Substituted quinolines as improved NF-KB-induced kinase (NIK) inhibitors

Abstract

The present invention provides novel compounds of formula (I) and pharmaceutical compositions containing such compounds. The compounds of formula (I) are useful as NF-[kappa] B-induced kinase (NIK) inhibitors, in particular, can induce intracellular degradation of NIK, which makes such compounds very advantageous for use in therapy, including the treatment or prevention of cancer, inflammatory diseases and autoimmune diseases. # imgabs0 #

Description

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

[0002] Activation of the NF-κB pathway has been implicated in many pathological conditions, including cancer and inflammatory diseases. In addition to the canonical NF-κB pathway, which is primarily triggered during proinflammatory processes, the atypical NF-κB pathway (or NF-κB2) is also overactive in many cancers and B-cell-mediated autoimmune pathologies. This atypical 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 constitutively expressed as a protein, but can also be constitutively degraded by the proteasome. Triggering of specific receptors (CD40LR, BAFFR, lymphotoxin βR) uncouples NIK from its protein partners, inhibiting its constitutive degradation and thereby constitutively increasing its stability in the cytosol, thereby enhancing its activity as a regulator 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 tumor-derived cancers and is described as one of the key molecules involved in cancer cell proliferation, tumorigenicity, and immune escape (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 inhibits the expression of immunogenic factors and genes involved in cell senescence (De Donatis GM et al., Oncogene, 2016, 35(21):2735-45, doi:10.1038 / onc.2015.331). Recently, an intracellular NIK pool located in the outer mitochondrial membrane of glioma cells has been discovered and found to be involved in mitochondrial fission, a process that allows cancer cells to double the number of mitochondria per cell to accommodate the high energy demands associated with intense proliferation. Interestingly, the role of NIK in mitochondrial fission is independent of its activity in the NF-κB2 pathway. In addition, NIK participates in the energy supply of cancer cells in a limited nutrient environment, causing malignant cells to switch from glycolysis to oxidative phosphorylation to produce ATP (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 cells into antibody-secreting memory B cells and is a key factor in autoimmune diseases driven by 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 diseases and autoimmune diseases, intensive research and development efforts have been conducted to discover small molecules with the ability to specifically modulate NIK kinase activity.

[0004] To date, a variety of small molecules have been described as NIK inhibitors. For example, the pan-kinase inhibitor staurosporine was found to inhibit kinase activity at the micromolar level (Mortier J et al., Bioorganic Med Chem Lett, 2010, 20(15):4515-4520, doi:10.1016 / j.bmcl.2010.06.027). In 2005, Sanofi first characterized a series of pyrazolo[4,3-c]isoquinoline derivatives (WO 2004 / 005287). After the first identification, in 2010, 49 hits were identified from 67,500 scaffold molecules by virtual screening (Mortier J et al., loc.cit.). These 49 hits were selected and tested in radioactivity assays to identify IC 50 The value was 51 μM for the compound.

[0005] In 2012, Genentech reported new potent NIK inhibitors through high-throughput screening and subsequent optimization, ultimately obtaining a novel inhibitor with nanomolar IC 50 Compounds with high values (De Leon-Boenig et al., Structure, 2012, 20(10):1704-1714, doi:10.1016 / j.str.2012.07.013). This first identification of NIK inhibitors by co-crystallization with the NIK catalytic domain was a starting point for many researchers in academia and the pharmaceutical industry. Thus, in 2013, Amgen reported another high-throughput screening that identified new IC 50 A hit with a value of 0.60 μM (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 inhibitors of NIK 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 further optimized their NIK inhibitors and discovered a series of tricyclic inhibitors in 2017 using 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). With the development of these compounds, a series of new 3-hydroxypyrrolidin-2-one derivatives were identified in 2018 (Blaquiere N et al., J Med Chem, 2018, 61(15):6801-6813, doi:10.1021 / acs.jmedchem.8b00678). To improve metabolic stability, researchers further identified a new 4-methoxy-2-aminopyridine compound with the highest potency and metabolic stability, also known as NIK SMI1 (Blaquiere N et al., loc.cit.). Based on this work and the identification of the binding mode, Zhao's team obtained a new 2-amino-5H-pyrrolo[3,2-d]-pyrimidine structure by replacing the 2-aminopyridine 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, N-acetyl-3-aminopyrazole was selected through screening of different Prestwick libraries, and its activity was increased to IC 50 The value is 8.4 μM (Pippione AC et al., Medchemcomm, 2018, 9(6):963-968, doi:10.1039 / c8md00068a).

[0009] In 2020, Chen's team 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). Janssen reported two new co-crystal structures containing NIK co-crystallized with indoline and azaindoline (Jacoby E et al., Futur Drug Discov, 2020, 2(3):FDD43, doi:10.4155 / fdd-2020-0004). Genentech optimized their series and recently obtained inhibitors containing azabicyclo[3.1.0]cyclohexanone (Crawford JJ et al., Synth, 2020, 52(22):3420-3426, doi:10.1055 / s-0040-1707279).

[0010] Other notable reports on 4-anilino-quinolines as NIK inhibitors and their use in treating cancers 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 intensive research and development efforts, previous attempts to provide small molecules with the ability to specifically modulate NIK kinase activity in cancer and inflammatory or autoimmune diseases have not resulted in drugs approved by regulatory authorities. Thus, there is a pressing and unmet need to provide new and improved compounds that modulate NIK for therapeutic use, particularly for therapeutic intervention in cancer, inflammatory diseases, and autoimmune diseases.

[0012] The present invention addresses this need and provides novel compounds that target NIK and possess highly favorable 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 diverse cellular functions involved in the pathogenesis of cancer, as well as inflammatory and autoimmune diseases, significantly reducing its intracellular concentration is an effective approach to shutting down NIK activity, both in the cytosol and in the mitochondria, and whether dependent on or independent of the NF-κB2 pathway. Therefore, the NIK-specific degradation inducers provided according to the present invention constitute a fundamentally novel and promising therapeutic approach. The clinically beneficial outcomes of NIK degradation induced by these novel molecules are manifold, including inhibition of cell proliferation and induction of cellular senescence without cytotoxicity. Furthermore, these novel NIK degradation inducers are able to modulate the role of NIK in mitochondrial fission by inhibiting NIK-induced DRP1 phosphorylation, a major player in this phenomenon. These effects make the compounds provided herein particularly advantageous for therapeutic applications, including treatment of cancer, inflammatory diseases, and autoimmune diseases.

[0013] Therefore, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below:

[0014]

[0015] In formula (I), ring A is an aromatic group selected from the following groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7):

[0016]

[0017] wherein the group (A-1) is a phenyl group or a 6-membered monocyclic heteroaryl group, wherein the phenyl group or the heteroaryl group is replaced by a group R at the indicated position. A1 and group R A2 substituted, and optionally also by one or more than one group R A3 replace;

[0018] wherein the groups (A-2) and (A-3) are each a 5-membered monocyclic heteroaryl group which is replaced at the indicated position by a group R A1 and group R A2 substituted, and optionally also by one or more than one group R A3 replace;

[0019] Wherein the group (A-4) is an 8-membered bicyclic heteroaryl group which is replaced by a group R at the indicated position A2 substituted, and optionally also by one or more than one group R A3 replace;

[0020] wherein groups (A-5) and (A-6) are each a 9-membered bicyclic heteroaryl group which is replaced at the indicated position by a group R A2 substituted, and optionally also by one or more than one group R A3 replace; and

[0021] wherein the group (A-7) is a naphthyl group or a 10-membered bicyclic heteroaryl group, wherein the naphthyl group or the heteroaryl group is replaced by a group R at the indicated position. A2 substituted, and optionally also by one or more than one group R A3 replace.

[0022] In the context of the present invention, it has been unexpectedly found that the compounds having two substituents R at the specific positions shown in the formulae (A-1), (A-2) and (A-3) above A1 and R A2 A compound of formula (I) having a ring A of 1, 2 or 3, or having a second fused ring and a substituent R at a specific position shown in formulas (A-4), (A-5), (A-6) and (A-7) above A2 The compounds of formula (I) having a ring A of R1 advantageously exhibit improved therapeutic properties, including significantly more effective inhibition of cell proliferation and significantly enhanced senescence induction activity. Therefore, as summarized in the following table, the compounds of formula (I) having a ring A but lacking the substituent R1 at the specific position required by the present invention are compared with the corresponding compounds having a ring A but lacking the substituent R1 at the specific position required by the present invention. A1 and R A2 and also compared with "Compound 42" and "Compound 43" disclosed in WO 2019 / 134969 (which do not simultaneously have the substituent R at the specific position required by the present invention). A1 and R A2 ), it has been demonstrated that the compounds of Examples 9 and 10 according to the present invention exhibit improved activity in the proliferation assay and the senescence assay described in Example 143:

[0023]

[0024] *—This reference compound, 7-chloro-N-(4-(2-methoxyethoxy)phenyl)quinolin-4-amine, corresponds to “Compound 42” disclosed on page 22 of WO2019 / 134969.

[0025] **—This reference compound, 7-chloro-N-(3-(hydroxy)-4-(methoxy)phenyl)quinolin-4-amine, corresponds to “Compound 43” disclosed on page 23 of WO2019 / 134969.

