -(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkylene)-O-(C 1~3 haloalkyl), -O(C 1~5 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -CO-NH-(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5alkyl), -SO2-(C 1~12 alkyl), -SO2-(C 1~12 haloalkyl), halogen, C 1~5 selected from haloalkyl, aryl (e.g., phenyl) and heteroaryl (e.g., monocyclic heteroaryl, particularly 5- or 6-membered monocyclic heteroaryl, such as pyrazolyl), wherein said aryl and said heteroaryl each contain one or more (e.g., 1, 2 or 3) groups R Cyc Even more preferably, R A2 is -O(C 1~5 alkyl), -O(C 1~5 alkylene)-O(C 1~5 alkyl), -O(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkylene)-O(C 1~3 alkyl), -SO2-(C 1~12 Alkyl), halogen, C 1~5 haloalkyl, phenyl, and heteroaryl, wherein said phenyl and said heteroaryl are each selected from one or more groups R Cyc Even more preferably, R A2 is -O(C 1~5 alkyl), -O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~5 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl) and monocyclic heteroaryl, wherein said monocyclic heteroaryl is selected from one or more groups RCyc are optionally substituted with. Therefore, R A2 Particularly preferred examples of include -OCH2CH2OCH3, -OCH2CH2OCF3 or pyrazolyl (such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl).

[0055] Each R A3 (if present) is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (e.g., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0056] Preferably, each R A3 (if present) is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-O(C 1~5alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (i.e., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl), -CO-, -S-, -SO-, and -SO2-. More preferably, each R A3 (if present) is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN. Even more preferably, each R A3(if present) is C 1~5 Alkyl (e.g., methyl), -OH, -O(C 1~5 alkyl) (e.g., -OCH3 or -OCH2CH3), -O(C 1~5 alkylene)-OH (e.g., -O-(CH2)2-OH or -O-(CH2)3-OH), -O(C 1~5 alkylene)-O(C 1~5 alkyl) (e.g., -O-(CH2)2-O-CH3, -O-(CH2)2-O-CH2CH3, -O-(CH2)3-O-CH3 or -O-(CH2)3-O-CH2CH3), -(C 1~3 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkyl) (e.g., -CH2-O-CH3), -(C 1~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), halogen (e.g., -F or -Cl), C 1~5 Haloalkyl (e.g., -CF3) and -O-(C 1~5 haloalkyl) (e.g., —OCF3).

[0057] R N is hydrogen, C 1~5 Alkyl and -CO-(C 1~5 alkyl).

[0058] Preferably R N is hydrogen or C 1~5 More preferably, R N is hydrogen, methyl or ethyl. Even more preferably, R N is hydrogen.

[0059] R 1 , R 4 and R 5 are hydrogen and C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (e.g., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0060] Preferably R 1 , R 4 and R 5 are hydrogen and C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl, -(C 0~3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more (i.e., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5Optionally substituted with groups independently selected from alkyl), -CO-, -S-, -SO-, and -SO2-. More preferably, R 1 , R 4 and R 5 are hydrogen and C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN. 1 , R 4 and R 5 It is particularly preferred that each is hydrogen.

[0061] R 2 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl and -(C 0~3 alkylene)-heterocyclyl, wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (e.g., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, and -SO-.

[0062] Preferably R 2 is hydrogen, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl and -(C 0~3alkylene)-heterocyclyl, wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more (i.e., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5 Optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, and -SO-. More preferably, R 2 is hydrogen, C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl) and —CN. 2 It is particularly preferred that is hydrogen.

[0063] R 3 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-OH, -(C 0~3 alkylene)-N(C 1~5 alkyl)-OH, -(C 0~3 alkylene)-NH-O(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-O(C 1~5 alkyl), -(C 0~3 alkylene)-CHF2, -(C 0~3 alkylene)-CHF, -(C 0~3 alkylene)-(C 2~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl and -(C 0~3 alkylene)-heterocyclyl, wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may contain one or more (e.g., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-; 3 is not morpholin-4-yl or -NH-phenyl, and the phenyl group in said -NH-phenyl is Cyc is optionally replaced by

[0064] Preferably R 3 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 alkyl), -CHF2, -CH2F, C 2~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CHO, -CO-(C 1~5 alkyl), -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-carbocyclyl (e.g., -(C 0~3 alkylene)-aryl or -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-phenyl) and -(C 0~3 alkylene)-heterocyclyl (e.g., -(C 0~3 alkylene)-heteroaryl, -(C 0~3 alkylene)-heterocycloalkenyl or -(C 0~3 alkylene)-heterocycloalkyl, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3,5,6,7-pentahydro-1,4-diazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, or spiro[azetidin-3,3′-azetidin]-1-yl), wherein said -(C 0~3 carbocyclyl group in -(C alkylene)-carbocyclyl and 0~3 Each heterocyclyl group in the alkylene-heterocyclyl may be one or more (i.e., one, two, or three) groups R Cyc and optionally substituted with -(C 0~3 alkylene)-carbocyclyl or the -(C 0~3 One or more (e.g., one or two) -CH2- units contained in the alkylene in the alkylene)-heterocyclyl may be -O-, -NH-, -N(C 1~5optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-, wherein R 3 is not morpholin-4-yl or -NH-phenyl, and the phenyl group in said -NH-phenyl is Cyc More preferably, R 3 is C 1~5 Alkyl, C 2~5 Alkenyl, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -CHF2, -CH2F, C 2~5 Haloalkyl, -O-(C 1~5 haloalkyl), phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein R 3 is not morpholin-4-yl, and each of the phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl may contain one or more (e.g., one, two, or three) groups R Cyc Even more preferably, R 3 is C 1~5 Alkyl (e.g., methyl), -O(C 1~5 alkyl) (e.g., methoxy), -CHF2, -CH2F, C 2~5 Haloalkyl, -O-(C 1~5 haloalkyl), phenyl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein R 3 is not morpholin-4-yl, and each of said phenyl, said cycloalkyl, said heteroaryl, and said heterocycloalkyl may contain one or more (e.g., one, two, or three) groups R Cyc Optionally replaced by R 3 Particularly preferred examples include methyl or -CHF2.

[0065] Each R Cyc is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 1~3 alkylene)-OH, -(C 1~3 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -R 6 -R 7 wherein said -(C 0~3 and the cycloalkyl group in the -(C alkylene)-cycloalkyl 0~3 Each heterocycloalkyl group in the alkylene-heterocycloalkyl is 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl) and -SO-(C 1~5 alkyl).

[0066] Each R 6 is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each independently selected from halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 and wherein each of said alkylene, alkenylene, or alkynylene groups is independently selected from the group consisting of -O-, -NH-, -N(C 1~5 and optionally substituted with groups independently selected from -alkyl)-, -CO-, -S-, -SO-, and -SO2-.

[0067] Each R 7 -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-OH, -N(C 1~5 alkyl)-OH, -NH-O(C 1~5 alkyl), -N(C 1~5 alkyl)-O(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0068] It is particularly preferred that the compound of formula (I) is any one of the specific compounds of formula (I) described in the Examples section of this specification, including any one of Examples 1-142, further described below, either as a non-salt form or as a pharmaceutically acceptable salt of the respective compound.

[0069] Thus, the compound of formula (I) is the following compound: N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-phenylquinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine, 7-methoxy-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine, 7-(4,4-difluoropiperidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(3,3-difluoroazetidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(prop-1-en-2-yl)quinolin-4-amine, 7-isopropyl-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(oxetan-3-yl)piperazin-1-yl)quinolin-4-amine, (S)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (R)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2-methoxyethyl)piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)quinolin-4-amine, 7-(4-ethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (S)-7-(2,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, tert-butyl 3-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-1-yl)azetidine-1-carboxylate, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(1-methylazetidin-3-yl)piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinolin-4-amine, 7-(4-(azetidin-3-yl)piperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (R)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol, (S)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol, tert-butyl 5-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)quinolin-4-amine, 4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-2-one, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, 7-methoxy-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2,4-dimethoxyphenyl)-7-phenylquinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-fluoro-2-methoxyphenyl)quinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-(2-methoxyethoxy)-2-morpholinophenyl)quinolin-4-amine, N-(2-cyclopropoxy-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, N-(4-(1,1-difluoroethyl)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2,4-dimethoxyphenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(methylsulfonyl)phenyl)quinolin-4-amine, N-cyclopropyl-4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxybenzamide, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)quinolin-4-amine, N-(4-(2-cyclopropoxyethoxy)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-fluoro-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone, 4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide, N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-3-methyl-1H-pyrazol-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2,4-dimethyl-1H-imidazol-5-yl)quinolin-4-amine, N-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-(difluoromethyl)quinolin-4-amine, N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]oxazol-7-amine, N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]thiazol-7-amine, 7-(difluoromethyl)-N-(1-methylimidazo[1,5-a]pyridin-3-yl)quinolin-4-amine, N-(1-bromoimidazo[1,5-a]pyridin-3-yl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(7-methyl-1H-indol-4-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(7-fluoro-1H-indol-4-yl)quinolin-4-amine, N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methylisoquinolin-1-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-fluoroisoquinolin-1-yl)quinolin-4-amine, 5-chloro-N-(7-(difluoromethyl)quinolin-4-yl)-1,7-naphthyridin-8-amine, N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-isopropylquinolin-4-amine, N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-fluoro-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(2-methoxyethoxy)-2-morpholinophenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(trifluoromethyl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(methylsulfonyl)phenyl)-7-methylquinolin-4-amine, N-(2-cyclopropoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(5-bromo-3-methoxypyrazin-2-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-(cyclopentyloxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(2-(trifluoromethoxy)ethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(2-isopropoxyethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(furan-2-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(furan-3-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(4-methyl-1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(thiophen-2-yl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(thiophen-3-yl)phenyl)-7-methylquinolin-4-amine, N-(7-bromobenzo[d][1,3]dioxol-4-yl)-7-methylquinolin-4-amine, N-(7-(1H-pyrazol-4-yl)benzo[d][1,3]dioxol-4-yl)-7-methylquinolin-4-amine, 3-methoxy-N-(2-methoxyethyl)-4-((7-methylquinolin-4-yl)amino)benzamide, N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, (3-methoxy-4-((7-methylquinolin-4-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone, N-(2-methoxy-6-(5-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, 1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazole-4-carbonitrile, N-(2-methoxy-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, 1-(1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazol-4-yl)ethan-1-one, N-(2-fluoro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(4-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(3-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-4-amine, N-(3-methoxy-5-(1H-pyrazol-4-yl)pyrazin-2-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(1H-pyrazol-4-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine, 7-methoxy-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methoxyquinolin-4-amine, or N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine or any one of its pharmaceutically acceptable salts.

[0070] The present invention also relates to each of the intermediates further described below in the Examples section of this specification, including any one of these intermediates in the non-salt form or in the salt (e.g., pharmaceutically acceptable salt) form of the respective compound. Such intermediates can be used, inter alia, in the synthesis of compounds of formula (I).

[0071] Various methods for preparing the compounds of formula (I) and their pharmaceutically acceptable salts will be readily apparent to those skilled in the art of synthetic chemistry. For example, the compounds of the present invention can be prepared according to, or in analogy with, the synthetic routes detailed in the Examples section.

[0072] Unless otherwise stated, the following definitions apply throughout the present specification and claims.

[0073] The term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0074] The term "alicyclic" is used in reference to a cyclic group to mean that the corresponding cyclic group is non-aromatic.

[0075] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be straight-chained or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1~5 "Alkyl" means an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless otherwise specified, the term "alkyl" preferably refers to a C 1~4 It refers to alkyl, more preferably methyl or ethyl, even more preferably methyl.

[0076] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight or branched, containing one or more (e.g., one or two) carbon-carbon double bonds but no carbon-carbon triple bonds. 2~5The term "alkenyl" refers to an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless otherwise specified, the term "alkenyl" preferably refers to an alkenyl group having 2 to 5 carbon atoms. 2~4 refers to alkenyl.

[0077] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group, which may be straight-chain or branched, containing one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. 2~5 The term "alkynyl" refers to an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless otherwise specified, the term "alkynyl" preferably refers to an alkynyl group having 2 to 5 carbon atoms. 2~4 refers to alkynyl.

[0078] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group, which may be linear or branched. 1~5 "Alkylene" means an alkylene group having 1 to 5 carbon atoms, 0~3 The term "alkylene" refers to a covalent bond (corresponding to the option "C0 alkylene") or a C 1~3 indicates the presence of an alkylene. Preferred exemplary alkylene groups are methylene (-CH-), ethylene (e.g., -CH-CH- or -CH(-CH)-), propylene (e.g., -CH-CH-CH-, -CH(-CH-CH)-, -CH-CH(-CH)- or -CH(-CH)-CH-), or butylene (e.g., -CH-CH-CH-CH-). Unless otherwise specified, the term "alkylene" preferably refers to a C 1~4Alkylene (especially linear C 1~4 alkylene), more preferably methylene or ethylene, and even more preferably methylene.

[0079] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be straight-chain or branched, containing one or more (e.g., one or two) carbon-carbon double bonds but no carbon-carbon triple bonds. 2~5 "Alkenylene" means an alkenylene group having 2 to 5 carbon atoms. Unless otherwise specified, the term "alkenylene" preferably refers to a C 2~4 Alkenylene (especially linear C 2~4 (including alkenylene).

[0080] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched, containing one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. 2~5 "Alkynylene" means an alkynylene group having 2 to 5 carbon atoms. Unless otherwise specified, the term "alkynylene" preferably refers to a C 2~4 Alkynylene (especially linear C 2~4 (including alkynylene).

[0081] The term "carbocyclyl," as used herein, refers to hydrocarbon ring groups, including monocyclic rings and bridged, spirocyclic, and / or fused ring systems (e.g., consisting of two or three rings), which may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise specified, "carbocyclyl" preferably refers to aryl, cycloalkyl, or cycloalkenyl.

[0082] The term "heterocyclyl," as used herein, refers to ring groups, including monocyclic rings and bridged, spiro, and / or fused ring systems (which may consist of, for example, two or three rings), containing one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, one or more carbon ring atoms are optionally oxidized (i.e., to form an oxo group), and further wherein said ring groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. For example, each heteroatom-containing ring contained in said ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Unless otherwise specified, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0083] As used herein, the term "aryl" refers to aromatic hydrocarbon ring groups, including monocyclic aromatic rings containing at least one aromatic ring, as well as bridged and / or fused ring systems (e.g., a ring system consisting of two or three fused rings, at least one of which is aromatic, or a bridged ring system consisting of two or three rings, at least one of which is aromatic). When aryl is a bridged and / or fused ring system containing at least one non-aromatic ring (e.g., a saturated or unsaturated alicyclic ring) in addition to one or more aromatic rings, one or more carbon ring atoms in each non-aromatic ring may optionally be oxidized (i.e., to form an oxo group). "Aryl" may refer, for example, to phenyl, naphthyl, dialinyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise specified, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, and even more preferably refers to phenyl or naphthyl, and most preferably phenyl.