[0026] In formula (I), R A1 Selected from -O(C 1-5 alkyl), -O(C2-5 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 the -(C 0-3 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 The heterocycloalkyl groups in the alkylene)-heterocycloalkyl groups are each optionally substituted by one or more than one group R Cyc substituted, and wherein said -(C 0-3 Alkylene)-cycloalkyl or said-(C 0-3 One or more -CH2- units contained in the alkylene group in the alkylene group)-heterocycloalkyl group are optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0027] R A2 Selected from 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 Halogenated alkyl), -CO(C 1-12 alkyl), -CO(C 1-12 Halogenated alkyl), -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)-heterocyclic group, wherein the C 1-12 Alkyl, the -(C 1-12 Alkylene)-OH, the -(C0-5 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 -SO2-(C 1-12 Alkyl) or the -SO2-(C 1-12 In the case of a haloalkyl group, one or more -CH2- units are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO- and -CH=CH-, wherein the -(C 0-5 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-5 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-5 Alkylene)-carbocyclic group or said-(C 0-5 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0028] Each R A3 , if present, independently selected from 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 0-3Alkylene)-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 0-3 Alkylene)-NH-CO-(C 1-5 Alkyl), -(C 0-3 Alkylene)-N(C 1-5 alkyl)-CO-(C 1-5 Alkyl), -(C0-3 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)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0029] R N Selected from hydrogen, C 1-5 Alkyl and -CO-(C 1-5 alkyl).

[0030] R 1、R 4 and R 5 are each independently selected from 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 1-5 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-(C1-5 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-(C 1-5 Alkyl), -(C 0-3 Alkylene)-SO2-(C 1-5 Alkyl), -(C 0-3 Alkylene)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0031] R 2 Selected from 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 1-5 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 1-5Haloalkyl), -(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), -(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)-carbocyclyl and -(C 0-3 Alkylene)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S- and -SO-.

[0032] R 3 Selected from 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 0-3Alkylene)-N(C 1-5 alkyl)-O(C 1-5 Alkyl), -(C 0-3 Alkylene)-CHF2, -(C 0-3 Alkylene)-CH2F, -(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 1-5 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), -(C0-3 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)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-; provided that R 3 is not morpholin-4-yl or -NH-phenyl, wherein the phenyl group in the -NH-phenyl group is optionally replaced by one or more than one group R Cyc replace.

[0033] Each R Cyc Independently selected from 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 1-5alkyl)-O(C 1-5 alkyl), halogen, C 1-5 Haloalkyl, -O-(C 1-5 Halogenated alkyl), -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 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 The heterocycloalkyl groups in the alkylene)-heterocycloalkyl groups are each optionally 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), -N(C 1-5 Alkyl)(C1-5 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 alkyl) is substituted with one or more groups.

[0034] Each R 6 Independently selected from covalent bonds, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein the alkylene, the alkenylene and the alkynylene are each optionally 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 wherein the one or more -CH2- units contained in the alkylene, alkenylene or alkynylene are each optionally substituted by one or more groups independently selected from -O-, -NH-, -N(C 1-5alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0035] Each R 7 Independently selected from -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 Halogenated alkyl), -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 1-5alkyl), -SO-(C 1-5 alkyl), aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the aryl, the heteroaryl, the cycloalkyl and the heterocycloalkyl are each optionally 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) is substituted with one or more groups.

[0036] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Therefore, 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.

[0037] The present invention also 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 treating or preventing cancer, inflammatory diseases or autoimmune diseases. Therefore, the present invention particularly provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, for use in treating or preventing cancer, inflammatory diseases or autoimmune diseases.

[0038] In addition, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing cancer, inflammatory diseases or autoimmune diseases.

[0039] The present invention also relates to a method for treating or preventing cancer, inflammatory diseases or autoimmune diseases, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the foregoing entities and a pharmaceutically acceptable excipient, to a subject (preferably a human) in need thereof. It should be understood that according to this method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (or pharmaceutical composition) is administered.

[0040] As mentioned above, the diseases / disorders to be treated or prevented by the compounds of formula (I) or pharmaceutically acceptable salts thereof (or corresponding pharmaceutical compositions) according to the present invention include, in particular, cancer, inflammatory diseases and autoimmune diseases.

[0041] The cancer to be treated or prevented can be, for example, a solid cancer or a blood cancer (or a hematological malignancy). In particular, the cancer to be treated or prevented according to the present invention is preferably selected from 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's cancer, lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, extranodal lymphoma, or non-extranodal lymphoma), leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, The cancer can be, for example, a primary cancer or a metastatic cancer.

[0042] As mentioned above, the cancer to be treated or prevented according to the present invention may be a blood cancer (or a blood system malignancy), in particular a lymphoma or a leukemia. Preferably, the blood cancer to be treated or prevented is selected from: Hodgkin's lymphoma (or Hodgkin's disease), including, for example, the nodular sclerosis subtype of Hodgkin's lymphoma, the mixed cellularity subtype of Hodgkin's lymphoma, the lymphocyte-rich subtype of Hodgkin's lymphoma, the lymphocyte-depleted subtype of 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); ); nodular lymphocyte-predominant Hodgkin lymphoma; peripheral / cutaneous T-cell lymphoma, including, for example, mycosis fungoides, Sézary syndrome, T-zone lymphoma, lymphoepithelioid lymphoma (e.g., Lennart lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; malignant immunoproliferative disorders, including, for example, Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin disease), or immunoproliferative enteropathy (e.g., thalassemia); multiple myeloma, including For example, Kahler's disease or myelomatosis; plasma cell leukemia; lymphoid leukemia, including, for example, acute lymphocytic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; myeloid leukemia, including, for example, acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myeloid sarcoma (e.g., chloroma or granulocytic sarcoma), acute promyelocytic leukemia, or acute myelomonocytic leukemia; chronic BCR-ABL-negative myeloproliferative disorders, including, for example, polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute polycythemia or erythroleukemia, including, for example, acute polycythemia vera myeloproliferation or diGuglielmo's disease; chronic polycythemia, including, for example, Heilmeyer- disease; acute megakaryocytic leukemia; mast cell leukemia; acute panmyeloproliferative disease; acute myelofibrosis; and Letterer-Siwe disease.

[0043] Furthermore, cancer can be, for example, a malignant tumor, carcinoma, undifferentiated carcinoma, giant cell and spindle cell carcinoma, small cell carcinoma, papillary carcinoma, squamous cell carcinoma, lymphoepithelial carcinoma, basal cell carcinoma, pilomatricoma, transitional cell carcinoma, papillary transitional cell carcinoma, adenocarcinoma, malignant gastrinoma, bile duct carcinoma, hepatocellular carcinoma, mixed hepatocellular and bile duct carcinoma, trabecular adenocarcinoma, adenoid cystic carcinoma, adenocarcinoma in adenomatous polyps, familial adenocarcinoma of the colon, solid carcinoma, malignant carcinoid, bronchioalveolar adenocarcinoma, adenocarcinoma), papillary adenocarcinoma, chromophobe cell carcinoma, oncocytic carcinoma, oncocytic adenocarcinoma, basophilic cell carcinoma, clear cell adenocarcinoma, granulosa cell carcinoma, follicular adenocarcinoma, papillary and follicular adenocarcinoma, non-encapsulated sclerosing carcinoma, adrenocortical carcinoma, endometrioid carcinoma, carcinoma of the skin appendages, apocrine carcinoma, sebaceous gland carcinoma, cerumenous gland carcinoma, adenocarcinoma, mucoepidermoid carcinoma, cystadenocarcinoma, papillary cystadenocarcinoma, papillary serous cystadenocarcinoma, mucinous cystadenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, infiltrating ductal carcinoma, medullary carcinoma, lobular carcinoma, inflammatory carcinoma, Paget's disease, acinar cell carcinoma, adenosquamous carcinoma, adenocarcinoma with squamous metaplasia, malignant thymoma, malignant ovarian stromal tumor, malignant theca cell tumor, malignant granulosa cell tumor, malignant blastomaroblastoma), Sertoli cell carcinoma, malignant Leydig cell tumor, malignant lipid cell tumor, malignant paraganglioma, malignant extramammary paraganglioma, pheochromocytoma, glomus sarcoma, malignant melanoma, amelanotic melanoma, superficial spreading melanoma, giant melanoma with malignant melanoma, epithelioid cell melanoma, malignant blue nevus, sarcoma, fibrosarcoma, malignant fibrous histiocytoma, myxosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, stromal sarcoma, malignant mixed tumor, mixed Müllerian tumor, Wilms' cell Tumor, hepatoblastoma, carcinosarcoma, malignant stromal tumor, malignant Brenner tumor, malignant phyllodes tumor, synovial sarcoma, malignant mesothelioma, dysgerminoma, embryonal carcinoma, malignant teratoma, malignant goiter, choriocarcinoma, malignant mesonephroma, angiosarcoma, malignant hemangioendothelioma, Kaposi's sarcoma, malignant hemangiopericytoma, lymphangiosarcoma, osteosarcoma, paracortical osteosarcoma, chondrosarcoma, malignant chondroblastoma, mesenchymal chondrosarcoma, giant cell tumor of bone, Ewing's sarcoma, malignant odontogenic tumor, ameloblastic odontosarcoma, malignant ameloblastoma, ameloblastic fibrosarcoma, malignant pinealoma, notochord tumors, malignant gliomas, ependymomas, astrocytomas, protoplasmic astrocytomas, fibrillary astrocytomas, astrocytomas, glioblastomas, oligodendrogliomas, oligodendrogliomas, primitive neuroectodermal tumors, cerebellar sarcomas, ganglioneuromas, neuroblastomas, retinoblastomas, olfactory neurogenic tumors, malignant meningiomas, neurofibrosarcomas, malignant neurilemmomas, malignant granular cell tumors, malignant lymphomas, natural killer (NK) leukemias, NK lymphomas (e.g., extranodal or nonnodal natural killer / T-cell (NK / T) lymphomas), malignant tumors of NK cell origin leukemia, acute NK leukemia, Hodgkin's disease, Hodgkin's lymphoma, paragranuloma, 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 enteropathy, leukemia, lymphoid leukemia, plasma cell leukemia, erythroleukemia, lymphosarcoma cell leukemia, myeloid leukemia, basophilic leukemia, eosinophilic leukemia, monocytic leukemia, mast cell leukemia, megakaryocyte leukemia, myeloid sarcoma, or hairy cell leukemia.

[0044] Preferably, the inflammatory disease to be treated or prevented according to the present invention is selected from arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, frozen shoulder, cervical arthritis, lumbosacral arthritis, enteropathic arthritis, ankylosing spondylitis, asthma, dermatitis, psoriasis, scleroderma, polymyositis, dermatomyositis, juvenile dermatomyositis, primary biliary cirrhosis, fibrosis, cystic fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, fibrosis), myelofibrosis, retroperitoneal fibrosis, nephrogenic fibrosis, keloids, scleroderma, arthrofibrosis, late and / or chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, pemphigus, pemphigus vulgaris, pemphigus herpetiformis, pemphigus proliferative, IgA pemphigus, pemphigus erythematosus, bullous pemphigoid, pemphigoid gestationis, mucocutaneous diseases, pemphigoid nodularis, linear IgA bullous dermatosis, bullous lichen planus, epidermolysis bullosa acquisita, autoimmune diabetes mellitus, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, and restenosis after angioplasty stenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves' disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina pectoris, arteriolar disease, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, systemic sclerosis, antiphospholipid syndrome, Sjögren'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), conditions associated with transplant rejection, post-traumatic degeneration, stroke, transplant rejection, allergic conditions, hypersensitivity reactions, allergic rhinitis, allergic eczema, and skin / dermal inflammatory conditions.

[0045] Furthermore, the autoimmune disease to be treated or prevented according to the present invention is preferably selected from lupus (e.g., lupus erythematosus or lupus nephritis), Hashimoto's thyroiditis, Wegener's granulomatosis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes (e.g., insulin-dependent diabetes mellitus, type I diabetes mellitus, or type II diabetes mellitus), Goodpasture's syndrome, myasthenia gravis, pemphigus, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic active hepatitis (CAI), and idiopathic thrombocytopenia. hepatitis), ulcerative colitis, Sjögren'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.

[0046] Other diseases that can be treated or prevented with the compounds according to the present invention include, for example, any of the diseases / disorders mentioned in the following documents: 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.

[0047] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an inhibitor of NF-κB-induced kinase (NIK) in research, that is, as a research tool compound for inhibiting NIK. In particular, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an inducer of intracellular NIK degradation in research, that is, as a research tool compound for inducing NIK degradation. Therefore, the present invention relates to the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a NIK inhibitor, in particular the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound as a NIK inhibitor. The present invention also relates to a method for inhibiting NIK (in particular an in vitro method), the method comprising applying a 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof as a NIK degradation inducer, in particular the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound as a NIK degradation inducer. In addition, the present invention relates to a method for inducing intracellular degradation of NIK (particularly an in vitro method), which comprises administering a 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, or cell extracts or subcellular extracts; biopsy material obtained from an animal (e.g., a human), or an extract thereof; or blood, serum, plasma, saliva, urine, feces, or any other body fluid or extract thereof. It should be understood that the term "in vitro" used in this particular context refers to "outside a living human or animal," including, in particular, experiments performed with cells, cell extracts or subcellular extracts and / or biomolecules in an artificial environment, such as an aqueous solution or culture medium provided in, for example, a flask, a test tube, a petri dish, a microtiter plate, or the like.

[0048] The compounds of formula (I) and their pharmaceutically acceptable salts are described in more detail below:

[0049]

[0050] In formula (I), ring A is an aromatic group selected from the following groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7):

[0051]

[0052] wherein the group (A-1) is a phenyl group or a 6-membered monocyclic heteroaryl group, wherein the phenyl group or the heteroaryl group is replaced by a group R at the indicated position. A1and group R A2 and optionally further substituted by one or more than one (eg, one or two) groups R A3 replace;

[0053] wherein the groups (A-2) and (A-3) are each a 5-membered monocyclic heteroaryl group which is replaced at the indicated position by a group R A1 and group R A2 substituted, and optionally also by one or more than one group R A3 replace;

[0054] Wherein the group (A-4) is an 8-membered bicyclic heteroaryl group which is replaced by a group R at the indicated position A2 and optionally further substituted by one or more than one (eg one, two or three) groups R A3 replace;

[0055] wherein groups (A-5) and (A-6) are each a 9-membered bicyclic heteroaryl group which is replaced at the indicated position by a group R A2 and optionally further substituted by one or more than one (eg, one, two or three) groups R A3 replace; and

[0056] wherein the group (A-7) is a naphthyl group or a 10-membered bicyclic heteroaryl group, wherein the naphthyl group or the heteroaryl group is replaced by a group R at the indicated position. A2 and optionally further substituted by one or more than one (eg, one, two or three) groups R A3 replace.

[0057] It will be appreciated that the ring atoms of groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) may each be a carbon atom or a heteroatom selected from oxygen, sulfur and nitrogen, which is reflected in the chemical formulae of these ring groups by the symbol "x". It will also be appreciated that, depending on the size of the monocyclic or bicyclic ring system, some of the ring atoms may be selected from carbon and nitrogen only, and some of the ring atoms may be carbon atoms only. Furthermore, it will be appreciated that if group (A-1) is phenyl, or if group (A-7) is naphthyl, all of the ring atoms are carbon atoms. As also shown in the chemical formulae of groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7), these groups may be replaced at specific positions by a group R A1 and a group R A2 (in the case of A-1, A-2 and A-3) or a group R A2 (In the case of A-4, A-5, A-6 and A-7) substituted. For example, the group (A-1) is phenyl or a 6-membered monocyclic heteroaryl group, which is replaced in the 2-position by a group R A1 Substituted at position 4 by a group RA2 substituted, wherein position 1 refers to the point of attachment of the phenyl or heteroaryl group to the rest of the compound of formula (I) [i.e., with a nitrogen atom N(R N ) is designated as position 1]. Thus, in other words, if ring A is group (A-1), the substituent R A1 Connected to group (A-1) at the ortho position, the substituent R A2 The group (A-2) is a 5-membered monocyclic heteroaryl group, which is connected to the group (A-1) at the para position. A1 Substituted at position 3 by a group R A2 substituted, wherein the 1-position refers to the point of attachment of the heteroaryl group to the rest of the compound of formula (I). Group (A-3) is a 5-membered monocyclic heteroaryl group which is replaced at the 2-position by a group R A1 Substituted at position 4 by a group R A2 Substitution, wherein position 1 refers to the point of attachment of the heteroaryl group to the rest of the compound of formula (I).

[0058] If the group (A-1) is a 6-membered monocyclic heteroaryl, the heteroaryl may, for example, comprise one or more than one (e.g. one, two or three) nitrogen ring atoms, the remaining ring atoms being carbon atoms. Thus, the group (A-1) may be, for example, a pyridyl group (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), 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), wherein each of the above groups may be optionally replaced by one or more than one R A3 replace.

[0059] The group (A-2) or (A-3) is a 5-membered monocyclic heteroaryl group which may contain one or more than one (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms. Thus, the group (A-2) may be, for example, 1H-pyrrolyl (e.g., 2-R A1 -3-RA2 -1H-pyrrol-1-yl, 1-R A1 -5-R A2 -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), furanyl (e.g., 3-R A1 -4-R A2 -furan-2-yl or 4-R A1 -5-R A2 -furan-3-yl), phenylthio (e.g., 3-R A1 -4-R A2 -thiophen-2-yl or 4-R A1 -5-R A2 -thiophen-3-yl), 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), 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), 1,2,3-triazolyl (e.g., 5-R A1 -4-R A2 -1,2,3-triazol-1-yl), 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), wherein each of the above groups may be optionally replaced by one or more than one R A3 Likewise, the (A-3) group may be, for example, a 1H-pyrrolyl group (e.g., a 2-R A1 -4-R A2 -1H-pyrrol-1-yl, 1-RA1 -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), furanyl (e.g., 3-R A1 -5-R A2 -furan-2-yl), phenylthio (e.g., 3-R A1 -5-R A2 -thiophen-2-yl), 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), 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), 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), 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-R A1 -2-R A2 -thiazol-5-yl), wherein each of the above groups may be optionally replaced by one or more than one R A3 replace.

[0060] It will be understood that in the bicyclic aromatic groups (A-4), (A-5), (A-6) and (A-7), at least one ring of the bicyclic fused ring system is aromatic; preferably, both rings of the bicyclic fused ring system are aromatic. Furthermore, it will be understood that in the groups (A-4), (A-5) and (A-6) that are bicyclic heteroaryl groups, at least one ring of the bicyclic fused ring system comprises one or more than one (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms; in particular, the two rings of the bicyclic fused ring system may each comprise one or more than one (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms. Similarly, if group (A-7) is a bicyclic heteroaryl group, at least one ring of the bicyclic fused ring system contains one or more than one (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms; in particular, the two rings of the bicyclic fused ring system may each contain one or more than one (e.g., one, two or three) heteroatoms independently selected from nitrogen, oxygen and sulfur, with the remaining ring atoms being carbon atoms.