[0084] The term "heteroaryl," as used herein, refers to aromatic ring groups, including monocyclic aromatic rings containing at least one aromatic ring, as well as bridged and / or fused ring systems (e.g., ring systems consisting of two or three fused rings, where at least one of the fused rings is aromatic, or bridged ring systems consisting of two or three rings, where at least one of the bridged rings is aromatic), which contain one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and further wherein one or more carbon ring atoms are optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl" includes, for example, thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyrazolyl, allyl, pyridyl (i.e., pyridinyl, e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 1H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,3 -triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g. 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g. 2,3-dihydrofuro[2,3-c]pyridinyl or or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,Unless otherwise specified, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably 5- to 10-membered) monocyclic ring or fused ring system containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized. Furthermore, unless otherwise specified, particularly preferred examples of "heteroaryl" include pyridinyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), imidazolyl, thiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., thiophenyl), or pyrimidinyl.

[0085] The term "cycloalkyl," as used herein, refers to saturated hydrocarbon ring groups, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings). "Cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise specified, "cycloalkyl" preferably refers to C 3~11 It refers to cycloalkyl, more preferably C 3~7 It refers to cycloalkyl. Particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members. Furthermore, unless otherwise specified, particularly preferred examples of "cycloalkyl" include cyclohexyl or cyclopropyl, especially cyclohexyl.

[0086] The term "heterocycloalkyl," as used herein, refers to saturated ring groups, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (which may consist of, for example, two or three rings; such as fused ring systems consisting of two or three fused rings), containing one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and further one or more carbon ring atoms are optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is one to four and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl" includes, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, and the like. It may refer to tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.Unless otherwise specified, "heterocycloalkyl" refers to a 3- to 11-membered saturated ring group that is preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings) containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5- to 7-membered saturated monocyclic ring group that contains one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized. Furthermore, unless otherwise specified, particularly preferred examples of "heterocycloalkyl" include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, or tetrahydrofuranyl.

[0087] The term "cycloalkenyl," as used herein, refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group containing one or more (e.g., one or two) carbon-carbon double bonds and no carbon-carbon triple bonds, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (which may be composed of, for example, two or three rings; e.g., fused ring systems composed of two or three fused rings, etc.). "Cycloalkenyl" may refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise specified, "cycloalkenyl" preferably refers to C 3~11 It refers to cycloalkenyl, more preferably C 3~7 It refers to cycloalkenyl. Particularly preferred "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two, preferably one) carbon-carbon double bonds.

[0088] The term "heterocycloalkenyl," as used herein, refers to unsaturated alicyclic (non-aromatic) ring groups, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (which may consist of, for example, two or three rings; such as fused ring systems consisting of two or three fused rings), containing one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, one or more carbon ring atoms are optionally oxidized (i.e., to form an oxo group), and further wherein said ring groups contain at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated alicyclic ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" includes, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise specified, "heterocycloalkenyl" refers to a 3- to 11-membered unsaturated alicyclic ring group, preferably a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and More preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and no triple bonds between adjacent ring atoms.

[0089] The term "halogen" as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I).

[0090] The term "haloalkyl," as used herein, refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluoro, chloro, bromo, and iodo, and preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available bonding sites, and thus determined by the number of carbon atoms included in the alkyl portion of the haloalkyl group. "Haloalkyl" may refer to, for example, -CF, -CHF, -CHF, -CF-CH, -CH-CF, -CH-CHF, -CH-CF-CH, -CH-CF-CF, or -CH(CF). A particularly preferred "haloalkyl" group is -CF.

[0091] The terms "bond" and "covalent bond" are used interchangeably herein unless otherwise indicated or contradicted by context.

[0092] As used herein, the terms "any," "optionally," and "may" mean that the indicated feature may or may not be present. Whenever the terms "any," "optionally," or "may" are used, the invention specifically relates to both possibilities, i.e., the presence of the corresponding feature, or alternatively, the absence of the corresponding feature. For example, the phrase "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is either substituted with Y or is not substituted. Similarly, when a component of a composition is indicated as "optional," the invention specifically relates to both possibilities, i.e., the presence of the corresponding component (including in the composition) or the absence of the corresponding component in the composition.

[0093] Various groups are referred to herein as "optionally substituted". Generally, these groups may have one or more substituents, such as one, two, three, or four substituents. It will be understood that the maximum number of substituents is limited by the number of available bonding sites on the substituted moiety. Unless otherwise specified, the "optionally substituted" groups referred to herein are preferably referred to as having up to two substituents, and may particularly have only one substituent. Furthermore, unless otherwise specified, it is preferred that there are no optional substituents, i.e., the corresponding group is not substituted.

[0094] Those skilled in the art will recognize that the substituents contained in the compounds of the present invention may be attached to the remainder of the respective compounds through several different positions of the corresponding specific substituent. Unless otherwise specified, the preferred positions of attachment for various specific substituents are as shown in the examples.

[0095] As used herein, unless otherwise indicated or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising "a" compound of Formula (I) can be interpreted as referring to a composition comprising "one or more" compounds of Formula (I).

[0096] Whenever numerical ranges are provided / disclosed herein, it is to be understood that all values ​​and subranges encompassed within each numerical range are intended to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value encompassed within the numerical ranges disclosed herein, and each subrange encompassed by the numerical ranges disclosed herein.

[0097] As used herein, the term "about" preferably refers to ±10% of the stated numerical value, more preferably ±5% of the stated numerical value, and particularly the exact numerical value stated. When the term "about" is used in connection with the endpoints of a range, it preferably refers to a range from the stated numerical value's lower endpoint minus 10% to the stated numerical value's upper endpoint plus 10%, more preferably a range from the stated numerical value's lower endpoint minus 5% to the stated numerical value's upper endpoint plus 5%, and even more preferably a range defined by the exact numerical values ​​of the lower and upper endpoints.

[0098] As used herein, the term "comprising" (or "comprise," "comprises," "contain," "contains," or "containing") means "comprising in particular," i.e., "including, among other optional elements," unless otherwise stated or contradicted by context. In addition, this term also includes the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" means "A comprising in particular B and C," where A may contain optional additional elements (e.g., including "A comprising B, C, and D"), but also includes the meanings "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not contain any components other than B and C).

[0099] The scope of the present invention includes all pharmaceutically acceptable salt forms of the compounds of formula (I), which may be formed by protonation of an atom having a lone pair of electrons susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, zinc salts, ammonium salts, aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt or choline salt, aralkylamine salts such as N,N-dibenzylethylenediamine salt, benzathine salt, benethamine salt, heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt or isoquinoline salt, quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt, and basic amino acid salts such as arginine salt, lysine salt or histidine salt.Exemplary acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate (such as sulfate or hydrogen sulfate), nitrate, phosphate (such as phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, hydrogen carbonate, perchlorate, mineral acid salts such as borate or thiocyanate, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, guanylate ... Organic acid salts such as licholate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate or pivalate; sulfonates such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate or camphorsulfonate; glycerophosphate and acidic amino acid salts such as aspartate or glutamate. Additional pharmaceutically acceptable salts are described, for example, in Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, 2002, and the references cited therein. Preferred pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. Particularly preferred pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride. Thus, the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is preferably in the form of hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate or phosphate, and particularly preferred is the compound of formula (I) in the form of hydrochloride.

[0100] The present invention also specifically relates to compounds of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.

[0101] Furthermore, the scope of the present invention includes the compounds of formula (I) in any solvated form, including, for example, solvates with water (i.e., hydrates) or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs) of the compounds of formula (I), are also encompassed within the scope of the present invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of formula (I) are also encompassed by the present invention.

[0102] Furthermore, compounds of formula (I) may exist in different isomeric, particularly stereoisomers (e.g., geometric isomers (or including cis / trans isomers), enantiomers and diastereomers) or tautomers (especially including prototropic tautomers such as keto / enol tautomers or thione / thiol tautomers). All such isomers of compounds of formula (I), either in mixtures or in pure or substantially pure form, are contemplated as part of the present invention. With respect to stereoisomers, the present invention encompasses isolated optical isomers of the compounds of the present invention and any mixtures thereof (especially racemic mixtures / racemates). Racemates can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates by salt formation with optically active acids followed by crystallization. The present invention further encompasses any tautomers of compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulas provided herein explicitly represent only one of the possible tautomeric forms. The formulas and chemical names provided herein are intended to encompass all tautomeric forms of the corresponding compounds, and are not limited to only the specific tautomeric form shown by the drawing or identified by the compound name.

[0103] The scope of the present invention also includes compounds of formula (I) in which one or more atoms are replaced with a specific isotope of the corresponding atom. For example, the present invention also includes compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced with a deuterium atom (i.e., 2 The present invention also encompasses compounds of formula (I) that are substituted with hydrogen (H; also referred to as "D"). Accordingly, the present invention also encompasses compounds of formula (I) that are deuterium-rich. Naturally occurring hydrogen is approximately 99.98 mole % hydrogen 1 ( 1 H) and about 0.0156 mole % deuterium ( 2The deuterium content at one or more hydrogen positions in the compound of formula (I) can be increased using deuteration techniques known in the art. For example, the compound of formula (I) or a reactant or precursor used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, for example, heavy water (DO). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless otherwise specified, it is preferred that the compound of formula (I) is not enriched in deuterium. Thus, in the compounds of formula (I), naturally occurring hydrogen atoms or 1 Preferably, H hydrogen atoms are present.

[0104] The present invention relates to a compound in which one or more atoms are e.g. 18 F, 11 C. 13 N, 15 O. 76 Br, 77 Br, 120 I and / or 124 The present invention also encompasses compounds of formula (I) that are substituted with a positron-emitting isotope of the corresponding atom, such as I. Such compounds can be used as tracers, trackers, or imaging probes in positron emission tomography (PET). Accordingly, the present invention provides compounds of formula (I) in which (i) one or more fluorine atoms (or, for example, all fluorine atoms) are 18 (ii) a compound of formula (I) in which one or more carbon atoms (or, for example, all carbon atoms) are substituted with a F atom; 11 (iii) Compounds of formula (I) in which one or more nitrogen atoms (or for example all nitrogen atoms) are substituted with a C atom 13(iv) a compound of formula (I) in which one or more oxygen atoms (or, for example, all oxygen atoms) are substituted with an N atom; 15 (v) a compound of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are substituted with an O atom; 76 (vi) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are substituted with Br atoms; 77 (vii) a compound of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with Br atoms; 120 and (viii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are substituted with iodine atoms. 124 This includes compounds of formula (I) that are substituted with an I atom. Generally, it is preferred that no atom in a compound of formula (I) is substituted with a specific isotope.

[0105] The compounds provided herein may be administered as compounds per se or may be formulated as drugs. The drug / pharmaceutical composition may optionally include one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0106] The pharmaceutical compositions may contain, for example, poly(ethylene glycols), including poly(ethylene glycols) having a molecular weight ranging from about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS), 15, CAS70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β The composition may comprise one or more solubility enhancers such as cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or any combination thereof.

[0107] The pharmaceutical compositions may also include one or more preservatives, particularly one or more antimicrobial preservatives such as, for example, benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methylphenol or 4-chloro-3-methylphenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0108] The pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd Edition. The pharmaceutical compositions can be formulated for oral or parenteral administration, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, reconstitutable powders and granules, dispersible powders and granules, medicated gums, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions, and reconstitutable powders and granules. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovulae. Dosage forms for nasal administration can be administered by inhalation and insufflation, for example, by metered-dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0109] The compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) may be administered to a subject by any convenient route of administration, whether systemic / peripheral or at a desired site of action, including, but not limited to, one or more of oral (e.g., as a tablet, capsule, or ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection or infusion techniques, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal, e.g., by implantation of a depot, e.g., subcutaneous or intramuscular), pulmonary (e.g., by inhalation or insufflation therapy using an aerosol, e.g., via the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal, or vaginal administration.

[0110] When the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracardiac, intracranial, intramuscular, or subcutaneous administration of the compound or pharmaceutical composition, and / or administration using infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

[0111] The compounds or pharmaceutical compositions may also be orally administered in the form of tablets, capsules, suppositories, elixirs, solutions, or suspensions, which may contain flavorings or colorants for immediate-release, delayed-release, modified-release, sustained-release, pulsed-release, or controlled-release applications. Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. In the case of aqueous suspensions and / or elixirs, the compounds may be combined with various sweeteners, flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol, glycerol, and combinations thereof.

[0112] For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition can be administered by mouth through the digestive tract, which can also be referred to as "oral digestive" administration.

[0113] Alternatively, the compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be administered transdermally, for example, by the use of a skin patch.

[0114] The compound or pharmaceutical composition can also be administered via a sustained-release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polylactic acid, copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Thus, the present invention also relates to liposomes containing the compounds of the present invention.

[0115] Said compound or pharmaceutical composition can also be administered by pulmonary route, rectal route or ocular route.For ophthalmic use, it can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, optionally combined with preservatives such as benzalkonium chloride, or preferably as a solution in isotonic pH-adjusted sterile saline.Alternatively, they can be formulated as an ointment such as petrolatum.

[0116] It is also contemplated to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that result in a substantially amorphous, glassy or substantially crystalline bioactive powder. Thus, dry powders of the compounds of the present invention can be prepared according to an emulsification / spray drying process.

[0117] For topical application to the skin, the compounds or pharmaceutical compositions can be formulated into a suitable ointment containing the active compound suspended or dissolved in a mixture including one or more of mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water, or they can be formulated into a suitable lotion or cream containing the active compound suspended or dissolved in a mixture including one or more of mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol, and water.

[0118] Thus, the present invention relates to compounds or pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition can be administered by any one of the following routes: oral, topical, including transdermal, intranasal, ocular, buccal, or sublingual, parenteral, using injection or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid, intrasternal, intraventricular, intraurethral, ​​or intracranial, pulmonary, including inhalation or insufflation therapy, gastrointestinal, intrauterine, intraocular, subcutaneous, ocular, including intravitreal or intracameral, rectal, or vaginal.

[0119] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dose and frequency of administration for any particular individual subject may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the particular condition, and the individual subject being treated.

[0120] The compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can be administered as a monotherapy (e.g., without the simultaneous administration of an additional therapeutic agent or without the simultaneous administration of any additional therapeutic agent for the same disease that can be treated or prevented with the compound of formula (I)). However, the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can also be administered in combination with one or more additional therapeutic agents. When the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition, the dosage of each compound may be different from the dosage when the corresponding compound is used alone, and in particular, a lower dose of each compound may be used. The combination of the compound of formula (I) and one or more additional therapeutic agents may involve simultaneous / concurrent administration of the compound of formula (I) and the additional therapeutic agent (either as a single pharmaceutical formulation or separate pharmaceutical formulations), or sequential / separate administration of the compound of formula (I) and the additional therapeutic agent. When the administration is sequential, either the compound of formula (I) of the present invention or one or more additional therapeutic agents may be administered first. When administration is simultaneous, the one or more additional therapeutic agents may be in the same pharmaceutical formulation as the compound of formula (I) or may be administered in two or more different (separate) pharmaceutical formulations.