[0061] Thus, the (A-4) group can be, for example, a 1,4-dihydropyrrolo[3,2-b]pyrrolyl group (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), 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), 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), 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), wherein each of the above groups may be optionally replaced by one or more than one R A3 replace.

[0062] The group (A-5) may be, 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.

[0063] The (A-6) group may be, for example, an indolyl group (e.g., 7-R A2 -1H-indol-4-yl or 4-R A2 -1H-indol-7-yl), indolizinyl (e.g., 8-R A2 -indolizin-5-yl or 5-R A2 -indolizin-8-yl), 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), 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) or benzodioxolyl (e.g., 7-R A2 -Benzodioxol-4-yl or 4-R A2 -benzodioxol-7-yl), wherein each of the above groups may be optionally replaced by one or more than one R A3 replace.

[0064] The group (A-7) may be, 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 -cinnolin-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 -benzodioxane-5-yl or 4-R A2 -naphthalen-1-yl (or 4-R A2 -naphthalen-1-yl).

[0065] Furthermore, as described above, each of the groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) is optionally replaced by one or more than one (e.g., one, two or three) groups R A3 It is understood that the optional substituent R A3The maximum number of substituents R depends on the number of available hydrogen atoms on the particular group (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) or (A-7). For example, if the group (A-1) is phenyl, then the phenyl group may have 0, 1, 2 or 3 substituents R A3 However, if the group (A-1) is a pyridyl group, the pyridyl group may have 0, 1 or 2 (but not more than 2) substituents R A3 , and if group (A-1) is, for example, pyrazinyl or pyridazinyl, said pyrazinyl or said pyridazinyl may carry 0 or 1 (but not more than 1) substituent R A3 Unless otherwise defined, it is generally preferred that each of the groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) is optionally replaced by one or two R A3 substituted, more preferably by one R A3 Even more preferably, each of the groups (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7) is not replaced by any optional substituent R A3 replace.

[0066] 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 (ie, 2-R A1 -4-R A2 -phenyl), pyridyl (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 the phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl are each optionally substituted by one or more than one R A3 Even more preferably, Ring A is phenyl (ie, 2-R A1 -4-R A2 -phenyl) or pyridyl (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 the phenyl or the pyridinyl is optionally substituted by one or more than one R A3 Still more preferably, Ring A is 2-R A1 -4-R A2 -phenyl, which is optionally substituted by one or more than one (eg one, two or three) groups R A3 replace.

[0067] Group R A1 Selected from -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 the -(C 0-3 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 Each heterocycloalkyl group in the alkylene)-heterocycloalkyl group is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-cycloalkyl or said-(C 0-3 One or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocycloalkyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0068] Preferably, R A1 Selected from -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 0-3alkylene)-heterocycloalkyl, wherein the -(C 0-3 Alkylene)-cycloalkyl or said-(C 0-3 The two -CH2- units contained in the alkylene group in the alkylene group)-heterocycloalkyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 More preferably, R A1 Selected from -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 Even more preferably, R A1 Selected from -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 1-5 and heterocycloalkyl (e.g., monocyclic heterocycloalkyl linked to the remainder of the compound of formula (I) via a nitrogen ring atom; e.g., pyrrolidin-1-yl, piperidin-1-yl or morpholin-4-yl). Even more preferably, R A1 Selected from -O(C 1-5 alkyl), halogen (e.g., -F, -Cl, or -Br), -O-(C 1-5 Still more preferably, R A1 Yes-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.

[0069] As further explained below, R A1 (including any of the aforementioned preferred or exemplary groups R A1) may also be replaced by deuterium ("D" or 2 H) replacement. Therefore, R A1 It may be, for example, the group -OCD3.

[0070] Group R A2 Selected from 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 Halogenated alkyl), -CO(C 1-12 alkyl), -CO(C 1-12 Halogenated alkyl), -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)-heterocyclic group, wherein the 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 -SO2-(C 1-12 Alkyl) or the -SO2-(C 1-12In one or more than one (e.g., one, two, or three) -CH2- units in a haloalkyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO- and -CH=CH-, wherein the -(C 0-5 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-5 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-5 Alkylene)-carbocyclic group or said-(C 0-5 The one or more than one (e.g., one, two, or three) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 The C 1-12 The alkyl group is preferably a straight chain C 1-12 Alkyl groups, such as -(CH2) 0-11 -CH3; said -(C 1-12 Alkylene)-OH is preferably a straight-chain -(C 1-12 Alkylene)-OH, such as -(CH2) 1-12 -OH; the -(C 0-5 Alkylene)-O(C 1-12 Alkyl) is preferably a linear -(C 0-5 Alkylene)-O(C 1-12 Alkyl), such as -(CH2) 0-5 -O-(CH2) 0-11 -CH3; said -(C 0-5 Alkylene)-O(C 1-12 Halogenated alkyl) is preferably a linear -(C 0-5 Alkylene)-O(C 1-12 haloalkyl); said -(C 0-5 Alkylene)-O-(C 1-12 Alkylene)-OH is preferably a straight-chain -(C 0-5 Alkylene)-O-(C 1-12 Alkylene)-OH, such as -(CH2) 0-5 -O-(CH2) 1-12 -OH; the -(C 0-5 Alkylene)-O-(C 1-5 Alkylene)-O(C 1-12 Alkyl) is preferably a linear -(C 0-5 Alkylene)-O-(C 1-5 Alkylene)-O(C1-12 Alkyl), such as -(CH2) 0-5 -O-(CH2) 1-5 -O-(CH2) 0-11 -CH3; said -(C 0-5 Alkylene)-O-(C 1-5 Alkylene)-O(C 1-12 Halogenated alkyl) is preferably a linear -(C 0-5 Alkylene)-O-(C 1-5 Alkylene)-O(C 1-12 haloalkyl); the -CO(C 1-12 Alkyl) is preferably a linear -CO(C 1-12 Alkyl), such as -CO-(CH2) 0-11 -CH3; the -CO(C 1-12 Halogenated alkyl) is preferably a linear -CO(C 1-12 haloalkyl); the -SO2-(C 1-12 Alkyl) is preferably a linear -SO2-(C 1-12 Alkyl), such as -SO2-(CH2) 0-11 -CH3; said -SO2-(C 1-12 Halogenated alkyl) is preferably a linear -SO2-(C 1-12 haloalkyl). In particular, R A2 can be any compound of formula (I) described in the Examples section containing the specific R A2 Any one of the groups.

[0071] Preferably, R A2 Selected from 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 1-3 Alkylene)-O(C 1-3 Alkylene)-O(C 1-3alkyl), -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 1-12 alkyl) (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 0-5alkylene)-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; such as 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 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], phenylthio [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]), -O-(C 0-4 Alkylene)-carbocyclyl (e.g., -O-(C 0-4 Alkylene)-aryl or -O-(C 0-4 Alkylene)-cycloalkyl; such as -O-cyclopentyl), -O-(C 0-4 Alkylene)-heterocyclyl (e.g., -O-(C 0-4 Alkylene)-heteroaryl or -O-(C 0-4 Alkylene) -heterocycloalkyl; such as -OCH2CH2- (morpholin-4-yl) or -OCH2CH2- (6-oxa-3-aza-bicyclo [2.1.2] heptane-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 0-4Alkylene)-heterocycloalkyl; such as -CO-(4-morpholinyl) or -CO-azetidinyl [e.g., -CO-(azetidin-1-yl)]), wherein the -(C 0-5 Alkylene)-carbocyclic group, the carbocyclic group in the -(C 0-5 Alkylene) -heterocyclic group, the heterocyclic group in the -O-(C 0-4 Alkylene)-carbocyclic group, the -O-(C 0-4 The heterocyclic group in the alkylene)-heterocyclic group, the -(C 0-4 Alkylene)-O-carbocyclic group in the carbocyclic group, the -(C 0-4 The heterocyclic group in the -CO-(C 0-4 Alkylene)-carbocyclic group and the carbocyclic group -CO-(C 0-4 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc More preferably, R A2 Selected from 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 1-5Haloalkyl), -(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), -SO2-(C 1-12 alkyl), -SO2-(C 1-12 haloalkyl), halogen, C 1-5 haloalkyl, aryl (e.g., phenyl) and heteroaryl (e.g., monocyclic heteroaryl, in particular 5-membered or 6-membered monocyclic heteroaryl, e.g., pyrazolyl), wherein the aryl and the heteroaryl are each optionally substituted by one or more than one (e.g., one, two or three) groups R Cyc Even more preferably, R A2 Selected from -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 optionally substituted by one or more than one group R Cyc Even more preferably, R A2 Selected from -O(C 1-5 alkyl), -O(C 1-5 Alkylene)-O(C 1-5 Alkyl), -(C1-5 Alkylene)-O(C 1-5 Alkyl), -(C 1-5 Alkylene)-O(C 1-5 Alkylene)-O(C 1-5 alkyl) and monocyclic heteroaryl, wherein the monocyclic heteroaryl is optionally substituted by one or more than one group R Cyc Therefore, R A2 Particularly preferred examples include -OCH2CH2OCH3, -OCH2CH2OCF3 or pyrazolyl (eg, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl).

[0072] Each R A3 (if present) independently selected from 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), -(C 0-3 Alkylene)-NH-SO2-(C 1-5 Alkyl), -(C 0-3 Alkylene)-N(C 1-5 alkyl)-SO2-(C1-5 Alkyl), -(C 0-3 Alkylene)-SO-(C 1-5 Alkyl), -(C 0-3 Alkylene)-SO2-(C 1-5 Alkyl), -(C 0-3 Alkylene)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0073] Preferably, each R A3 (if present) independently selected from 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 1-5 Alkylene)-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(C1-5 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-(C 1-5 Alkyl), -(C 0-3 Alkylene)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl group in the alkylene)-heterocyclyl group is optionally substituted by one or more than one (ie, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C1-5 More preferably, each R A3 (if present) independently selected from 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) independently selected from 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 1-5Haloalkyl (e.g., -CF3) and -O-(C 1-5 haloalkyl) (e.g., -OCF3).

[0074] R N Selected from hydrogen, C 1-5 Alkyl and -CO-(C 1-5 alkyl).

[0075] Preferably, R N is hydrogen or C 1-5 More preferably, R N is hydrogen, methyl or ethyl. Even more preferably, R N It's hydrogen.

[0076] R 1 、R 4 and R 5 are each independently selected from 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 1-5 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(C 1-5 Alkyl)(C 1-5 Alkyl), -(C 0-3 Alkylene)-NH-SO2-(C 1-5 Alkyl), -(C0-3 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)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0077] Preferably, R 1 、R 4 and R 5 are each independently selected from 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(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-(C1-5 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-(C 1-5 Alkyl), -(C 0-3 Alkylene)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl group in the alkylene)-heterocyclyl group is optionally substituted by one or more than one (ie, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 More preferably, R 1 、R 4 and R 5 are each independently selected from hydrogen, C1-5 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 Especially preferably, R 1 、R 4 and R 5 Each is hydrogen.

[0078] R 2 Selected from 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 1-5 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), -(C 0-3 Alkylene)-NH-SO2-(C 1-5 Alkyl), -(C 0-3 Alkylene)-N(C 1-5 alkyl)-SO2-(C1-5 Alkyl), -(C 0-3 Alkylene)-SO-(C 1-5 Alkyl), -(C 0-3 Alkylene)-carbocyclyl and -(C 0-3 Alkylene)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S- and -SO-.

[0079] Preferably, R 2 Selected from 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(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 1-5Alkyl)(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 0-3 Alkylene)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl group in the alkylene)-heterocyclyl group is optionally substituted by one or more than one (ie, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 More preferably, R 2 Selected from 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 Especially preferably, R 2 It's hydrogen.

[0080] R 3 Selected from C 1-5Alkyl, 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)-CH2F, -(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 0-3Alkylene)-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 and -(C 0-3 Alkylene)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl in the alkylene)-heterocyclyl is optionally substituted by one or more than one (eg, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-; provided that R 3 is not morpholin-4-yl or -NH-phenyl, wherein the phenyl group in the -NH-phenyl group is optionally replaced by one or more than one group R Cyc The group is substituted.

[0081] Preferably, R 3 Selected from 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(C 1-5 Alkyl), -O-CO-NH(C 1-5Alkyl), -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; such as -(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-diazepine yl, 1,2,3,6-tetrahydropyridinyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl or spiro[azetidine-3,3'-azetidine]-1-yl), wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 Each heterocyclyl group in the alkylene)-heterocyclyl group is optionally substituted by one or more than one (ie, one, two or three) groups R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more than one (e.g., one or two) -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-; provided that R 3 is not morpholin-4-yl or -NH-phenyl, wherein the phenyl group in the -NH-phenyl group is optionally replaced by one or more than one group R Cyc More preferably, R 3 Selected from C 1-5 Alkyl, C 2-5 Alkenyl, -OH, -O(C 1-5 alkyl), -SH, -S(C1-5 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 each of the phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl groups is optionally substituted by one or more than one (e.g., one, two, or three) groups R Cyc Replace; provided that R 3 is not morpholin-4-yl. Even more preferably, R 3 Selected from 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 each of the phenyl, the cycloalkyl, the heteroaryl and the heterocycloalkyl is optionally substituted by one or more than one (e.g., one, two or three) groups R Cyc Replace; provided that R 3 Not morpholin-4-yl. 3 Particularly preferred examples include methyl or -CHF2.

[0082] Each R Cyc Independently selected from 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(C1-5 Alkyl), -N(C 1-5 alkyl)-O(C 1-5 alkyl), halogen, C 1-5 Haloalkyl, -O-(C 1-5 Halogenated alkyl), -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 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 Each of the heterocycloalkyl groups in the alkylene)-heterocycloalkyl group is optionally substituted by one or more than one (e.g., one, two, or three) 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 1-5alkyl), -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 alkyl) groups.

[0083] Each R 6 Independently selected from covalent bonds, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein the alkylene, the alkenylene and the alkynylene are each optionally substituted by one or more than one (e.g., one, two or three) 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 1-5wherein the one or more than one (e.g., one, two, or three) -CH2- units contained in the alkylene, alkenylene, or alkynylene groups are each optionally substituted by independently selected -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-.

[0084] Each R 7 Independently selected from -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 Halogenated alkyl), -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)(C1-5 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 the aryl, the heteroaryl, the cycloalkyl and the heterocycloalkyl are each optionally substituted by one or more than one (e.g., one, two or three) 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) groups.

[0085] Particularly preferably, 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 to 142 further described below, which is in the non-salt form of the corresponding compound or as a pharmaceutically acceptable salt.

[0086] Therefore, it is particularly preferred that the compound of formula (I) is any one of the following compounds or a pharmaceutically acceptable salt thereof:

[0087] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-phenylquinolin-4-amine;

[0088] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine;

[0089] 7-methoxy-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0090] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine;

[0091] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine;

[0092] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine;

[0093] 7-(4,4-difluoropiperidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0094] 7-(3,3-Difluoroazetidin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0095] 7-(Difluoromethyl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0096] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine;

[0097] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine;

[0098] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(prop-1-en-2-yl)quinolin-4-amine;

[0099] 7-Isopropyl-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0100] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine;

[0101] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine;

[0102] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(oxetan-3-yl)piperazin-1-yl)quinolin-4-amine;

[0103] (S)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0104] (R)-7-(3,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0105] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-methyl-1,4-diazepan-1-yl)quinolin-4-amine;

[0106] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2-methoxyethyl)piperazin-1-yl)quinolin-4-amine;

[0107] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)quinolin-4-amine;

[0108] 7-(4-ethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0109] (S)-7-(2,4-dimethylpiperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0110] tert-Butyl 3-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-1-yl)azetidine-1-carboxylate;

[0111] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(piperazin-1-yl)quinolin-4-amine;

[0112] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(1-methylazetidin-3-yl)piperazin-1-yl)quinolin-4-amine;

[0113] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinolin-4-amine;

[0114] 7-(4-(azetidin-3-yl)piperazin-1-yl)-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0115] (R)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol;

[0116] (S)-(4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-1-methylpiperazin-2-yl)methanol;

[0117] tert-Butyl 5-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0118] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinolin-4-amine;

[0119] N-(2-methoxy-4-(2-methoxyethoxy)phenyl)-7-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)quinolin-4-amine;

[0120] 4-(4-((2-methoxy-4-(2-methoxyethoxy)phenyl)amino)quinolin-7-yl)piperazin-2-one;

[0121] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine;

[0122] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(4-methylpiperazin-1-yl)quinolin-4-amine;

[0123] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methylpiperidin-4-yl)quinolin-4-amine;

[0124] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine;

[0125] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0126] 7-methoxy-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0127] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyrazin-2-yl)quinolin-4-amine;

[0128] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(pyridin-2-yl)quinolin-4-amine;

[0129] N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(thiazol-4-yl)quinolin-4-amine;

[0130] 7-(Difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0131] N-(2,4-dimethoxyphenyl)-7-phenylquinolin-4-amine;

[0132] 7-(Difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine;

[0133] 7-(Difluoromethyl)-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0134] 7-(Difluoromethyl)-N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine;

[0135] 7-(difluoromethyl)-N-(2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-yl)quinolin-4-amine;

[0136] 7-(Difluoromethyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)quinolin-4-amine;

[0137] 7-(Difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0138] 7-(Difluoromethyl)-N-(4-fluoro-2-methoxyphenyl)quinolin-4-amine;

[0139] N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine;

[0140] 7-(Difluoromethyl)-N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)quinolin-4-amine;

[0141] 7-(Difluoromethyl)-N-(4-(2-methoxyethoxy)-2-morpholinophenyl)quinolin-4-amine;

[0142] N-(2-cyclopropyloxy-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine;

[0143] 7-(Difluoromethyl)-N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0144] N-(4-chloro-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine;

[0145] N-(4-(1,1-difluoroethyl)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine;

[0146] 7-(Difluoromethyl)-N-(2,4-dimethoxyphenyl)quinolin-4-amine;

[0147] 7-(Difluoromethyl)-N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)quinolin-4-amine;

[0148] 7-(Difluoromethyl)-N-(2-methoxy-4-(methylsulfonyl)phenyl)quinolin-4-amine;

[0149] N-cyclopropyl-4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxybenzamide;

[0150] 7-(Difluoromethyl)-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0151] 7-(Difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)quinolin-4-amine;

[0152] N-(4-(2-cyclopropyloxyethoxy)-2-methoxyphenyl)-7-(difluoromethyl)quinolin-4-amine;

[0153] 7-(Difluoromethyl)-N-(2-fluoro-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0154] 7-(Difluoromethyl)-N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine;