[0121] For the treatment or prevention of cancer, the one or more additional therapeutic agents administered in combination with the compounds of the present invention (or corresponding pharmaceutical compositions) are preferably anti-cancer agents. Anti-cancer agents administered in combination with the compounds of formula (I) according to the present invention include, for example, tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors or vascular endothelial growth factor receptor kinase inhibitors), cytotoxic drugs (e.g., antimetabolites such as purine and pyrimidine analog antimetabolites), antimitotic agents (e.g., microtubule-stabilizing agents or antimitotic alkaloids), platinum complexes, antitumor antibiotics, alkylating agents (e.g., nitrogen mustards or nitrosoureas), endocrine agents (e.g., corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists or somatostatin analogs), or compounds that target enzymes or receptors involved in specific metabolic pathways that are overexpressed and / or otherwise unregulated (or misregulated) in tumor cells (e.g., ATP and GTP phospholipase C receptors). The inhibitors may be selected from phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitors) and various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors), methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), poly ADP-ribose polymerase inhibitors (PARP inhibitors) and epidermal growth factor receptor (EGFR) inhibitors / antagonists.

[0122] Alkylating agents that can be used as anti-cancer agents in combination with the compounds of the present invention may be, for example, nitrogen mustards (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), alkylsulfonates (such as busulfan, mannosulfan, or treosulfan), aziridines (such as hexamethylmelamine (altretamine), triethylenemelamine, thiotepa (N,N'N'-triethylenethiophosphoramide), carboquone, or triaziquone), hydrazines (such as procarbazine), triazenes (such as dacarbazine), or imidazotetrazines (such as temozolomide). Platinum complexes that can be used as anticancer agents in combination with the compounds of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate. Cytotoxic drugs that can be used as anticancer agents in combination with the compounds of the present invention may be, for example, antimetabolites, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug form capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).An antimitotic agent that can be used as an anti-cancer agent in combination with a compound of the invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel or nab-paclitaxel (e.g., Abraxane®)), a vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E or epothilone F) or an epothilone B analogue (such as ixabepilone / azaepothilone B). Antitumor antibiotics that can be used as anticancer agents in combination with the compounds of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin or zorubicin), an anthracenedione (such as mitoxantrone or pixantrone) or an antitumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C) or plicamycin). The tyrosine kinase inhibitor that can be used as an anticancer agent in combination with the compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib or vemurafenib.The topoisomerase inhibitor that can be used as an anticancer agent in combination with the compound of the present invention may be, for example, topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan or lamellarin D) or topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide or doxorubicin). The PARP inhibitor that can be used as an anti-cancer agent in combination with the compound of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP9722, MK4827, E7016 or 3-aminobenzamide.The EGFR inhibitor / antagonist that can be used in combination with the compound of the present invention as an anti-cancer agent can be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigutinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, poziotinib, ABT-414, AV-412, PD153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab or matuzumab.Other anti-cancer agents can also be used in combination with the compound of the present invention. Anticancer drugs include TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, and tretinoin. The compound may include a biological or chemical molecule such as benzodiazepine, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucide, lonidamine, lucantone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, citimaprine, seradenovec, tegafur, testolactone, tiazofurin, tipifarnib, vorinostat, iniparib, or copanlisib.

[0123] Anti-cancer agents that can be used in combination with the compounds of the invention can also be cancer immunotherapeutics, such as antibodies (e.g., monoclonal or polyclonal antibodies), antibody fragments, antibody constructs (e.g., single-chain constructs), or modified antibodies (e.g., CDR-grafted antibodies, humanized antibodies, or "fully human" antibodies), that target, for example, any one of CTLA-4, PD-1, PD-L1, TIGIT, TIM3, LAG3, OX40, CSF1R, IDO, or CD40.Examples of such cancer immunotherapeutic agents include anti-CTLA-4 antibodies (particularly antagonistic or pathway-blocking anti-CTLA-4 antibodies, such as ipilimumab or tremelimumab), anti-PD-1 antibodies (particularly antagonistic or pathway-blocking anti-PD-1 antibodies, such as nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab (CT-011), cemiplimab, dostallimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, and jimbecile. rellimab, AMP-224, AMP-514 (or MEDI0680), JTX-4014, INCMGA00012 (or MGA012) or APE02058), anti-PD-L1 antibodies (particularly pathway-blocking anti-PD-L1 antibodies, e.g., atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, MEDI6469 or vintrafusp alfa), anti TIGIT antibodies (e.g. tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939 or M6223), anti-TIM3 antibodies (particularly pathway-blocking anti-TIM3 antibodies), anti-LAG3 antibodies (particularly antagonistic or pathway-blocking anti-LAG3 antibodies, e.g. leratolimab (or BMS-986016), yelamilimab (or LAG525), encelimab ( or TSR-033), tebotelimab (or MGD013), REGN3767 (or R3767), FS118, IMP701 or IMP731), anti-OX40 antibodies (particularly antagonistic anti-OX40 antibodies, such as MEDI0562), anti-CSF1R antibodies (particularly pathway-blocking anti-CSF1R antibodies, such as IMC-CS4 or RG7155), anti-IDO antibodies (particularly pathway-blocking anti-IDO antibodies), or anti-CD40 antibodies (particularly antagonistic anti-CD40 antibodies, such as CP-870, 893 or Chi Lob7 / 4). Further examples of cancer immunotherapeutics include anti-HER2 antibodies (e.g., trastuzumab), anti-CD20 antibodies (e.g., rituximab), anti-CD19 / CD3 constructs, and anti-TNF antibodies.

[0124] In particular, the compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) may be administered in combination with an immune checkpoint inhibitor, preferably an antibody (or antigen-binding fragment or antibody construct thereof) against CTLA-4, PD-1, PD-L1, TIGIT or LAG3. Corresponding preferred examples include, but are not limited to, any one of the anti-CTLA-4 antibodies ipilimumab or tremelimumab, the anti-PD-1 antibodies nivolumab, pembrolizumab, pidilizumab, cemiplimab, dostallimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, AMP-224, AMP-514, JTX-4014, INCMGA00012 or APE02058, and the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559. , MEDI4736, MPDL3280A, MDX-1105, MEDI6469 or vintrafusp alfa; any one of the anti-TIGIT antibodies tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939 or M6223; and / or any one of the anti-LAG3 antibodies leratolimab, yeramilimab, enselimab, tebotelimab, REGN3767, FS118, IMP701 or IMP731.Accordingly, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or any of the above entities in combination with a pharmaceutically acceptable excipient for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition can be administered in combination with one or more immune checkpoint inhibitors, wherein said one or more immune checkpoint inhibitors are preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-TIGIT antibodies and / or anti-LAG3 antibodies, more preferably said one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, cemiplimab, dostallimab, spartalizumab, camrelizumab, scinti Limab, tislelizumab, toripalimab, zimberelimab, AMP-224, AMP-514, JTX-4014, INCMGA00012, APE02058, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, Vintravspual selected from fa, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, leratolimab, yelamilimab, enselimab, tebotelimab, REGN3767, FS118, IMP701 and IMP731.

[0125] The combinations mentioned above can be conveniently provided for use in the form of pharmaceutical preparations. The individual components of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical preparations by any convenient route. When administration is sequential, either the compound of the present invention (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or the additional therapeutic agent can be administered first. When administration is simultaneous, the combination can be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same preparation, it will be understood that the two or more compounds must be stable and compatible with each other and with the other components of the preparation. When formulated separately, they may be provided in any convenient preparation and administered by any convenient route.

[0126] The compound of formula (I) can also be administered in combination with physical therapy, such as radiation therapy. Radiation therapy can be initiated before, after, or simultaneously with the administration of the compound of the present invention. For example, radiation therapy can be initiated about 1-10 minutes, about 1-10 hours, or about 24-72 hours after administration of the compound of formula (I). The subject / patient is exposed to radiation, preferably gamma radiation, which can be administered in a single dose or multiple doses administered over several hours, days, and / or weeks. Gamma radiation can be administered according to standard radiation therapy protocols using standard doses and regimens.

[0127] The present invention therefore relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the above entities in combination with a pharmaceutically acceptable excipient for use in the treatment or prevention of cancer, which may be administered in combination with one or more anti-cancer agents (including any one or more of the specific anti-cancer agents described hereinabove) and / or radiation therapy.

[0128] However, the compounds of formula (I) can also be used as monotherapy, in particular in the monotherapy treatment or prevention of cancer (i.e., no other anti-cancer drugs are administered until treatment with the compound of formula (I) has ceased). The present invention therefore also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the above entities in combination with a pharmaceutically acceptable excipient for use in the monotherapy treatment or prevention of cancer.

[0129] Additionally, the compounds of Formula (I) can be administered in combination with one or more additional anti-cancer agents (including any of the exemplary anti-cancer agents described above), or in combination with an anti-emetic agent without any additional anti-cancer agent. Anti-emetic agents include, for example, alosetron, azasetron, bemesetron, cilansetron, clozapine, dazopride, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (e.g., palonosetron alone or in combination with netupitant), quetiapine, ramosetron, licasetron, tropisetron, zatosetron, clozapine, cyproheptadine, hydroxyzine, olanzapine, risperidone, ziprasidone, dronabinol, nabilone, tetrahydrocannabinol, alizapride, bromopride, chlorpromazine, and the like. The antihypertensive agent may be selected from phenhydramine, clebopride, domperidone, haloperidol, hydroxyzine, itopride, metoclopramide, metopimazine, prochlorperazine, thiethylperazine, trimethobenzamide, cyclizine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, promethazine, atropine, diphenhydramine, hyoscyamine, scopolamine, aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, vespitant, cerium oxalate, dexamethasone, lorazepam, midazolam, propofol, or a combination thereof. Preferably, the antiemetic agent is a 5-HT3 antagonist (or "setron") such as, for example, alosetron, azasetron, bemesetron, cilansetron, clozapine, dazopride, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (optionally in combination with netupitant), quetiapine, ramosetron, licasetron, tropisetron or zatosetron.

[0130] The subject or patient to be treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male or female human) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cow, or pig, etc.). Most preferably, the subject / patient to be treated according to the present invention is a human.

[0131] The term "treatment" of a disorder or disease as used herein is well known in the art. "Treatment" of a disorder or disease means that the disorder or disease is suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically exhibits specific clinical and / or pathological symptoms, which can be easily attributed to a specific pathological condition by a person skilled in the art (i.e., the disorder or disease can be diagnosed).

[0132] "Treatment" of a disorder or disease may result, for example, in halting the progression of the disorder or disease (e.g., not worsening symptoms) or slowing the progression of the disorder or disease (if the halt in progression is merely transient in nature). "Treatment" of a disorder or disease may also result in a partial response (e.g., alleviation of symptoms) or a complete response (e.g., disappearance of symptoms) in the subject / patient suffering from the disorder or disease. Thus, "treatment" of a disorder or disease may also refer to remission of the disorder or disease, which may result, for example, in halting the progression of the disorder or disease or slowing the progression of the disorder or disease. Such a partial or complete response may be followed by relapse. It is understood that a subject / patient may experience a wide range of responses to treatment (e.g., the exemplary responses described herein above). Treatment of a disorder or disease may include, in particular, curative treatment (preferably resulting in a complete response, and ultimately resulting in cure of the disorder or disease) and symptomatic treatment (including relief of symptoms).

[0133] The term "prevention" of a disorder or disease as used herein is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may particularly benefit from prevention of that disorder or disease. A subject / patient may have a susceptibility or predisposition to the disorder or disease, including, but not limited to, a genetic predisposition. Such a predisposition can be determined by standard methods or assays using, for example, genetic markers or phenotypic indicators. It is understood that the disorder or disease prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit clinical or pathological symptoms). Thus, the term "prevention" includes the use of a compound of the present invention before clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0134] It is to be understood that the present invention particularly relates to any and all combinations of features and embodiments described herein, including any and all combinations of general and / or preferred features / embodiments. In particular, the present invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables contained in formula (I).

[0135] Many documents, including patent applications and scientific literature, have been cited herein. The disclosures of these documents are not considered relevant to the patentability of this invention, but are incorporated herein by reference in their entirety. More specifically, all references are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0136] Reference in this specification to any prior publication (or information derived therefrom) is not, and should not be, taken as an acknowledgement, admission or any form of suggestion that the corresponding prior publication (or information derived therefrom) forms part of the common general knowledge in the art to which this specification pertains.

[0137] The invention is also illustrated in the following figures. [Brief explanation of the drawings]

[0138] [Figure 1] Western blot analysis of NIK degradation for A375 cells treated with 10 μM of the compound of Example 3 for 72 hours (see Example 143). [Example]

[0139] The present invention is further illustrated by the following examples. The compounds of formula (I) described in the examples section are defined by their chemical formula and their corresponding chemical name. In the event of a discrepancy between any chemical formula and the corresponding chemical name shown herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly to the compound defined by the chemical formula.

[0140] Introduction Compounds of the invention may be synthesized, for example, as illustrated with reference to the compounds of Examples 1-142 in Schemes 1-4 below.

[0141] Scheme 1 Example 1 can be prepared according to Reaction Scheme 1 below. [ka]

[0142] Compound 1 can be synthesized from 7-bromo-4-chloroquinoline and phenylboronic acid using the Suzuki coupling reaction, followed by coupling of compound 1 with 2-methoxy-4-(2-methoxyethoxy)aniline to give Example 1.

[0143] Scheme 2 Examples 3, 9-10, 39-40, 46-55, 58-65, 71-72, 75-89, 103-110, 115, 119, 121, 126-130, 133 and 135-139 can be prepared according to Reaction Scheme 2 below. [ka]

[0144] A mixture of the desired 4-chloroquinoline and the corresponding aniline was refluxed at 80°C.

[0145] Scheme 3 Examples 2, 4-8, 11-44, 56-57, 66-70, 73-74, 101-102, 122-125 and 131-132 can be prepared according to Reaction Scheme 3 below. [ka] 1: A mixture of the desired 4-chloroquinoline and 4-amino-3-methoxyphenol was stirred at 80° C. overnight. 2: A mixture of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol and 2-methoxyethyl 4-methylbenzenesulfonate or 1-bromo-2-(trifluoromethoxy)ethane was stirred at 60° C. in the presence of cesium carbonate. 3: The desired 7-bromoquinoline was coupled with the desired aryltributylstannyl using a Stille coupling reaction. 4: The desired 7-bromoquinoline was coupled with the desired boronic acid using the Suzuki coupling reaction. 5: The desired 7-bromoquinoline was coupled with the desired amine using the Buchwald coupling reaction. 6: The desired alkene was hydrogenated using Pd / C with H2 (5 bar). 7: The desired Boc-protected amine was deprotected under acidic conditions. 8: The desired Boc-protected amine was reduced to the corresponding methylamine using lithium aluminum hydride.