[0155] N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine;

[0156] N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine;

[0157] (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;

[0158] 4-((7-(Difluoromethyl)quinolin-4-yl)amino)-3-methoxy-N-(2-methoxyethyl)benzamide;

[0159] N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine;

[0160] N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-(difluoromethyl)quinolin-4-amine;

[0161] 7-(Difluoromethyl)-N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)quinolin-4-amine;

[0162] 7-(Difluoromethyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinolin-4-amine;

[0163] 7-(Difluoromethyl)-N-(4-methoxy-3-methyl-1H-pyrazol-5-yl)quinolin-4-amine;

[0164] 7-(Difluoromethyl)-N-(2,4-dimethyl-1H-imidazol-5-yl)quinolin-4-amine;

[0165] N-(4-chloro-2-methyl-1H-imidazol-5-yl)-7-(difluoromethyl)quinolin-4-amine;

[0166] N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]oxazol-7-amine;

[0167] N-(7-(difluoromethyl)quinolin-4-yl)-5-methylimidazo[5,1-b]thiazol-7-amine;

[0168] 7-(Difluoromethyl)-N-(1-methylimidazo[1,5-a]pyridin-3-yl)quinolin-4-amine;

[0169] N-(1-bromoimidazo[1,5-a]pyridin-3-yl)-7-(difluoromethyl)quinolin-4-amine;

[0170] 7-(Difluoromethyl)-N-(7-methyl-1H-indol-4-yl)quinolin-4-amine;

[0171] 7-(Difluoromethyl)-N-(7-fluoro-1H-indol-4-yl)quinolin-4-amine;

[0172] N-(7-chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-7-(difluoromethyl)quinolin-4-amine;

[0173] 7-(Difluoromethyl)-N-(4-methylisoquinolin-1-yl)quinolin-4-amine;

[0174] 7-(Difluoromethyl)-N-(4-fluoroisoquinolin-1-yl)quinolin-4-amine;

[0175] 5-chloro-N-(7-(difluoromethyl)quinolin-4-yl)-1,7-naphthyridin-8-amine;

[0176] N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-isopropylquinolin-4-amine;

[0177] N-(4-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine;

[0178] N-(2-methoxy-6-(2-methoxyethoxy)pyridin-3-yl)-7-methylquinolin-4-amine;

[0179] 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;

[0180] N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0181] N-(4-fluoro-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0182] N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0183] N-(4-(2-methoxyethoxy)-2-morpholinophenyl)-7-methylquinolin-4-amine;

[0184] N-(2-methoxy-4-(trifluoromethyl)phenyl)-7-methylquinolin-4-amine;

[0185] N-(2-methoxy-4-(methylsulfonyl)phenyl)-7-methylquinolin-4-amine;

[0186] N-(2-cyclopropyloxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0187] N-(2-(methoxy-d3)-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0188] N-(5-bromo-3-methoxypyrazin-2-yl)-7-methylquinolin-4-amine;

[0189] N-(4-methoxy-2-(2-methoxyethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine;

[0190] N-(4-(cyclopentyloxy)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0191] N-(4-methoxy-2-(2-(trifluoromethoxy)ethoxy)pyrimidin-5-yl)-7-methylquinolin-4-amine;

[0192] N-(4-chloro-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0193] N-(4-(2-isopropoxyethoxy)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0194] N-(2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0195] N-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine;

[0196] N-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0197] N-(4-(Furan-2-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0198] N-(4-(Furan-3-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0199] N-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-7-methylquinolin-4-amine;

[0200] N-(2-methoxy-4-(4-methyl-1H-pyrazol-1-yl)phenyl)-7-methylquinolin-4-amine;

[0201] N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-7-methylquinolin-4-amine;

[0202] N-(2-methoxy-4-(thiophen-2-yl)phenyl)-7-methylquinolin-4-amine;

[0203] N-(2-methoxy-4-(thiophen-3-yl)phenyl)-7-methylquinolin-4-amine;

[0204] N-(7-bromobenzo[d][1,3]dioxol-4-yl)-7-methylquinolin-4-amine;

[0205] 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;

[0206] N-(2-chloro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine;

[0207] N-(2-bromo-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine;

[0208] N-(2-chloro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0209] N-(2-bromo-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0210] (3-methoxy-4-((7-methylquinolin-4-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;

[0211] N-(2-methoxy-6-(5-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0212] 1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0213] N-(2-methoxy-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0214] 1-(1-(6-methoxy-5-((7-methylquinolin-4-yl)amino)pyridin-2-yl)-1H-pyrazol-4-yl)ethan-1-one;

[0215] N-(2-fluoro-4-(2-methoxyethoxy)phenyl)-7-methylquinolin-4-amine;

[0216] N-(2-fluoro-4-(2-(trifluoromethoxy)ethoxy)phenyl)-7-methylquinolin-4-amine;

[0217] N-(2-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0218] N-(4-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0219] N-(3-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-4-amine;

[0220] N-(3-methoxy-5-(1H-pyrazol-4-yl)pyrazin-2-yl)-7-methylquinolin-4-amine;

[0221] N-(4-methoxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine;

[0222] N-(4-methoxy-6-(1H-pyrazol-1-yl)pyridin-3-yl)-7-methylquinolin-4-amine;

[0223] N-(4-methoxy-2-(1H-pyrazol-4-yl)pyrimidin-5-yl)-7-methylquinolin-4-amine;

[0224] 7-methoxy-N-(2-(methoxy-d3)-4-(2-methoxyethoxy)phenyl)quinolin-4-amine;

[0225] N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-methoxyquinolin-4-amine; or

[0226] N-(4-(2-(difluoromethoxy)ethoxy)-2-methoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)quinolin-4-amine.

[0227] The present invention also relates to each intermediate further described below in the Examples section of this specification, including any of these intermediates in the form of a non-salt or salt (e.g., a pharmaceutically acceptable salt) of the corresponding compound. These intermediates can be used, in particular, in the synthesis of compounds of formula (I).

[0228] Various methods for preparing 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 may be prepared according to or in analogy to the synthetic routes described in detail in the Examples section.

[0229] Unless otherwise stated, the following definitions apply throughout the specification and claims.

[0230] The term "hydrocarbyl" refers to a group consisting of carbon and hydrogen atoms.

[0231] The term "alicyclic" is used in conjunction with a cyclic group to indicate that the corresponding cyclic group is non-aromatic.

[0232] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group that can be straight 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 defined, the term "alkyl" preferably refers to a C 1-4 Alkyl more preferably refers to methyl or ethyl, even more preferably refers to methyl.

[0233] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be linear or branched and contains one or more than one (e.g., one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bonds. 2-5 The 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., isopentenyl). Unless otherwise defined, the term "alkenyl" preferably refers to a C 2-4 Alkenyl.

[0234] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be linear or branched and contains one or more than one (e.g., one or two) carbon-carbon triple bonds and optionally one or more than one (e.g., one or two) carbon-carbon double bonds. 2-5 "Alkynyl" means an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (eg, propargyl) or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to a C 2-4 Alkynyl.

[0235] As used herein, the term "alkylene" refers to an alkylidene group, which is a divalent saturated acyclic hydrocarbon group that may be straight-chain or branched. 1-5 "Alkylene" means an alkylene group having 1 to 5 carbon atoms. 0-3 "Alkylene" indicates the presence of a covalent bond (corresponding to option "C0 alkylene") or C 1-3 Alkylene. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)- or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless otherwise defined, the term "alkylene" preferably refers to a C 1-4 Alkylene (including, in particular, straight-chain C 1-4alkylene), more preferably methylene or ethylene, even more preferably methylene.

[0236] As used herein, the term "alkenylene" refers to an alkenylidene group, which is a divalent unsaturated acyclic hydrocarbon group that may be linear or branched and contains one or more than one (e.g., one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bonds. 2-5 "Alkenylene" means an alkenylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to a C 2-4 Alkenylene (including, in particular, straight-chain C 2-4 alkenylene).

[0237] As used herein, the term "alkynylene" refers to an alkynylidene group, which is a divalent unsaturated acyclic hydrocarbon group that may be linear or branched and contains one or more than one (e.g., one or two) carbon-carbon triple bonds and optionally one or more than one (e.g., one or two) carbon-carbon double bonds. 2-5 "Alkynyl" means an alkynyl group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkynylene" preferably refers to a C 2-4 Alkynylidene (including, in particular, straight-chain C 2-4 alkynylene).

[0238] As used herein, the term "carbocyclyl" refers to a hydrocarbon ring group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may be composed of, for example, two or three rings), wherein the ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to an aryl, cycloalkyl or cycloalkenyl group.

[0239] As used herein, the term "heterocyclyl" refers to cyclic groups, including monocyclic rings as well as bridged, spiro and / or fused ring systems (which may be composed of, for example, two or three rings), wherein the cyclic group includes one or more than one (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) may be optionally oxidized, wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxy group), and wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring contained in the cyclic 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 that there is at least one ring carbon atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0240] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system composed of two or three fused rings, wherein at least one of the fused rings is aromatic; or a bridged ring system composed of two or three rings, wherein at least one of the bridged rings is aromatic). If the aryl group is a bridged and / or fused ring system that contains at least one non-aromatic ring (e.g., a saturated ring or an unsaturated aliphatic ring) in addition to one or more aromatic rings, one or more ring carbon atoms in each non-aromatic ring may be optionally oxidized (i.e., to form an oxy group). "Aryl" can be, for example, phenyl, naphthyl, dihydronaphthyl (i.e., 1,2-dihydronaphthyl), tetrahydronaphthyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0241] As used herein, the term "heteroaryl" refers to aromatic ring groups, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of the fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more than one (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) can be optionally oxidized, and wherein one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxy group). For example, each heteroatom-containing ring contained in the aromatic ring group can contain one or two O atoms and / or one or two S atoms (which can be optionally oxidized) and / or one, two, three or four N atoms (which can 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 ring carbon atom (which can be optionally oxidized) in the corresponding heteroatom-containing ring."Heteroaryl" can refer to, for example, thienyl (i.e., phenylthio), 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, benzothienyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridyl; for example, 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 1H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, piperidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 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-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]thienyl (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-

[00145] Examples of the aryl radicals include triazinyl or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl 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 1,4-benzodioxanyl), and coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably a 5- to 10-membered) monocyclic or fused ring system comprising one or more than one (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more than one N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring comprising one or more than one (e.g., one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more than one N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. Furthermore, unless otherwise defined, particularly preferred examples of “heteroaryl” include pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), imidazolyl, thiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, thienyl (i.e., phenylthio) or pyrimidinyl.

[0242] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group, including a monocyclic ring as well as a bridged ring, a spirocyclic ring and / or a fused ring system (which can be composed of, for example, two or three rings; for example, a fused ring system composed of two or three fused rings). "Cycloalkyl" can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl (i.e., decahydronaphthyl) or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to a C 3-11 Cycloalkyl, more preferably refers to C 3-7 Cycloalkyl. A particularly preferred "cycloalkyl" is a 3- to 7-membered monocyclic saturated hydrocarbon ring. Furthermore, unless otherwise defined, particularly preferred examples of "cycloalkyl" include cyclohexyl or cyclopropyl, particularly cyclohexyl.

[0243] As used herein, the term "heterocycloalkyl" refers to a saturated ring group, including monocyclic rings as well as bridged rings, spirocyclic and / or fused ring systems (which may be composed of, for example, two or three rings; for example, a fused ring system composed of two or three fused rings), wherein the ring group contains one or more than one (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) may be optionally oxidized, and wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxy group). For example, each heteroatom-containing ring contained in the saturated cyclic group can contain one or two O atoms and / or one or two S atoms (which can be optionally oxidized) and / or one, two, three or four N atoms (which can be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one ring carbon atom (which can be optionally oxidized) is present in the corresponding heteroatom-containing ring. "Heterocycloalkyl" can, for example, refer to 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, oxadiazol ... alkyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiirane, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thihepanyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]heptan-5-yl. Unless otherwise defined, "heterocycloalkyl" preferably refers to a 3- to 11-membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more than one (e.g., one, two, three, or four) 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 atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5- to 7-membered saturated monocyclic ring group containing one or more than one (e.g., one, two, or three) 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.Furthermore, unless otherwise defined, particularly preferred examples of the "heterocycloalkyl group" include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl or tetrahydrofuranyl.

[0244] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including a monocyclic ring as well as a bridged ring, a spirocyclic and / or fused ring system (which can be composed of, for example, two or three rings; for example, a fused ring system composed of two or three fused rings), wherein the hydrocarbon ring group contains one or more than one (for example, one or two) carbon-carbon double bonds and does not contain any carbon-carbon triple bonds. "Cycloalkenyl" may, for example, refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 Cycloalkenyl, more preferably C 3-7 Particularly preferred "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 members and containing one or more than one (eg, one or two; preferably one) carbon-carbon double bonds.

[0245] As used herein, the term "heterocyclenyl" refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged, spiro and / or fused ring systems (which may be composed of, for example, two or three rings; for example, a fused ring system composed of two or three fused rings), wherein the ring group contains one or more than one (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) may be optionally oxidized, wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxy group), and wherein the ring group includes at least one double bond between adjacent ring atoms and does not include any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated alicyclic ring group can contain one or two O atoms and / or one or two S atoms (which can be optionally oxidized) and / or one, two, three or four N atoms (which can 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 ring carbon atom (which can be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" can, for example, refer to an imidazolinyl group (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), a tetrahydropyridinyl group (e.g., 1,2,3,6-tetrahydropyridinyl), a dihydropyridinyl group (e.g., 1,2-dihydropyridinyl, or 2,3-dihydropyridinyl), a pyranyl group (e.g., 2H-pyranyl, or 4H-pyranyl), a thiopyranyl group (e.g., 2H-thiopyranyl, or 4H-thiopyranyl), a dihydropyranyl group, a dihydrofuranyl group, a dihydropyrazolyl group, a dihydropyrazinyl group, a dihydroisoindolyl group, an octahydroquinolinyl group (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl), or an octahydroisoquinolinyl group (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3- to 11-membered unsaturated alicyclic ring group that is a monocyclic ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more than one (e.g., one, two, three, or four) 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 carbon ring atom between adjacent ring atoms. double bonds and does not contain any triple bonds between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more than one (e.g., one, two, or three) 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 does not contain any triple bonds between adjacent ring atoms.

[0246] As used herein, the term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0247] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more than one (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluorine, chlorine, bromine and iodine, preferably all fluorine atoms. It should be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. For example, "haloalkyl" can, for example, refer to CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3 or -CH(CF3)2. Particularly preferred "haloalkyl" is -CF3.

[0248] The terms "bond" and "covalent bond" are used synonymously herein unless expressly stated otherwise or contradicted by context.

[0249] As used herein, the terms "optional," "optionally," and "may" indicate that the indicated feature may be present, but may also be absent. Whenever the terms "optional," "optionally," or "may" are used, the present invention specifically relates to both possibilities, i.e., the presence of the corresponding feature, or the absence of the corresponding feature. For example, "X is optionally substituted by Y" (or "X may be substituted by Y") means that X is either substituted by Y or not substituted. Similarly, if a component of a composition is indicated as "optional," the present invention specifically relates to both possibilities, i.e., the presence of the corresponding component (included in the composition) or the absence of the corresponding component in the composition.

[0250] In this specification, various groups are referred to as "optionally substituted". Typically, these groups may carry one or more than one substituent, for example one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of available attachment sites on the substituted moiety. Unless otherwise defined, "optionally substituted" groups referred to in this specification preferably carry no more than two substituents, and in particular, may carry only one substituent. Furthermore, unless otherwise defined, preferably no optional substituents are present, i.e., the corresponding group is unsubstituted.

[0251] It will be appreciated by those skilled in the art that the substituents included in the compounds of the present invention can be connected to the remainder of the corresponding compound through many different positions of the corresponding specific substituents. Unless otherwise defined, the preferred connection positions of the various specific substituents are shown in the examples.

[0252] As used herein, unless expressly stated otherwise or contradicted by context, a quantifier preceding an element means "one or more than one" 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 than one" compound of formula (I).

[0253] It should be understood that no matter what numerical range is provided / disclosed herein, all values and subranges contained by the corresponding numerical range are meant to be included within the scope of the present invention. Therefore, the present invention specifically and individually relates to each value falling within the numerical range disclosed herein, and each subrange contained in the numerical range disclosed herein.

[0254] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and especially refers to the exact indicated numerical value. If the term "about" is used in conjunction with the endpoints of a range, it preferably refers to a range from -10% of the indicated numerical value as the lower endpoint to +10% of the indicated numerical value as the upper endpoint, more preferably a range from -5% as the lower endpoint to +5% as the upper endpoint, and even more preferably a range defined by the exact numerical value as the lower and upper endpoints.

[0255] As used herein, the term "comprising" (or "including", "containing", etc.), unless expressly stated otherwise or contradicted by the context, has the meaning of "containing ... and other elements", that is, "containing ..., and other optional elements". In addition, the term also includes the narrower meanings of "essentially consisting of" and "consisting of". For example, the term "A contains B and C" has the meaning of "A contains B and C", where A may contain other optional elements (for example, "A contains B, C and D" will also be included), but the term also includes the meaning of "A mainly consists of B and C" and the meaning of "A consists of B and C" (that is, A does not contain other components other than B and C).

[0256] The scope of the present invention includes all pharmaceutically acceptable salt forms of the compounds of formula (I), which can be formed, for example, by protonation of an atom carrying an electron lone pair that is easily protonated, 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, for example, alkali metal salts such as 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 salts, meglumine salts, ethylenediamine salts, or choline salts; arylalkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridinium salts, picoline salts, quinolinium salts, or isoquinolinium salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or bisulfate), nitrate, phosphate (e.g., phosphate, hydrogenphosphate or dihydrogenphosphate), carbonate, bicarbonate, perchlorate, borate or thiocyanate; organic acid salts such as acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, Pharmaceutically acceptable salts include, but are not limited to, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucono-heptanoate, or pivalate; sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate (isethionate), benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphate; and acidic amino acid salts such as aspartate or glutamate. Other pharmaceutically acceptable salts are described in the literature, for example in Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, 2002, and references cited therein. Preferred pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride.Therefore, it is preferred that the compound of formula (I), including any specific compound of formula (I) described herein, is in the form of a hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate or phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0257] The present invention also particularly relates to compounds of formula (I) in non-salt form, including any one of the specific compounds of formula (I) described herein.

[0258] In addition, the scope of the present invention includes any solvated form of formula (I) compound, including for example solvates (that is, hydrates) with water or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO or acetonitrile. All physical forms of formula (I) compound, including any amorphous or crystalline form (that is, polymorphs), are also included within the scope of the present invention. It should be understood that the pharmaceutically acceptable salts of these solvates and physical forms of formula (I) compound are also included in the present invention.