[0146] Scheme 4 Examples 111-114, 116-118, 120 and 134 can be prepared according to Reaction Scheme 4 below. [ka]

[0147] A mixture of the desired 4-chloroquinoline and the corresponding aniline was refluxed at 80° C., and then the corresponding bromine derivative was coupled with the desired boronic acid using Suzuki coupling conditions.

[0148] Experimental section Several methods for preparing compounds of the present invention are illustrated in the following examples. Reagents were commercially available and used without further purification. All temperatures are in °C. TLC was performed on 254 nM (60 Å median pore size) aluminum-backed silica gel plates containing a fluorescent indicator. Flash column chromatography was performed using a Biotage Isolera One system with KP-Sil or Ultra silica gel columns or an Isco CombiFlash Rf with FlashPure or RediSep Rf / RediSep Rf Gold silica gel columns. NMR spectra were recorded on 400 or 500 MHz spectrometers at ambient probe temperature (nominal 298 K). Chemical shifts (δ) are given in ppm and are calibrated using the residual solvent peak as the internal standard (CDCl3, δ = 7.26 ppm; DMSO-d6, δ = 2.50 ppm). Coupling constants are given in hertz (Hz). LRMS were recorded using an Advion Plate Express expression® compact mass spectrometer equipped with an APCI ion source.

[0149] LCMS analysis was performed using a Waters Acquity UPLC equipped with either a CSH C18 or BEH C18 column (2.1 x 30 mm) at 40 °C and 0.77 mL / min with a linear 2-100% acetonitrile gradient over 3 or 10 min, appropriate for the lipophilicity of the compound. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded from 210 to 400 nm using a Waters Acquity photodiode array detector. Mass spectra were recorded using a Waters Acquity QDa detector with ESI switching between positive and negative ion modes.

[0150] Method A Apparatus: Waters HClass; Quaternary solvent pump, SM-FTN, CMA, PDA: 210–400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30 × 2.1 mm, 1.7 μm, Temperature: 40 °C, Flow rate: 0.77 mL / min, Gradient: t 0 = 2% B, t 2.5 min = 100% B, t 3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0151] Method B Apparatus: Waters HClass; binary solvent pump, SM-FTN, CMA, PDA: 210–400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 × 2.1 mm, 1.7 μm; Temperature: 40 °C; Flow rate: 0.77 mL / min; Gradient: t 0 = 2% B, t 2.5 min = 100% B, t 3.0 min = 100% B; Eluent A: 0.1% NH 3 in water; Eluent B: acetonitrile.

[0152] Method C Apparatus: Waters HClass; Quaternary solvent pump, SM-FTN, CMA, PDA: 210–400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30 × 2.1 mm, 1.7 μm; Temperature: 40 °C; Flow rate: 0.77 mL / min; Gradient: t 0 = 2% B, t 9.5 min = 100% B, t 10.0 min = 100% B; Eluent A: 0.1% formic acid in water; Eluent B: acetonitrile.

[0153] Method D Apparatus: Waters HClass; binary solvent pump, SM-FTN, CMA, PDA: 210–400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 × 2.1 mm, 1.7 μm; Temperature: 40 °C; Flow rate: 0.77 mL / min; Gradient: t 0 = 2% B, t 9.5 min = 100% B, t 10.0 min = 100% B; Eluent A: 0.1% NH3 in water; Eluent B: acetonitrile.

[0154] Method E Apparatus: Agilent 1260; binary pump, HiP sampler, column compartment, DAD: 260 + / - 90 nm, G6150MSD: ESI; Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 μm, Temperature: 40 °C, Flow rate: 1.35 mL / min, Gradient: t0 = 5% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0155] General Procedure Substituted 4-chloroquinolines S N General Procedure for Ar A solution of the desired 4-chloroquinoline (1.0 equiv.) and 2-methoxy-4-(2-methoxyethoxy)aniline (1.2 equiv.) in EtOH (2 mL) was heated to 80 °C and stirred for 18 h. The solvent was evaporated, and the residue was dissolved in acetone (5 mL) and then sonicated to form a suspension. The precipitate was collected by filtration, washed with acetone (10 mL × 3), and then dried in a vacuum desiccator at 50 °C to give the title compound.

[0156] Acid catalysis of substituted 4-chloroquinolines N General Procedure for Ar To a solution of the desired 4-chloroquinoline (1.0 equiv.) and the desired aniline (1.2 equiv.) in IPA (0.3 M) was added 4.0 M HCl in dioxane (1.2 equiv.). The reaction mixture was heated to 80 °C and stirred for 18 h. The solvent was evaporated, and the residue was dissolved in acetone (5 mL) and then sonicated to form a suspension. The precipitate was collected by vacuum filtration, washed with acetone (10 mL × 3), and then optionally purified by silica gel column chromatography or reverse-phase preparative HPLC. If necessary, the final product was optionally converted to its hydrochloride salt using 4.0 M HCl in dioxane and then dried in a vacuum desiccator at 50 °C to give the title compound.

[0157] General Procedure C for Suzuki Reaction of 7-Bromoquinolines To a stirred solution of the desired 7-bromoquinoline (1.0 equiv.) in 1,4-dioxane (2 mL) was added K2CO3 (3.0 equiv.) at room temperature. A stream of nitrogen gas was bubbled through the reaction mixture for 10 minutes to degas it. To this mixture was added the desired boronic acid (2.0 equiv.) and XPhos Pd G4 (5 mol%). The reaction mixture was heated and stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature and adsorbed onto silica. The crude product was purified by silica gel chromatography to give the title compound.

[0158] General Procedure D for the Buchwald Reaction of 7-Bromoquinolines To a stirred solution of the desired 7-bromoquinoline in 1,4-dioxane (4 mL) was added the desired amine (2.0 equiv.) at room temperature. A stream of nitrogen gas was bubbled through the mixture for 10 minutes to degas it. To this mixture was added 2.0 M NaOt-Bu and RuPhos Pd G3 (10 mol%) in THF (5.0 equiv.). The reaction mixture was heated and stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and adsorbed onto silica. The crude product was purified by silica gel chromatography to give the title compound.

[0159] Procedure E for the Buchwald reaction of 7-bromoquinoline and piperazin-2-one A reactor was charged with 7-bromo-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine (1.0 equiv.), piperazin-2-one (248 mg, 4.0 equiv., 2.48 mmol), XantPhos Pd G3 (20 mol%), and K3PO4 (4.0 equiv.). t-BuOH (0.3 M) was added, and the reaction mixture was degassed with nitrogen and heated to 120 °C under microwave irradiation for 2 h. Aqueous workup (DCM-MeOH = 9:1 / water) followed by preparative HPLC afforded the title compound.

[0160] General Procedure F for the Hydrogenation of Alkene and Nitro Intermediates To a stirred solution of alkene in a 4:1 mixture of EtOH and MeOH (5 mL) was added 10% Pd / C (50 wt % water, 0.1 equiv.) in EtOH (1 mL) at room temperature. The mixture was then hydrogenated with H (5 bar) for 24 hours. The reaction mixture was filtered, and the solution was concentrated in vacuo to give the title compound.

[0161] General Procedure G for Stille Coupling of 7-Bromoquinolines To a degassed, stirred solution of the desired 7-bromoquinoline (1 equiv.) in DMF (0.15 molar) in a sealed tube at room temperature was added lithium chloride (3.0 equiv.), tetrakis(triphenylphosphine)palladium(0) (10 mol%), and then the desired aryltributylstannyl (3.0 equiv.). The reaction was heated to 110 °C and stirred for 3 h. The reaction was cooled to room temperature, and then MeCN (40 mL) was added. The acetonitrile solution was extracted with heptane (5 × 10 mL). Potassium fluoride (2 g) and sodium sulfate (2 g) were added to the acetonitrile phase, and the mixture was stirred for 30 min at room temperature. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0.7 M NH3 in MeOH / DCM). The product was further purified by preparative HPLC to give the title compound.

[0162] General Procedure H for Deprotection of Boc-Protected Amines A solution of the Boc-protected amine (1 equiv.) and HCl (4 M in dioxane) (20 equiv.) in THF (1.00 mL) was stirred for 18 h at 40° C. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (0.7 M NH in MeOH / DCM) to give the title compound.

[0163] General Procedure I for the Reduction of Boc-Protected Amines to the Corresponding Methylamines A solution of the Boc-protected amine (1 equiv.) in THF (0.05 molar) was cooled to 0°C, followed by the dropwise addition of 1.0 M LiAlH4 in THF (5.49 equiv.). The reaction was stirred at 0°C for 10 minutes and then at room temperature for 15 minutes, after which it was heated to 65°C for 3 hours. The reaction mixture was then cooled to 0°C and quenched with water (200 μL) and 2 M aqueous NaOH (150 μL). The suspension was filtered and washed successively with THF (5 mL), EtOAc (10 mL), and DCM (20 mL). The filtrate was concentrated under reduced pressure. The crude product was further purified by trituration in cold Et2O to give the title compound.

[0164] General procedure for the alkylation of phenols with alkyl tosylates A mixture of the desired phenol (1 equivalent), 2-(trifluoromethoxy)ethyl 4-methylbenzenesulfonate (1.05 equivalents), and cesium carbonate (2.1 equivalents) in acetone (0.08 molar) was stirred at 60° C. for 18 hours. The solvent was removed in vacuo, the residue was triturated in water (20 mL), and the solid was collected by vacuum filtration. The crude product was purified by silica gel chromatography ([0.7 M ammonia / MeOH] / DCM), and the resulting material was dissolved in 4 M HCl in dioxane (2 mL), and the solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and then concentrated (3 times). The residue was then triturated in diethyl ether, and the resulting solid was collected and dried to give the title compound.

[0165] General Procedure K for Suzuki Reaction with N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine A solution of N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine (1 equiv.), the desired boronic acid (2.0 equiv.), and KCO (3 equiv.) in a toluene / EtOH / HO (1 / 0.5 / 0.25) mixture was degassed with a stream of argon gas. Tetrakis(triphenylphosphine)palladium(0) (5 mol%) was added, and the mixture was stirred at 90 °C overnight. Upon completion, the product was extracted with EtOAc, washed with brine, dried over MgSO, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to give the title compound.

[0166] Preparation of synthetic intermediates Preparation of Compound 1 (4-chloro-7-phenylquinoline) A reactor was charged with 7-bromo-4-chloroquinoline (1.0 g, 4.12 mmol), cesium carbonate (2.7 g, 8.29 mmol), phenylboronic acid (530 mg, 4.35 mmol), and tetrakis(triphenylphosphine)palladium(0) (500 mg, 433 μmol). The reactor was evacuated and purged with nitrogen, then 1,4-dioxane (10.0 mL) and water (2.0 mL) were added. The reaction mixture was evacuated and purged with nitrogen three times, then stirred at 80 °C for 18 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NH4Cl (20 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (10 mL × 2), and the combined organic phases were washed with brine (20 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude product was dry-loaded onto silica gel (40 g cartridge, gradient elution: 0-50% (10% MeOH in DCM) / isohexane) to give 4-chloro-7-phenylquinoline (570 mg, 55%) as a white solid. UPLC (Method A): m / z 240.3 [M+H] at 2.19 min + . 1H NMR (400MHz, chloroform-d) δ8.81(d,J=4.7Hz,1H),8.38(d,J=1.8Hz,1H),8.31(d,J=8.7Hz,1 H),7.94(dd,J=8.7,1.8Hz,1H),7.80-7.73(m,2H),7.57-7.48(m,3H),7.48-7.40(m,1H).

[0167] Preparation of Compound 2 (4-chloro-7-(difluoromethyl)quinoline) To a solution of 4-chloroquinoline-7-carbaldehyde (166 mg, 1 equiv., 866 μmol) in dry DCM (2 mL) at room temperature was added 50% DeoxoFluor in toluene (420 mg, 350 μL, 50 wt.%, 1.10 equiv., 949 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM (10 mL) and saturated NaHCO3 (10 mL), and the phases were separated. The aqueous phase was extracted with DCM (10 mL × 2), and the combined organic phases were washed with brine (20 mL), dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was dry-loaded onto silica and purified by silica gel chromatography (12 g cartridge, 0-50% MTBE / isohexane) to give 4-chloro-7-(difluoromethyl)quinoline as a white solid (119 mg, 0.53 mmol, 61%, purity: 95%). UPLC (Method A): m / z 214.1 [M+H] at 1.73 min + . 1 H NMR(400MHz,DMSO-d6)δ8.95(d,J=4.7Hz,1H),8.38(d,J=8.7Hz,1H),8.34-8.2 9(m,1H),7.93(d,J=8.7Hz,1H),7.90(d,J=4.7Hz,1H),7.32(t,J=55.4Hz,1H).

[0168] Preparation of Compound 3 (4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinoline) A reactor was charged with 7-bromo-4-chloroquinoline (1.0 equiv.), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.3 equiv.), XPhos Pd G4 (5 mol%), and K2CO3 (3.0 equiv.). The reactor was evacuated and purged with nitrogen, then a 4:1 mixture of 1,4-dioxane (0.3 M) was added. The reaction mixture was evacuated and purged with nitrogen three times, then heated to 80°C and stirred under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, and additional (1-methyl-1H-pyrazol-4-yl)boronic acid (0.5 equiv.) and XPhos Pd G4 (3 mol%) were added. The reaction mixture was evacuated and purged with nitrogen three times, heated to 80°C, and stirred under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and partitioned between 9:1 EtOAc / MeOH (50 mL) and water (50 mL). The phases were separated, the aqueous phase was extracted with 9:1 EtOAc / MeOH (25 mL × 2), and the combined organic phases were washed with brine (50 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0–10% (0.7 M NH3 / MeOH) in dichloromethane. The product was then triturated with MTBE (10 mL) followed by Et2O (10 mL × 2), and the solid was collected by vacuum filtration to give the title compound as a white solid (124 mg, 12%). UPLC (Method A): m / z 244.0 [M+H] at 1.38 min + . 1 H NMR(400MHz,DMSO-d6)δ8.80(d,J=4.7Hz,1H),8.43(s,1H),8.26(d,J=1.7Hz,1H),8.17(d,J=8. 7Hz,1H), 8.13(d,J=0.8Hz,1H),8.01(dd,J=8.8,1.8Hz,1H),7.67(d,J=4.7Hz,1H),3.91(s,3H).

[0169] Preparation of Compound 4 (2-(methoxy-d3)-4-(2-methoxyethoxy)-1-nitrobenzene) To a stirred solution of 5-(2-methoxyethoxy)-2-nitrophenol (771 mg, 3.62 mmol) in acetone (4.0 mL) in a sealed tube at room temperature was added K2CO3 (750 mg, 5.42 mmol) and iodomethane-d3 (1.0 g, 6.9 mmol). The reaction mixture was stirred at room temperature for 7 days. Saturated aqueous NaHCO3 (20 mL) was added to the reaction. The mixture was extracted with DCM (3 × 40 mL), and the combined organic phase was washed with brine (20 mL), passed through a phase separator, and dried, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (40 g cartridge, 10–100% [1:4 MeOH / EtOAc solution] / isohexane) to give 2-(methoxy-d3)-4-(2-methoxyethoxy)-1-nitrobenzene (237 mg, 1.03 mmol, 29%) as a pale yellow powder. LCMS (Method E): m / z 231.1 [M+H] at 1.23 min + . 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=9.1Hz,1H),6.81(d,J=2.5Hz,1H),6.67(dd,J=9.1,2.5Hz,1H),4.28-4.21(m,2H),3.71-3.64(m,2H),3.31(s,3H).

[0170] Preparation of Compound 5 (2-(methoxy-d3)-4-(2-methoxyethoxy)aniline) General procedure F was used to give the title compound as a dark red oil (134 mg, 68%). UPLC (Method A): m / z 201.5 [M+H] at 0.46 min + . 1 H NMR(400MHz,DMSO-d6)δ6.53(d,J=8.4Hz,1H),6.45(d,J=2.6Hz,1H),6.28(dd,J=8.4,2.6Hz,1H),4.23(br s, 2H), 3.99-3.92 (m, 2H), 3.63-3.56 (m, 2H), 3.29 (s, 3H).

[0171] Preparation of Compound 6 (4-(benzyloxy)-2-cyclopropoxy-1-nitrobenzene) To a suspension of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (1.0 equiv.) and CsCO (1.6 equiv.) in DMF (0.3 M) was added cyclopropanol (1.5 equiv.), and the reaction mixture was heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature and then partitioned between EtOAc (40 mL) and water (30 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over MgSO, filtered, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0–100% (25% EtOAc in isohexane) / isohexane to give the title compound as a yellow oil (192 mg, 81%). UPLC (Method A): No m / z observed at 2.13 min [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=9.1Hz,1H),7.52-7.46(m,2H),7.45-7.39(m,2H),7.39-7.34(m,1H),7.15(d, J=2.6Hz,1H),6.79(dd,J=9.1,2.6Hz,1H),5.26(s,2H),4.11-4.04(m,1H),0.90-0.81(m,2H),0.74-0.66(m,2H).

[0172] Preparation of Compound 7 (4-(benzyloxy)-2-cyclopropoxy-1-nitrobenzene) General procedure F was used to give the title compound as a black solid (91 mg, 78%). UPLC (Method B): m / z 164.0 [M+H] in 0.74 min + . 1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),6.59(d,J=2.5Hz,1H),6.43(d,J=8.3Hz,1H),6.13(dd,J=8 .3,2.5Hz,1H),3.95(s,2H),3.72(tt,J=6.1,3.0Hz,1H),0.76-0.68(m,2H),0.68-0.60(m,2H).

[0173] Preparation of Compound 8 (4-(benzyloxy)-2-(methoxy-d3)-1-nitrobenzene) To a solution of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (1.0 equiv.) in THF (3 mL) was added methan-d3-ol (3.5 equiv.), followed by NaOH (1.2 equiv.). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (30 mL x 2), and the combined organic phases were washed with brine (30 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo to give the title compound as a pale orange-yellow solid (312 mg, 98%). UPLC (Method A): m / z 263.2 [M+H] at 1.97 min + . 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=9.1Hz,1H),7.52-7.44(m,2H),7.44-7.40(m,2H) ,7.40-7.32(m,1H),6.91(d,J=2.5Hz,1H),6.75(dd,J=9.1,2.5Hz,1H),5.25(s,2H).

[0174] Preparation of Compound 9 (4-amino-3-(methoxy-d3)phenol) General procedure F was used to give the title compound as a dark brown solid (165 mg, 88%). UPLC (Method B): No m / z observed at 0.70 min [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.44(s,1H), 6.43(d,J=8.3Hz,1H), 6.28(d,J=2.6Hz,1H), 6.11(dd,J=8.3,2.6Hz,1H),4.03(s,2H).

[0175] Preparation of Compound 10 (4-(cyclopentyloxy)-2-methoxy-1-nitrobenzene) To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (1.0 equiv.) and CsCO (3.0 equiv.) in MeCN (0.3 M) was added cyclopentanol (2.5 equiv.). The reaction mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (40 mL) and water (40 mL). The aqueous phase was extracted with EtOAc (20 mL × 3), and the combined organic phase was washed with brine (30 mL), dried over MgSO, filtered, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0–20% (25% EtOH in EtOAc) / isohexane to give the title compound as a yellow oil (305 mg, 73%). UPLC (Method A): m / z 238.0 [M+H] at 2.00 min + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=9.1Hz,1H),6.72(d,J=2.5Hz,1H),6.64(dd,J=9.1,2.4Hz, 1H), 5.03-4.97 (m, 1H), 3.91 (s, 3H), 2.03-1.91 (m, 2H), 1.79-1.65 (m, 4H), 1.67-1.54 (m, 2H).

[0176] Preparation of Compound 11 (4-(cyclopentyloxy)-2-methoxyaniline) Purification by silica gel chromatography using general procedure F and eluting with 0-5% (0.7M NH3 / MeOH) / DCM afforded the title compound as a brown oil (229 mg, 86%). UPLC (Method A): m / z208.2[M+H] in 0.83 min + . 1H NMR(400MHz,DMSO-d6)δ6.51(d,J=8.4Hz,1H),6.39(d,J=2.6Hz,1H),6.25(dd,J=2.6,8.4Hz,1H),4.64(t t,J=2.5,5.8Hz,1H),4.20(s,2H),3.72(s,3H),1.89-1.75(m,2H),1.72-1.61(m,4H),1.61-1.47(m,2H).

[0177] Preparation of Compound 12 (4-(2-isopropoxyethoxy)-2-methoxy-1-nitrobenzene) To a suspension of 4-fluoro-2-methoxy-1-nitrobenzene (1.0 equiv.) and 2-isopropoxyethan-1-ol (1.5 equiv.) in MeCN (0.4 M) was added 2.0 M NaOt-Bu in THF (1.1 equiv.) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was partitioned between EtOAc (40 mL) and water (40 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (30 mL × 2), and the combined organic phases were washed with brine (30 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was dry-loaded onto silica and purified by silica gel chromatography eluting with 0–100% (25% EtOAc in isohexane) / isohexane to give the title compound as a pale orange-yellow oil (578 mg, 70%). LCMS (Method E): m / z 256.2 [M+H] at 1.72 min + . 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J=9.1Hz,1H),6.81(d,J=2.5Hz,1H),6.67(dd,J=9.2,2.5Hz,1H ),4.24-4.18(m,2H),3.92(s,3H),3.75-3.68(m,2H),3.68-3.56(m,1H),1.11(d,J=1.2Hz,6H).

[0178] Preparation of Compound 13 (4-(2-isopropoxyethoxy)-2-methoxyaniline) General procedure F was used to give the title compound as a dark red / brown oil (358 mg, 97%). LCMS (Method E): m / z 226.2 [M+H] at 0.41 min + . 1 H NMR(400MHz,DMSO-d6)δ6.53(d,J=8.4Hz,1H),6.46(d,J=2.6Hz,1H),6.28(dd,J=8.4,2.6Hz,1H),4.2 3(s,2H),3.95-3.89(m,2H),3.73(s,3H),3.64-3.61(m,2H),3.61-3.57(m,1H),1.10(d,J=6.2Hz,6H).

[0179] Preparation of Compound 14 (4-Methoxy-2-(2-methoxyethoxy)-5-nitropyridine) To a solution of 2-chloro-4-methoxy-5-nitropyridine (100 mg, 530 μmol) and CsCO (200 mg, 614 μmol) in MeCN (2 mL) was added 2-methoxyethanol (50 μL, 0.63 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by silica gel chromatography (0-100% MTBE / isohexane) to give 4-methoxy-2-(2-methoxyethoxy)-5-nitropyridine (31 mg, 0.13 mmol, 24%) as an orange-yellow solid. UPLC (Method A): m / z 229.1 [M+H] at 1.36 min + . 1 H NMR (400 MHz, chloroform-d) δ 8.76 (s, 1H), 6.39 (s, 1H), 4.59-4.52 (m, 2H), 3.96 (s, 3H), 3.77-3.70 (m, 2H), 3.44 (s, 3H).

[0180] Preparation of Compound 15 (4-Methoxy-6-(2-methoxyethoxy)pyridin-3-amine) General procedure F was used to give the title compound as a dark orange-yellow oil (24 mg, 0.12 mmol, 87%). UPLC (Method B): m / z 199.2 [M+H] at 0.65 min + . 1H NMR (400 MHz, chloroform-d) δ 7.53 (s, 1H), 6.30 (s, 1H), 4.46-4.39 (m, 2H), 3.87 (s, 3H), 3.76-3.68 (m, 2H), 3.43 (s, 3H).

[0181] Preparation of Compound 16 (2-Methoxy-6-(2-methoxyethoxy)-3-nitropyridine) To a solution of 6-chloro-2-methoxy-3-nitropyridine (100 mg, 530 μmol) and CsCO (200 mg, 614 μmol) in MeCN (2.0 mL) was added 2-methoxyethanol (50 μL, 0.63 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by silica gel chromatography (0-50% MTBE / isohexane) to give 2-methoxy-6-(2-methoxyethoxy)-3-nitropyridine (65 mg, 0.27 mmol, 51%) as an off-white solid. UPLC (Method A): No m / z observed at 1.48 min [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.35(d,J=8.8Hz,1H),6.44(d,J=8.8Hz,1H),4.59-4.52(m,2H),4.10(s,3H),3.79-3.73(m,2H),3.45(s,3H).

[0182] Preparation of Compound 17 (2-Methoxy-6-(2-methoxyethoxy)pyridin-3-amine) General procedure F was used to give the title compound as a dark red oil (55 mg, 0.26 mmol, 95%). UPLC (Method B): m / z 199.2 [M+H] at 0.83 min + . 1 H NMR (400 MHz, chloroform-d) δ 7.05 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 8.1 Hz, 1H), 4.46-4.34 (m, 2H), 3.95 (s, 3H), 3.77-3.69 (m, 2H), 3.43 (s, 3H).

[0183] Preparation of Compound 18 (4-Methoxy-2-(2-methoxyethoxy)-5-nitropyrimidine) To a solution of 2-chloro-4-methoxy-5-nitropyrimidine (1.0 equiv.) and 2-methoxyethanol (1.1 equiv.) in anhydrous THF (2 mL) was added NaOt-Bu (1.2 equiv.) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between saturated NH4Cl (20 mL) and dichloromethane (20 mL). The phases were separated, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phases were passed through a phase separator, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0–50% MTBE / isohexane to give the title compound as a pale yellow gum (112 mg, 71%). UPLC (Method A): m / z 200.1 [M-OMe+H] at 0.79 min + . 1 H NMR (400 MHz, chloroform-d) δ 9.08 (s, 1H), 4.66-4.59 (m, 2H), 4.17 (s, 3H), 3.85-3.74 (m, 2H), 3.43 (s, 3H).

[0184] Preparation of Compound 19 (2-Methoxy-6-(2-methoxyethoxy)pyrimidin-3-amine) General procedure F was used to give the title compound as a light brown solid (149 mg, 91%). UPLC (Method B): m / z 200.1 [M+H] at 0.79 min + . 1 H NMR (400MHz, DMSO-d6) δ7.63(s,1H),4.51(s,2H),4.28-4.21(m,2H),3.89(s,3H),3.64-3.57(m,2H),3.28(s,3H).

[0185] Preparation of Compound 20 (2-Methoxy-3-nitro-6-(2-(trifluoromethoxy)ethoxy)pyridine) To a solution of 2-(trifluoromethoxy)ethan-1-ol (72.0 mg, 554 μmol) in THF (2 mL) was added NaOtBu (61.0 mg, 635 μmol) and 6-chloro-2-methoxy-3-nitropyridine (100 mg, 530 μmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between saturated NH4Cl (20 mL) and DCM (20 mL). The phases were separated, and the aqueous phase was extracted with DCM (10 mL x 2). The combined organic phase was filtered through a phase separator, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (0–100% DCM / isohexane) to give 2-methoxy-3-nitro-6-(2-(trifluoromethoxy)ethoxy)pyridine (112 mg, 0.38 mmol, 71%) as a pale yellow gum. UPLC (Method A): No m / z observed at 1.91 min [M+H] + . 1 H NMR (400MHz, chloroform-d) δ8.38(d,J=8.8Hz,1H),6.45(d,J=8.8Hz,1H),4.68-4.61(m,2H),4.35-4.28(m,2H),4.11(s,3H).

[0186] Preparation of Compound 21 (2-Methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-amine) General procedure F was used to give the title compound as a dark brown gum (97 mg, 0.37 mmol, 95%). UPLC (Method A): m / z 253.1 [M+H] at 1.26 min + . 1 H NMR (400MHz, DMSO-d6) δ6.96(d,J=8.0Hz,1H),6.20(d,J=8.0Hz,1H),4.45-4.32(m,6H),3.85(s,3H).

[0187] Preparation of Compound 22 (2-Methoxy-3-nitro-6-(2-(trifluoromethoxy)ethoxy)pyrimidine) To a solution of 2-chloro-4-methoxy-5-nitropyrimidine (1.0 equiv.) and 2-(trifluoromethoxy)ethan-1-ol (1.1 equiv.) in anhydrous THF (0.3 M) was added NaOt-Bu (1.2 equiv.) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was partitioned between saturated NH4Cl (20 mL) and dichloromethane (20 mL). The phases were separated, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phases were passed through a phase separator, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0–50% MTBE / isohexane to give the title compound as a pale yellow gum (112 mg, 71%). UPLC (Method A): No m / z observed at 1.36 min [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 4.72-4.66 (m, 2H), 4.51-4.44 (m, 2H), 4.10 (s, 3H).

[0188] Preparation of Compound 23 (2-Methoxy-6-(2-(trifluoromethoxy)ethoxy)pyrimidin-3-amine) General procedure F was used to give the title compound as a dark brown oil (165 mg, 91%). UPLC (Method B): m / z254.2[M+H] in 1.05 min + . 1 H NMR (400MHz, DMSO-d6) δ7.64 (s, 1H), 4.60-4.55 (m, 2H), 4.46-4.32 (m, 4H), 3.91 (s, 3H).

[0189] Preparation of Compound 24 (4-(3-methoxy-4-nitrophenyl)-1H-pyrazole) A vial was charged with PdOAc (8 mg, 37 μmol), tricyclohexylphosphonium tetrafluoroborate (26 mg, 69.8 μmol), 4-bromo-2-methoxy-1-nitrobenzene (200 mg, 863.3 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (281 mg, 955 μmol), and KCO (476.7 mg, 3.449 mmol). The mixture was degassed with N for 5 minutes. 1,4-Dioxane (4.0 mL) and water (0.20 mL) were added, and the suspension was again degassed with N for 5 minutes. The reaction mixture was heated to 90 °C for 20 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0-100% EtOAc / heptane) to give 4-(3-methoxy-4-nitrophenyl)-1H-pyrazole as a yellow solid (107 mg, 0.47 mmol, 54%). UPLC (Method A): m / z 220.1 [M+H] at 1.32 min + . 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),8.30(s,2H),7.90(d,J=8.5Hz,1H),7.52(d,J=1.7Hz,1H),7.36(dd,J=8.5,1.7Hz,1H),3.99(s,3H).

[0190] Preparation of Compound 25 (2-Methoxy-4-(1H-pyrazol-4-yl)aniline) General procedure F was used to give the title compound as an off-white solid (88 mg, 393 μmol, 86%). UPLC (Method B): m / z 190.2 [M+H] at 0.70 min + . 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),7.96(s,1H),7.76(s,1H),7.01(d,J=1.8Hz, 1H),6.91(dd,J=7.9,1.8Hz,1H),6.60(d,J=7.9Hz,1H),4.62(s,2H),3.81(s,3H).

[0191] Preparation of Compound 26 (2-Methoxy-3-nitro-6-(1H-pyrazol-4-yl)pyridine) A reactor was charged with 6-chloro-2-methoxy-3-nitropyridine (1.0 equiv.), Pd(dppf)Cl (5 mol%), and KPO (3.8 equiv.). The mixture was degassed and purged with nitrogen, then a 3:1 mixture of 1,4-dioxane / water was added. The reaction mixture was degassed and purged with nitrogen three times, then heated to 90° C. and stirred under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, and then water (20 mL) was added. The resulting precipitate was collected by vacuum filtration to give the title compound as a brown / gray solid (193 mg, 78%). LCMS (Method E): m / z 221.0 [M+H] at 1.30 min + . 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.54(s,1H),8.44(d,J=8.3Hz,1H),8.20(s,1H),7.49(d,J=8.3Hz,1H),4.10(s,3H).

[0192] Preparation of Compound 27 (2-Methoxy-6-(1H-pyrazol-4-yl)pyridin-3-amine) General procedure F was used to give the title compound as a brown solid (134 mg, 91%). LCMS (Method E): m / z 191.2 [M+H] at 0.35 min + . 1H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.01(s,1H),7.84(s,1H),7.00(d,J=7.7Hz,1H),6.86(d,J=7.7Hz,1H),4.80(s,2H),3.91(s,3H).

[0193] Preparation of Compound 28 (4-(2-(difluoromethoxy)ethoxy)-2-methoxy-1-nitrobenzene) To a stirred solution of 2-(3-methoxy-4-nitrophenoxy)ethan-1-ol (884 mg, 4.06 mmol) in DCM (3 mL) and water (3 mL) in a sealed tube at 0 °C, KHF (3.17 g, 40.6 mmol) was added and the mixture was stirred for 10 min. (Bromodifluoromethyl)trimethylsilane (3.8 mL, 24 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred for 3 days. Saturated aqueous NaHCO (20 mL) was added, and the mixture was extracted with DCM (3 × 40 mL). The combined organic phase was washed with brine (20 mL), filtered through a phase separator, and the solvent was removed in vacuo to give 4-(2-(difluoromethoxy)ethoxy)-2-methoxy-1-nitrobenzene as a light brown powder (1.05 g, 3.6 mmol, 88%). UPLC (Method A): m / z 264.1 [M+H] at 1.74 min + . 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=9.1Hz,1H),6.84(d,J=2.5Hz,1H),6.76(t,J=75.6H z,1H),6.69(dd,J=9.1,2.5Hz,1H),4.37-4.31(m,2H),4.23-4.16(m,2H),3.93(s,3H).

[0194] Preparation of Compound 29 (4-(2-(difluoromethoxy)ethoxy)-2-methoxyaniline) General procedure F was used to give the title compound as a dark black / red oil (893 mg, 3.83 mmol, 100%). UPLC (Method B): m / z 234.2 [M+H] at 1.06 min + . 1 H NMR(400MHz,DMSO-d6)δ6.94-6.51(m,2H),6.48(d,J=2.6Hz,1H),6.31(dd,J=8 .4,2.6Hz,1H),4.36(s,2H),4.12-4.07(m,2H),4.07-4.01(m,2H),3.74(s,3H).

[0195] Preparation of Compound 30 (2-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene) To a solution of 3-fluoro-4-nitrophenol (2.00 g, 12.73 mmol) in DMF (20 mL) were added 1-bromo-2-methoxyethane (5.98 mL, 63.65 mmol) and K2CO3 (3.52 mg, 25.46 mmol). The mixture was stirred at 70 °C for 4 h. The solvent was evaporated, and the product was extracted with EtOAc and washed with water (three times) and brine (twice). The organic phase was dried over MgSO4, filtered, and evaporated. The crude product was purified by flash column chromatography to give 2-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene as a white powder (1.95 g, 71%). 1 H NMR (400 MHz, chloroform-d) δ 8.14-8.05 (m, 1H), 6.84-6.73 (m, 2H), 4.23-4.16 (m, 2H), 3.81-3.74 (m, 2H), 3.45 (s, 3H).

[0196] Preparation of Compound 31 (4-(5-(2-methoxyethoxy)-2-nitrophenyl)morpholine) A solution of morpholine (240 μL, 2.79 mmol) in ethanol (2 mL) was slowly added to a solution of compound 18 (200 mg, 0.92 mmol) at 0° C. The reaction was stirred at 50° C. for 30 minutes. After cooling to room temperature, NaHCO3 solution was added. The product was extracted with DCM. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(5-(2-methoxyethoxy)-2-nitrophenyl)morpholine as a yellow solid (278 mg, 100%). 1H NMR (400MHz, chloroform-d) δ7.98(d,J=9.1Hz,1H),6.64(d,J=2.6Hz,1H),6.57(dd,J=9.1,2.6Hz,1H),4.25-4.13(m,2 H),3.87(ddd,J=6.3Hz,4.6Hz,2.9Hz,4H),3.79-3.73(m,2H),3.46(s,3H),3.06(ddd,J=6.3Hz,4.6Hz,2.9Hz,4H).

[0197] Preparation of Compound 32 (4-(2-Methoxyethoxy)-2-morpholinoaniline) General procedure F was used to give the title compound as a purple oil (176 mg, 98%). 1 H NMR (400MHz, chloroform-d) δ6.68(d,J=2.7Hz,1H),6.66(d,J=8.5Hz,1H),6.55(dd,J=8.5,2.7Hz,1H),4.10-4.02( m,2H),3.83(ddd,J=6.3,4.6,2.9Hz,4H),3.75-3.69(m,2H),3.45(s,3H),2.90(ddd,J=6.3,4.6Hz,2.9Hz,4H).

[0198] Preparation of Compound 33 (7-Bromo-N-(2,4-dimethoxyphenyl)quinolin-4-amine hydrochloride) To a solution of 7-bromo-4-chloroquinoline (100 mg, 412 μmol) in EtOH (2.0 mL) was added 2,4-dimethoxyaniline (70.0 mg, 457 μmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. The reaction mixture was diluted with acetone (10 mL), and the precipitate was collected by filtration and washed with acetone (10 mL × 3). The product was dried in a vacuum desiccator overnight to give 7-bromo-N-(2,4-dimethoxyphenyl)quinolin-4-amine hydrochloride as a dark yellow solid (135 mg, 0.34 mmol, 82%). UPLC (Method A): m / z 359.2 / 361.2 [M+H] at 0.84 min + . 1H NMR(400MHz,DMSO-d6)δ14.23(br s,1H),10.65(s,1H),8.65(d,J=9.1Hz,1H),8.44(d,J=7.0Hz,1H),8.22(d,J=2.0Hz,1H),7.97(dd,J=9.0,2.0Hz,1H),7. 31(d,J=8.7Hz,1H),6.83(d,J=2.6Hz,1H),6.70(dd,J=8.6,2.6Hz,1H),6.31(d,J=7.0Hz,1H),3.85(s,3H),3.78(s,3H).

[0199] Preparation of Compound 34 (7-bromo-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine) A mixture of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol hydrochloride (1.87 g, 4.65 mmol), 2-methoxyethyl 4-methylbenzenesulfonate (1.02 mL, 5.35 mmol), and cesium carbonate (3.18 g, 9.77 mmol) in acetone (30.0 mL) was stirred at 60° C. for 18 hours. The solvent was removed in vacuo, the residue was triturated from water (50 mL), and the solid was collected by filtration. The solid was then triturated from isohexane (30 mL), then again collected by filtration and dried in a vacuum oven (40° C.) to give 7-bromo-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine (2.00 g, 100%) as a brown solid. UPLC (Method A): m / z 403.1 / 405.1 [M+H] at 1.18 min + . 1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.37(d,J=9.0Hz,1H),8.30(d,J=5.4Hz,1H),8.00(d,J=2.1Hz,1H),7.61(dd,J=9.0,2.1Hz,1H),7.18(d,J=8. 5Hz,1H),6.75(d,J=2.6Hz,1H),6.61(dd,J=8.6,2.7Hz,1H),6.10(d,J=5. 4Hz, 1H), 4.18-4.12 (m, 2H), 3.73 (s, 3H), 3.71-3.66 (m, 2H), 3.33 (s, 3H).

[0200] Preparation of Compound 35 (7-bromo-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine hydrochloride) To a stirred solution of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol hydrochloride (750 mg, 1.97 mmol) in acetone (10.0 mL) at room temperature were added CsCO (1.50 g, 4.60 mmol) and 1-bromo-2-(trifluoromethoxy)ethane (465 mg, 2.41 mmol). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resulting precipitate was collected by filtration and washed with water (3 × 20 mL) and then isohexane (2 × 20 mL). The product was dried in a vacuum desiccator overnight to give 7-bromo-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine as a pale yellow solid (725 mg, 77%). UPLC (Method A): m / z457.1 / 459.1[M+H] in 1.41 min + . 1H NMR(400MHz,DMSO-d6)δ14.72(s,1H),10.80(s,1H),8.73(d,J=9.1Hz,1H),8.44(d,J=7.0Hz,1H),8.32(d,J=1.9Hz,1H),7.96(dd,J=9.1,1.9Hz,1H) ,7.32(d,J=8.6Hz,1H),6.87(d,J=2.5Hz,1H),6.73(dd,J=8.6,2.6Hz,1H) ,6.30(d,J=7.0Hz,1H),4.50-4.41(m,2H),4.41-4.30(m,2H),3.79(s,3H).

[0201] Preparation of Compound 36 (4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol hydrochloride) A solution of 7-bromo-4-chloroquinoline (1.47 g, 6.04 mmol), 4-amino-3-methoxyphenol (801 mg, 5.76 mmol), and HCl (4 M in dioxane) (2.16 mL, 8.63 mmol) in propan-2-ol (15.0 mL) was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, the solvent evaporated, and the residue triturated from acetone (30 mL), cooled to 0° C., and the precipitate collected by filtration to give 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol hydrochloride as a green solid (1.87 g, 4.7 mmol, 81%). UPLC (Method A): m / z 345.0 / 347.0 [M+H] at 1.05 min + . 1 H NMR(400MHz,DMSO-d6)δ14.44(s,1H),10.66(s,1H),9.99(s,1H),8.67(d,J=9.1Hz,1H),8.43(d,J=7.0Hz,1H),8.27(d,J=2.0Hz,1H),7. 96(dd,J=9.1,2.0Hz,1H),7.16(d,J=8.5Hz,1H),6.66(d,J=2.5Hz,1H),6.53(dd,J=8.5,2.4Hz,1H),6.31(d,J=7.0Hz,1H),3.72(s,3H).

[0202] Preparation of Compound 37 (4-((7-methylquinolin-4-yl)amino)-3-methoxyphenol hydrochloride) Purification by silica gel chromatography eluting with 0-100% (10% 0.7M NH3 in DCM) / DCM using general procedure A-2 afforded the title compound as a pink / brown solid (30 mg, 64%). UPLC (Method A): m / z 284.2 [M+H] at 0.98 min + . 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.31–8.17 (m, 3H), 7.59 (s, 1H), 7.28 (dd, J = 8.6, 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 6.43 (dd, J = 8.4, 2.5 Hz, 1H), 6.01 (d, J = 5.3 Hz, 1H), 3.67 (s, 3H), 2.47 (s, 3H). No HCl peak was observed.

[0203] Preparation of Compound 38 (3-(methoxy-d3)-4-((7-methylquinolin-4-yl)amino)phenol hydrochloride) Purification by silica gel chromatography using general procedure B, eluting with 0-100% (10% 0.7M NH3 in DCM) / DCM, afforded the title compound as a pink / brown solid (30 mg, 64%). UPLC (Method A): m / z 284.2 [M+H] at 0.98 min + . No NMR data available.

[0204] Preparation of Compound 39 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxyphenol hydrochloride) General procedure B was used to give the title compound as a dark yellow solid (26 mg, 69%). UPLC (Method A): m / z 317.1 [M+H] at 1.64 min + . 1H NMR(400MHz,DMSO-d6)δ14.48(s,1H),10.69(s,1H),9.98(s,1H),8.86(d,J=8.8Hz,1H),8.50(d,J=7.0Hz,1H),8.21(s,1H),7.96-7.89(m, 1H),7.35(t,J=55.2Hz,1H),7.17(d,J=8.5Hz,1H),6.67(d,J=2.5Hz,1H),6.54(dd,J=8.4,2.5Hz,1H),6.37(d,J=7.1Hz,1H),3.73(s,3H).

[0205] Preparation of Compound 40 (3-cyclopropoxy-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol hydrochloride) Purification by silica gel chromatography using general procedure B, eluting with 0-10% (0.7M NH3 / MeOH) / DCM, afforded the title compound as a dark brown solid (21 mg, 47%). UPLC (Method A): m / z 343.2 [M+H] at 1.13 min + . No NMR data available.

[0206] Preparation of Compound 41 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-(methoxy-d3)phenol hydrochloride) Purification by silica gel chromatography using general procedure B, eluting with 0-10% (0.7M NH3 / MeOH) / DCM, afforded the title compound as a pale green solid (28 mg, 66%). UPLC (Method A): m / z 320.2 [M+H] at 0.95 min + . No NMR data available.

[0207] Preparation of Compound 42 (3-cyclopropoxy-4-((7-methylquinolin-4-yl)amino)phenol hydrochloride) Purification by silica gel chromatography using general procedure B, eluting with 0-10% (0.7M NH3 / MeOH) / DCM, afforded the title compound as a dark brown solid (17 mg, 35%). UPLC (Method A): m / z 307.2 [M+H] at 0.97 min + . No NMR data available.

[0208] Preparation of Compound 43 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-fluorophenol hydrochloride) General procedure B was used to give the title compound as a dark yellow solid (81 mg, 94%). UPLC (Method A): m / z 317.1 [M+H] at 1.64 min + . 1 H NMR(400MHz,DMSO)δ14.70(br s,1H),10.78(s,1H),10.42(s,1H),8.87(d,J=8.8Hz,1H),8.60(d,J=6.9Hz,1H),8.27-8.22(m,1H),8.00-7.93(m,1H),7.36(t ,J=55.1Hz,1H),7.36(t,J=8.9Hz,1H),6.88(dd,J=12.1,2.5Hz,1H),6.82(dd,J=8.6,2.6Hz,1H),6.53(dd,J=6.9,2.0Hz,1H).

[0209] Preparation of Compound 44 (3-chloro-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol hydrochloride) General procedure B was used to give the title compound as a yellow solid (80 mg, 89%). UPLC (Method A): m / z 321.3 [M+H] at 1.04 min + . 1H NMR(400MHz,DMSO)δ14.91-14.55(m,1H),10.97(s,1H),10.46(s,1H),8.88(d,J=8.8Hz,1H),8.59(d,J=6.9Hz,1H),8.25(d,J=1.6Hz,1H),7.98 (dd,J=8.8,1.7Hz,1H),7.41(d,J=8.6Hz,1H),7.37(t,J=55.1Hz,1H),7.13(d,J=2.6Hz,1H),6.97(dd,J=8.6,2.7Hz,1H),6.38(d,J=6.9Hz,1H).

[0210] Preparation of Compound 45 (3-Bromo-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol hydrochloride) General procedure B was used to give the title compound as a light brown solid (87 mg, 88%). UPLC (Method A): m / z 365.3 / 367.3 [M+H] at 1.04 min + . 1 H NMR(400MHz,DMSO)δ14.91-14.55(m,1H),10.97(s,1H),10.46(s,1H),8.88(d,J=8.8Hz,1H),8.59(d,J=6.9Hz,1H),8.25(d,J=1.6Hz,1H),7.98 (dd,J=8.8,1.7Hz,1H),7.41(d,J=8.6Hz,1H),7.37(t,J=55.1Hz,1H),7.13(d,J=2.6Hz,1H),6.97(dd,J=8.6,2.7Hz,1H),6.38(d,J=6.9Hz,1H).

[0211] Preparation of Compound 46 (3-chloro-4-((7-methylquinolin-4-yl)amino)phenol hydrochloride) General procedure B was used to give the title compound as a dark beige solid (18 mg, 57%). UPLC (Method A): m / z285.0 / 287.0[M+H] in 1.04 min + . 1H NMR(400MHz,DMSO)δ14.14(s,1H),10.66(s,1H),10.39(s,1H),8.59(d,J=8.7Hz,1H),8.48-8.42(m,1H),7.80-7.75(m,1H),7.6 7(dd,J=8.7,1.6Hz,1H),7.43-7.36(m,1H),7.11(d,J=2.6Hz,1H),6.95(dd,J=8.6,2.7Hz,1H),6.29-6.22(m,1H),2.58(s,3H).

[0212] Preparation of Compound 47 (3-Bromo-4-((7-methylquinolin-4-yl)amino)phenol hydrochloride) General procedure B was used to give the title compound as a light brown solid (60 mg, 69%). UPLC (Method A): m / z 329 / 331 [M+H] at 1.09 min + . 1 H NMR(400MHz,DMSO-d6)δ14.31(s,1H),10.71(s,1H),10.42(s,1H),8.61(d,J=8.7Hz,1H),8.44(d,J=6.9Hz,1H),7.81(s,1H),7.67( dd,J=1.7,8.7Hz,1H),7.38(d,J=8.6Hz,1H),7.28(d,J=2.6Hz,1H),7.00(dd,J=2.7,8.6Hz,1H),6.22(d,J=6.9Hz,1H),2.58(s,3H).

[0213] Preparation of Compound 48 (3-fluoro-4-((7-methylquinolin-4-yl)amino)phenol hydrochloride) General procedure B was used to give the title compound as a light brown solid (75 mg, 83%). UPLC (Method A): m / z 269.2 [M+H] at 0.95 min + . 11H NMR (400 MHz, DMSO) δ 14.33 (br s, 1H), 10.56 (br s, 1H), 10.40 (s, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 7.0 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.66 (dd, J = 8.7, 1.6 Hz, 1H), 7.34 (t, J = 9.0 Hz, 1H), 6.87 (dd, J = 12.1, 2.6 Hz, 1H), 6.83 - 6.79 (m, 1H), 6.40 (dd, J = 7.0, 1.9 Hz, 1H), 2.58 (s, 3H).

[0214] Preparation of Examples

Chemical Structure

Table 2

Chemical Structure

Table 3

Chem.

Table 4

Chem.

Table 5

Chem.

Table 6

[0215] Pharmacological Part Example 143: Evaluation of pharmacological activity against growth inhibition, senescence induction, and NIK degradation

[0216] Proliferation and senescence A375 (American Type Culture Collection; CRL-1619) cells were seeded into 96-well plates (1,200 cells / well; Perkin Elmer; 6005225) and incubated overnight at 37°C and 5% CO2. Compounds prepared in culture medium (Dulbecco's modified Eagle's medium + 10% fetal bovine serum + 1% penicillin / streptomycin) were added to the cells and incubated for 4 days at 37°C and 5% CO2. The culture medium was then aspirated from the cells, and freshly prepared compounds were added to the cells, which were then incubated for an additional 3 days at 37°C and 5% CO2. After a total of 7 days of incubation in the presence of compounds, the medium was removed and cells were labeled with Hoechst (1 / 1,000; Thermo Fisher Scientific; 62249), TOTO™-3 (1 / 10,000; Thermo Fisher Scientific; T3604), and SPiDER βGAL (1.0 μM; Sigma-Aldrich Scientific; 94433) prepared in Hank's balanced salt solution supplemented with 1.0 mM HEPES buffer for 20 minutes at 37°C. Cells were imaged at 10x magnification by confocal microscopy using ImageXpress (Molecular Devices). Images were analyzed using MetaXpress software (Molecular Devices).

[0217] NIK degradation Western blot experiment A375 cells were plated in a 6-well dish at 2,000 cells / cm. 2 The cells were seeded at 100°C. The next day, cells were treated with 10 μM of the example compound for 72 hours. For the final 4 hours of the treatment period, cells were treated with 5 μM of MG132 to inhibit proteasomal degradation. For protein isolation, cells were washed twice with PBS and lysed using RIPA buffer (1x) containing protease and phosphatase inhibitors. After sonication, the lysate was centrifuged at 4°C and 20,000 g for 10 minutes, and the supernatant was collected and assayed for protein concentration using a BCA kit (Pierce).

[0218] Total protein (20 μg) was separated by 10% SDS-polyacrylamide gel electrophoresis and transferred to a PVDF membrane (Millipore). Blocking was performed with 3% BSA in Tris-buffered saline. The membrane was incubated overnight at 4°C with the appropriate primary antibody (NIK, CST#4994, 1 / 2000) and β-actin (Santa-Cruz, sc-47778, 1 / 5000). After three washes, the membrane was incubated with a horseradish peroxidase-conjugated secondary antibody for 1 hour. Bound antibodies were detected using the Enhanced Chemiluminescence Plus kit (GE Healthcare).

[0219] The compounds of Examples 3, 4, 5, 6, 10 and 11 were tested and confirmed for NIK degradation (see the corresponding table below). For illustrative purposes, a Western blot analysis of NIK degradation in cells treated with the compound of Example 3 (10 μM for 72 hours) is shown in Figure 1. [Table 9] [Table 10] [Table 11]

Claims

1. A compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, Ring A is selected from the groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7): 【Chemistry 2】 is an aromatic group selected from Group (A-1) is a group R Ａ１ and group R Ａ２ and is substituted with one or more groups R Ａ３ phenyl or 6-membered monocyclic heteroaryl optionally further substituted with Groups (A-2) and (A-3) each have a group R Ａ１ and group R Ａ２ and is substituted with one or more groups R Ａ３ is a 5-membered monocyclic heteroaryl optionally further substituted with Group (A-4) is a group R Ａ２ and is substituted with one or more groups R Ａ３ an 8-membered bicyclic heteroaryl optionally further substituted with Groups (A-5) and (A-6) each have a group R Ａ２ and is substituted with one or more groups R Ａ３ is a 9-membered bicyclic heteroaryl optionally further substituted with Group (A-7) is a group R Ａ２ and is substituted with one or more groups R Ａ３ naphthyl or 10-membered bicyclic heteroaryl optionally further substituted with R Ａ１ Ha-O(C １～５ alkyl), —O(C ２～５ alkenyl), C １～５ Alkyl, C ２～５ Alkenyl, —N(C １～５ alkyl) (C １～５ alkyl), halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), -CN, -(C ０～３ alkylene)-cycloalkyl and -(C ０～３ alkylene)-heterocycloalkyl, wherein said -(C ０～３ and the cycloalkyl group in the -(C alkylene)-cycloalkyl. ０～３ Each heterocycloalkyl group in the (alkylene)-heterocycloalkyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～３ alkylene)-cycloalkyl or the above-(C ０～３ alkylene)-heterocycloalkyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, and optionally substituted with groups independently selected from R Ａ２ is C １～１２ Alkyl, -(C １～１２ alkylene)-OH, -(C ０～５ alkylene)-O(C １～１２ alkyl), -(C ０～５ alkylene)-O(C １～１２ haloalkyl), -(C ０～５ alkylene)-O-(C １～１２ alkylene)-OH, -(C ０～５ alkylene)-O-(C １～５ alkylene)-O(C １～１２ alkyl), -(C ０～５ alkylene)-O-(C １～５ alkylene)-O(C １～１２ haloalkyl), —CO(C １～１２ alkyl), -CO(C １～１２ haloalkyl), —SO ２ -(C １～１２ alkyl), -SO ２ -(C １～１２ haloalkyl), halogen, C １～５ Haloalkyl, -(C ０～５ alkylene)-carbocyclyl and -(C ０～５ alkylene)-heterocyclyl, wherein said C １～１２ alkyl, the -(C １～１２ alkylene)-OH, the -(C ０～５ alkylene)-O(C １～１２ alkyl), the -(C ０～５ alkylene)-O(C １～１２ haloalkyl), the -(C ０～５ alkylene)-O-(C １～１２ alkylene)-OH, the -(C ０～５ alkylene)-O-(C １～５ alkylene)-O(C １～１２ alkyl), the -(C ０～５ alkylene)-O-(C １～５ alkylene)-O(C １～１２ haloalkyl), the —CO(C １～１２ alkyl), the —CO(C １～１２ haloalkyl), the —SO ２ -(C １～１２ alkyl) or the —SO ２ -(C １～１２ haloalkyl) ２ - units are -O-, -NH-, and -N(C １～５ and optionally substituted with a group independently selected from -(C alkyl)-, -CO-, and -CH=CH-, ０～５ alkylene)-carbocyclyl and the carbocyclyl group in the -(C ０～５ Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～５ alkylene)-carbocyclyl or the above-(C ０～５ alkylene)-heterocyclyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, and optionally substituted with groups independently selected from Each R Ａ３ If present, C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-OH, -(C ０～３ alkylene)-N(C １～５ alkyl)-OH, -(C ０～３ alkylene)-NH-O(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-O(C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-carbocyclyl, -(C ０～３ alkylene)-heterocyclyl and -R ６ -R ７ wherein said -(C ０～３ alkylene)-carbocyclyl and the carbocyclyl group in the -(C ０～３ Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～３ alkylene)-carbocyclyl or the above-(C ０～３ alkylene)-heterocyclyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, and optionally substituted with groups independently selected from R Ｎ is hydrogen, C １～５ Alkyl and —CO—(C １～５ alkyl), R １ , R ４ and R ５ are hydrogen and C, respectively. １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-OH, -(C ０～３ alkylene)-N(C １～５ alkyl)-OH, -(C ０～３ alkylene)-NH-O(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-O(C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-carbocyclyl, -(C ０～３ alkylene)-heterocyclyl and -R ６ -R ７ wherein said -(C ０～３ alkylene)-carbocyclyl and the carbocyclyl group in the -(C ０～３ Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～３ alkylene)-carbocyclyl or the above-(C ０～３ alkylene)-heterocyclyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, and optionally substituted with groups independently selected from R ２ is hydrogen, C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-OH, -(C ０～３ alkylene)-N(C １～５ alkyl)-OH, -(C ０～３ alkylene)-NH-O(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-O(C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ alkylene)-carbocyclyl and -(C ０～３ alkylene)-heterocyclyl, wherein said -(C ０～３ alkylene)-carbocyclyl and the carbocyclyl group in the -(C ０～３ Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～３ alkylene)-carbocyclyl or the above-(C ０～３ alkylene)-heterocyclyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ optionally substituted with groups independently selected from —alkyl)-, —CO—, —S—, and —SO—; R ３ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-OH, -(C ０～３ alkylene)-N(C １～５ alkyl)-OH, -(C ０～３ alkylene)-NH-O(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-O(C １～５ alkyl), -(C ０～３ (alkylene)-CHF ２ , -(C ０～３ alkylene)-CH ２ F, -(C ０～３ alkylene)-(C ２～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -(C １～５ alkyl), -(C ０～３ alkylene)-carbocyclyl and -(C ０～３ alkylene)-heterocyclyl, wherein said -(C ０～３ alkylene)-carbocyclyl and the carbocyclyl group in the -(C ０～３ Each heterocyclyl group in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ and is optionally substituted with -(C ０～３ alkylene)-carbocyclyl or the above-(C ０～３ alkylene)-heterocyclyl contains one or more —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, where R ３ is not morpholin-4-yl or —NH-phenyl, and the phenyl group in said —NH-phenyl is Ｃｙｃ is optionally replaced by Each R Ｃｙｃ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, —OH, —O(C １～５ alkyl), —O(C １～５ alkylene)-OH, -O(C １～５ alkylene)-O(C １～５ alkyl), -(C １～３ alkylene)-OH, -(C １～３ alkylene)-O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -S(C １～５ alkylene)-SH, -S(C １～５ alkylene)-S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl), -N(C １～５ alkyl) (C １～５ alkyl), -NH-OH, -N(C １～５ alkyl)-OH, -NH-O(C １～５ alkyl), -N(C １～５ alkyl)-O(C １～５ alkyl), halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), -CN, -CHO, -CO(C １～５ alkyl), -COOH, -COO(C １～５ alkyl), —O—CO(C １～５ alkyl), —CO—NH ２ , —CO—NH(C １～５ alkyl), —CO—N(C １～５ alkyl) (C １～５ alkyl), —NH—CO(C １～５ alkyl), -N(C １～５ alkyl)-CO(C １～５ alkyl), —NH—COO(C １～５ alkyl), -N(C １～５ alkyl)-COO(C １～５ alkyl), —O—CO—NH(C １～５ alkyl), —O—CO—N(C １～５ alkyl) (C １～５ alkyl), -SO ２ -NH ２ , -SO ２ -NH(C １～５ alkyl), -SO ２ -N(C １～５ alkyl) (C １～５ alkyl), —NH—SO ２ -(C １～５ alkyl), -N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -SO ２ -(C １～５ alkyl), —SO—(C １～５ alkyl), -(C ０～３ alkylene)-cycloalkyl, -(C ０～３ alkylene)-heterocycloalkyl and -R ６ -R ７ wherein said -(C ０～３ and the cycloalkyl group in the -(C alkylene)-cycloalkyl. ０～３ Each heterocycloalkyl group in the alkylene-heterocycloalkyl is １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), —CN, —OH, —O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl), -N(C １～５ alkyl) (C １～５ alkyl), -CHO, -CO(C １～５ alkyl), -COOH, -COO(C １～５ alkyl), —O—CO(C １～５ alkyl), —CO—NH ２ , —CO—NH(C １～５ alkyl), —CO—N(C １～５ alkyl) (C １～５ alkyl), -NH-CO(C １～５ alkyl), -N(C １～５ alkyl)-CO(C １～５ alkyl), —NH—COO(C １～５ alkyl), -N(C １～５ alkyl)-COO(C １～５ alkyl), —O—CO—NH(C １～５ alkyl), —O—CO—N(C １～５ alkyl) (C １～５ alkyl), -SO ２ -NH ２ , -SO ２ -NH(C １～５ alkyl), -SO ２ -N(C １～５ alkyl) (C １～５ alkyl), —NH—SO ２ -(C １～５ alkyl), -N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -SO ２ -(C １～５ alkyl) and —SO—(C １～５ alkyl), Each R ６ is a covalent bond, C １～５ Alkylene, C ２～５ Alkenylene and C ２～５ alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each independently selected from halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), —CN, —OH, —O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl) and —N(C １～５ alkyl) (C １～５ and wherein the alkylene, alkenylene, or alkynylene is optionally substituted with one or more groups independently selected from the group consisting of —CH ２ - units are -O-, -NH-, and -N(C １～５ alkyl)-, -CO-, -S-, -SO- and -SO ２ -, and Each R ７ is -OH, -O(C １～５ alkyl), —O(C １～５ alkylene)-OH, -O(C １～５ alkylene)-O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -S(C １～５ alkylene)-SH, -S(C １～５ alkylene)-S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl), -N(C １～５ alkyl) (C １～５ alkyl), -NH-OH, -N(C １～５ alkyl)-OH, -NH-O(C １～５ alkyl), -N(C １～５ alkyl)-O(C １～５ alkyl), halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), -CN, -CHO, -CO(C １～５ alkyl), -COOH, -COO(C １～５ alkyl), —O—CO(C １～５ alkyl), —CO—NH ２ , —CO—NH(C １～５ alkyl), —CO—N(C １～５ alkyl) (C １～５ alkyl), -NH-CO(C １～５ alkyl), -N(C １～５ alkyl)-CO(C １～５ alkyl), —NH—COO(C １～５ alkyl), -N(C １～５ alkyl)-COO(C １～５ alkyl), —O—CO—NH(C １～５ alkyl), —O—CO—N(C １～５ alkyl) (C １～５ alkyl), -SO ２ -NH ２ , -SO ２ -NH(C １～５ alkyl), -SO ２ -N(C １～５ alkyl) (C １～５ alkyl), —NH—SO ２ -(C １～５ alkyl), -N(C １～５ (alkyl)-SO ２ -(C １～５ alkyl), -SO ２ -(C １～５ alkyl), —SO—(C １～５ alkyl), aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each independently selected from C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, halogen, C １～５ haloalkyl, —O—(C １～５ haloalkyl), —CN, —OH, —O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl) and —N(C １～５ alkyl) (C １～５ and optionally substituted with one or more groups independently selected from alkyl.

2. Ring A is a group (A-1): 【Transformation 3】 and Group (A-1) is a group R Ａ１ and group R Ａ２ and said phenyl or said pyridinyl is substituted with one or more groups R Ａ３ 2. The compound of claim 1, wherein the phenyl or pyridinyl is optionally further substituted with

3. Ring A may contain one or more groups R Ａ３ 2-R optionally substituted with Ａ１ -4-R Ａ２ 3. The compound according to claim 1, wherein the aryl group is -phenyl.

4. R Ａ１ Ha-O(C １～５ alkyl), —O(C ２～５ alkenyl), C １～５ Alkyl, C ２～５ Alkenyl, —N(C １～５ alkyl) (C １～５ alkyl), halogen, C １～５ haloalkyl, —O—(C １～５ The compound of any one of claims 1 to 3, selected from -haloalkyl), -CN, cycloalkyl, -O-cycloalkyl, heterocycloalkyl and -O-heterocycloalkyl.

5. R Ａ１ Ha-O(C １～５ The compound according to any one of claims 1 to 4, wherein the aryl group is aryl, aryl, aryl(alkyl), or halogen.

6. R Ａ２ is C １～５ Alkyl, -(C １～５ alkylene)-OH, -O(C １～５ alkyl), —O—(C １～５ alkylene)-OH, -O-(C １～５ alkylene)-O(C １～５ alkyl), -(C １～５ alkylene)-O-(C １～５ alkylene)-OH, -(C １～５ alkylene)-O-(C １～５ alkylene)-O(C １～５ alkyl), —O(C １～５ alkylene)-O(C １～５ alkyl), —O(C １～３ alkylene)-O(C １～３ alkylene)-O(C １～３ alkyl), —O(C ２～５ alkenyl), -(C １～５ alkylene)-O(C １～５ alkyl), -(C １～５ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C １～３ alkylene)-O(C １～３ alkylene)-O(C １～３ alkylene)-O(C １～３ alkyl), —O—(C １～５ haloalkyl), —O(C １～５ alkylene)-O-(C １～５ haloalkyl), —O(C １～３ alkylene)-O(C １～３ alkylene)-O-(C １～３ haloalkyl), -(C １～５ alkylene)-O-(C １～５ haloalkyl), -(C １～５ alkylene)-O(C １～５ alkylene)-O-(C １～５ haloalkyl), -(C １～３ alkylene)-O(C １～３ alkylene)-O(C １～３ alkylene)-O-(C １～３ haloalkyl), —O(C １～５ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), -(C １～５ alkylene)-O(C １～５ alkylene)-N(C １～５ alkyl) (C １～５ alkyl), —CO—NH—(C １～５ alkyl), —CO—N(C １～５ alkyl) (C １～５ alkyl), -SO ２ -(C １～１２ alkyl), -SO ２ -(C １～１２ haloalkyl), halogen, C １～５ Haloalkyl, -(C ０～５ alkylene)-carbocyclyl, -(C ０～５ alkylene)-heterocyclyl, —O—(C ０～４ alkylene)-carbocyclyl, —O—(C ０～４ alkylene)-heterocyclyl, -(C ０～４ alkylene)-O-carbocyclyl, -(C ０～４ alkylene)-O-heterocyclyl, —CO—(C ０～４ alkylene)-carbocyclyl and —CO—(C ０～４ alkylene)-heterocyclyl, wherein said -(C ０～５ carbocyclyl in the -(alkylene)-carbocyclyl, ０～５ heterocyclyl in the -O-(C alkylene)-heterocyclyl ０～４ carbocyclyl in the —O—(C alkylene)-carbocyclyl ０～４ alkylene)-heterocyclyl, the heterocyclyl in the -(C ０～４ carbocyclyl in the -(C alkylene)-O-carbocyclyl ０～４ alkylene)-O-heterocyclyl, the heterocyclyl in the —CO—(C ０～４ carbocyclyl in the -CO-(C alkylene)-carbocyclyl ０～４ Each heterocyclyl in the alkylene-heterocyclyl may be one or more groups R Ｃｙｃ The compound of any one of claims 1 to 5, optionally substituted with

7. R ２ is hydrogen, C １～５ Alkyl, —OH, —O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl), -N(C １～５ alkyl) (C １～５ alkyl), halogen, C １～５ haloalkyl, —O—(C １～５ The compound of any one of claims 1 to 6, wherein the alkyl group is selected from -haloalkyl) and -CN.

8. R ３ is C １～５ Alkyl, C ２～５ Alkenyl, —OH, —O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -NH ２ , —NH(C １～５ alkyl), -N(C １～５ alkyl) (C １～５ alkyl), -CHF ２ , -CH ２ F, C ２～５ haloalkyl, —O—(C １～５ haloalkyl), phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl, wherein R ３ is not morpholin-4-yl, and each of the phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl may be one or more groups R Ｃｙｃ The compound of any one of claims 1 to 7, optionally substituted with

9. The compound is N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-phenylquinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine, 7-methoxy-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine, 7-(4,4-difluoropiperidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(3,3-difluoroazetidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(prop-1-en-2-yl)quinolin-4-amine, 7-isopropyl-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(oxetan-3-yl)piperazin-1-yl)quinolin-4-amine, (S)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (R)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2-methoxyethyl)piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)quinolin-4-amine, 7-(4-ethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (S)-7-(2,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, tert-butyl 3-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-1-yl)azetidine-1-carboxylate, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(1-methylazetidin-3-yl)piperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinolin-4-amine, 7-(4-(azetidin-3-yl)piperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, (R)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol, (S)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol, tert-butyl 5-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)quinolin-4-amine, 4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-2-one, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, 7-methoxy-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine, N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2,4-dimethoxyphenyl)-7-phenylquinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-fluoro-2-methoxyphenyl)quinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-(2-methoxyethoxy)-2-morpholinophenyl)quinolin-4-amine, N-(2-cyclopropoxy-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, N-(4-(1,1-difluoroethyl)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2,4-dimethoxyphenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-4-(methylsulfonyl)phenyl)quinolin-4-amine, N-cyclopropyl-4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxybenzamide, 7-(difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)quinolin-4-amine, N-(4-(2-cyclopropoxyethoxy)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-fluoro-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone, 4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide, N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methoxy-3-methyl-1H-pyrazol-5-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(2,4-dimethyl-1H-imidazol-5-yl)quinolin-4-amine, N-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-(difluoromethyl)quinolin-4-amine, N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]oxazol-7-amine, N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]thiazol-7-amine, 7-(difluoromethyl)-N-(1-methylimidazo[1,5-a]pyridin-3-yl)quinolin-4-amine, N-(1-bromoimidazo[1,5-a]pyridin-3-yl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(7-methyl-1H-indol-4-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(7-fluoro-1H-indol-4-yl)quinolin-4-amine, N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-7-(difluoromethyl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-methylisoquinolin-1-yl)quinolin-4-amine, 7-(difluoromethyl)-N-(4-fluoroisoquinolin-1-yl)quinolin-4-amine, 5-chloro-N-(7-(difluoromethyl)quinolin-4-yl)-1,7-naphthyridin-8-amine, N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-isopropylquinolin-4-amine, N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-fluoro-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(2-methoxyethoxy)-2-morpholinophenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(trifluoromethyl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(methylsulfonyl)phenyl)-7-methylquinolin-4-amine, N-(2-cyclopropoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(5-bromo-3-methoxypyrazin-2-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-(cyclopentyloxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(2-(trifluoromethoxy)ethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-chloro-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(2-isopropoxyethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(furan-2-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(4-(furan-3-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(4-methyl-1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine, N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(thiophen-2-yl)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-4-(thiophen-3-yl)phenyl)-7-methylquinolin-4-amine, N-(7-bromobenzo[d][1,3]dioxol-4-yl)-7-methylquinolin-4-amine, N-(7-(1H-pyrazol-4-yl)benzo[d][1,3]dioxol-4-yl)-7-methylquinolin-4-amine, 3-methoxy-N-(2-methoxyethyl)-4-((7-methylquinolin-4-yl)amino)benzamide, N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, (3-methoxy-4-((7-methylquinolin-4-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone, N-(2-methoxy-6-(5-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, 1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazole-4-carbonitrile, N-(2-methoxy-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, 1-(1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazol-4-yl)ethan-1-one, N-(2-fluoro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine, N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(4-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(3-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-4-amine, N-(3-methoxy-5-(1H-pyrazol-4-yl)pyrazin-2-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine, N-(4-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine, N-(4-methoxy-2-(1H-pyrazol-4-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine, 7-methoxy-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine, N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methoxyquinolin-4-amine, N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine or a pharmaceutically acceptable salt of any one of these compounds.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

11. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in the treatment or prevention of cancer, an inflammatory disease or an autoimmune disease.

12. 12. The compound or pharmaceutical composition for use according to claim 11, wherein the compound or pharmaceutical composition is for use in the treatment or prevention of cancer, and the cancer is selected from breast cancer, prostate cancer, liver cancer, lung cancer, colon cancer, colorectal cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, kidney cancer, head cancer, neck cancer, blood cancer, Merkel cell carcinoma, lymphoma, leukemia, bone cancer, bone marrow cancer, brain cancer, esophageal cancer, gum cancer, nasopharyngeal cancer, skin cancer, melanoma, stomach cancer, tongue cancer, uterine cancer, anal cancer, genitourinary tract cancer, bladder cancer, endometrial cancer, vaginal cancer, vulvar cancer, testicular cancer, biliary tract cancer, hepatic and gallbladder cancer, neuroblastoma, epidermoid carcinoma, squamous cell carcinoma, fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, laryngeal cancer, oral cancer, thymoma, neuroendocrine carcinoma, and multiple myeloma.

13. The compound or the pharmaceutical composition is for use in the treatment or prevention of an inflammatory disease, and the inflammatory disease is selected from the group consisting of arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, uric acid arthritis, gout, chronic polyarthritis, shoulder periarthritis, cervical arthritis, lumbosacral arthritis, enteropathic arthritis, ankylosing spondylitis, asthma, dermatitis, psoriasis, scleroderma, polymyositis, dermatomyositis, juvenile dermatomyositis, primary biliary cirrhosis, fibrosis, cystic fibrosis, pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, and the like. fibrosis), myelofibrosis, retroperitoneal fibrosis, renal fibrosis, keloids, scleroderma, arthrofibrosis, delayed and / or chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, pemphigus, pemphigus vulgaris, pemphigus herpetiformis, pemphigus vegetans, IgA pemphigus, pemphigus erythematosus, bullous pemphigoid, pemphigoid of pregnancy, mucodermatoses, nodular pemphigoid, linear IgA bullous dermatosis, bullous lichen planus, epidermolysis bullosa acquisita, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy 12. A compound for use according to claim 11 or a pharmaceutical composition for use according to claim 11 selected from the group consisting of inflammatory bowel diseases, urinary tract infections, urinary tract infections (urinary tract infections), ...

14. The compound or the pharmaceutical composition is for use in treating or preventing an autoimmune disease, and the autoimmune disease is selected from the group consisting of lupus, Hashimoto's thyroiditis, Wegener's disease, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes, Goodpasture's syndrome, myasthenia gravis, pemphigus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, 12. A compound for use according to claim 11 or a pharmaceutical composition for use according to claim 11 selected from idiopathic thrombocytopenia, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis, Sjogren's syndrome, arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, polymyositis, scleroderma, psoriasis, primary sclerosing cholangitis, asthma, transplant rejection, host-versus-graft disease, graft-versus-host disease and mixed connective tissue disease.

15. 10. In vitro use of a compound according to any one of claims 1 to 9 as an NIK inhibitor.

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