[0259] In addition, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, original tautomers, such as keto / enol tautomers or thiol / thiol tautomers). All these isomers of the compounds of formula (I) are considered to be part of the present invention, whether in the form of a mixture or in pure or substantially pure form. As for stereoisomers, the present invention includes the isolated optical isomers of the compounds of the present invention and any mixtures thereof (including, in particular, racemic mixtures / racemates). Racemates can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates by forming salts with optically active acids and then crystallizing them. The present invention also includes any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In this case, the formulas provided herein only explicitly describe one possible tautomeric form. The molecular formulas and chemical names provided herein are intended to include any tautomeric form of the corresponding compounds and are not limited to the specific tautomeric form shown in the drawings or identified by the compound name.

[0260] The scope of the present invention also includes compounds of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, the present invention includes compounds of formula (I) in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as "D"). Therefore, the present invention also includes deuterium-enriched compounds of formula (I). Naturally occurring hydrogen is an isotopic mixture containing about 99.98 mol% of hydrogen 1 ( 1 H) and about 0.0156 mol% deuterium ( 2 H or D). The deuterium content of one or more hydrogen positions in the compound of formula (I) can be increased by deuteration techniques known in the art. For example, the compound of formula (I) or the reactants or precursors used to synthesize the compound of formula (I) can be subjected to an H / D exchange reaction with, for example, heavy water (D2O). Other suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20 (18), 5658-5667, 2012; William JS et al., Journal of Labelled 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, by using mass spectrometry or NMR spectroscopy. Unless otherwise specified, it is preferred that the compound of formula (I) is not enriched in deuterium. Therefore, it is preferred that the naturally occurring hydrogen atoms or 1 H hydrogen atom.

[0261] The present invention also includes compounds of formula (I) in which one or more atoms are substituted by positron-emitting isotopes of the corresponding atoms, e.g. 18 F. 11 C. 13 N. 15 O. 76 Br, 77 Br, 120 I and / or 124 I. Such compounds are useful as tracers, tracking agents or imaging probes in positron emission tomography (PET). Thus, the present invention includes (i) compounds of formula (I) wherein one or more than one fluorine atom (or, for example, all fluorine atoms) is 18 F atom replacement, (ii) a compound of formula (I) in which one or more than one carbon atom (or, for example, all carbon atoms) is replaced by 11 C atom replacement, (iii) a compound of formula (I) in which one or more than one nitrogen atom (or, for example, all nitrogen atoms) is replaced by 13 N atom, (iv) a compound of formula (I) in which one or more than one oxygen atom (or, for example, all oxygen atoms) is replaced by 15 O atom, (v) a compound of formula (I) wherein one or more than one bromine atom (or, for example, all bromine atoms) is replaced by 76Br atoms, (vi) compounds of formula (I) in which one or more than one bromine atom (or, for example, all bromine atoms) is replaced by 77 Br atoms, (vii) compounds of formula (I) wherein one or more than one iodine atom (or, for example, all iodine atoms) is replaced by 120 I atom, and (viii) compounds of formula (I) in which one or more than one iodine atom (or, for example, all iodine atoms) is replaced by 124 I atom substitution. In general, it is preferred that no atom in the compounds of formula (I) is replaced by a specific isotope.

[0262] The compounds provided herein can be administered as the compounds themselves or can be formulated into pharmaceuticals. The pharmaceutical / pharmaceutical compositions can optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0263] The pharmaceutical composition may comprise one or more solubility enhancers, such as poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight ranging from about 200 Da to about 5000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tetrabutylamyl, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., HS15, CAS 70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucose methyl-β-cyclodextrin, carboxyalkyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0264] The pharmaceutical composition may further comprise one or more preservatives, in particular one or more antimicrobial preservatives, such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), 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.

[0265] The pharmaceutical composition can be formulated by techniques known to those skilled in the art, such as those disclosed in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22nd edition. The pharmaceutical composition can be formulated into oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal) dosage forms. Oral dosage forms include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gelatin, chewable tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersants, and powders and granules for reconstitution. Emulsions are preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovulas. Dosage forms for nasal administration can be administered by inhalation and insufflation, for example, by a metered dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0266] The compound of formula (I) or the above-mentioned pharmaceutical composition comprising the compound of formula (I) can be administered to the subject by any convenient route of administration, whether systemically / peripherally or at the desired site of action, including but not limited to one or more of the following: orally (e.g., as a tablet, capsule or as an ingestible solution), topically (e.g., transdermally, intranasally, ocularly, buccally and sublingually), parenterally (e.g., using injection techniques or infusion techniques, and including, for example, by injection, such as subcutaneously, Administration may be intradermal, intramuscular, intravenous, intraarterial, intracardial, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, or intrasternal, by, for example, implantation of a reservoir, e.g., subcutaneous or intramuscular), pulmonary (e.g., by inhalation or insufflation therapy, e.g., through the mouth or nose, using, for example, an aerosol), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal, or vaginal.

[0267] If the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following routes: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracardial, intracranial, intramuscular or subcutaneous administration of the compound or pharmaceutical composition, and / or by using infusion techniques. For parenteral administration, the compounds are preferably used in the form of sterile aqueous solutions, which may contain other substances, for example, salts or glucose sufficient to make the solution isotonic with blood. If necessary, the aqueous solution should be suitably buffered (preferably at a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0268] The compound or pharmaceutical composition can also be orally administered in the form of tablets, capsules, oval suppositories, elixirs, solutions or suspensions, which can contain flavorings or coloring agents for quick release, delayed release, modified release, sustained release, pulse release or controlled release applications. Tablets can contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine, disintegrants such as starch (preferably corn starch, potato starch or tapioca starch), sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and some composite silicates, and granulation binders such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc can also be included. Similar types of solid compositions can also be used as fillers in gelatin capsules. In this regard, preferred excipients include lactose, starch, cellulose or high molecular weight polyethylene glycol. For aqueous suspensions and / or elixirs, the compound may be combined with various sweetening or flavoring agents, coloring materials or dyes, with emulsifying and / or suspending agents, and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0269] For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, particularly swallowing. Thus, the compound or pharmaceutical composition can be administered to enter the gastrointestinal tract through the mouth, which can also be referred to as "oral-gastrointestinal" administration.

[0270] Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or pessary, or 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 or transdermally, for example, by use of a skin patch.

[0271] 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 molded articles, such as films or microcapsules. Sustained-release matrices include, for example, polylactic acid, a copolymer 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 liposome-encapsulated compounds. Therefore, the present invention also relates to liposomes containing the compounds of the present invention.

[0272] The compounds or pharmaceutical compositions may also be administered via the pulmonary, rectal or ocular routes. For ocular administration, they may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably, as solutions in isotonic, pH-adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0273] It is also contemplated that dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation, may be prepared. Such dry powders may be prepared by spray drying under conditions that produce a substantially amorphous glassy or substantially crystalline biologically active powder. Thus, dry powders of the compounds of this invention may be prepared according to an emulsification / spray drying process.

[0274] 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, for example, with one or more of the following substances: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they can be formulated into a suitable lotion or cream suspended or dissolved in a mixture, for example, of one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol, and water.

[0275] Thus, the present invention relates to compounds or pharmaceutical compositions provided herein, wherein the corresponding compounds or pharmaceutical compositions are administered by any of the following: oral route; topical route, including transdermal, intranasal, ocular, buccal or sublingual route; parenteral route using injection techniques or infusion techniques, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ocular route, including intravitreal or intracameral route; rectal route; or vaginal route.

[0276] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dosage level and frequency of administration for any particular individual subject can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of the compound, age, weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual subject being treated.

[0277] Compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) can be administered as monotherapy (e.g., without administering any other therapeutic agent at the same time, or without administering any other therapeutic agent at the same time for the same disease to be treated or prevented by compounds of formula (I)). However, compounds of formula (I) or pharmaceutical compositions comprising compounds of formula (I) can also be administered in combination with one or more other therapeutic agents. If compounds of formula (I) are used in combination with a second therapeutic agent active for the same disease or condition, the dosage of each compound can be different from the dosage when the corresponding compound is used alone, and in particular, each compound of a lower dose can be used. The combination of compounds of formula (I) and one or more other therapeutic agents can include administration of compounds of formula (I) and other therapeutic agents simultaneously / concomitantly (in the form of a single pharmaceutical preparation or a separate pharmaceutical preparation), or administration of compounds of formula (I) and other one or more therapeutic agents in sequence / separately. If administration is sequential, compounds of formula (I) according to the present invention or one or more other therapeutic agents can be administered first. If administered simultaneously, the one or more than one other therapeutic agent may be contained in the same pharmaceutical formulation as the compound of formula (I), or they may be administered in two or more different (separate) pharmaceutical formulations.

[0278] For the treatment or prevention of cancer, one or more other therapeutic agents administered in combination with the compounds of the present invention (or corresponding pharmaceutical compositions) are preferably anticancer drugs. One or more anticancer drugs administered in combination with the compounds of formula (I) according to the present invention can, for example, be selected from: 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 drugs or antimitotic alkaloids); platinum coordination complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine agents (e.g., adrenocortical steroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists or somatostatin analogs); or compounds targeting enzymes or receptors of specific metabolic pathways that are overexpressed in tumor cells and / or otherwise involved in dysregulation (or misregulation) (e.g., ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitor) 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.

[0279] Alkylating agents that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, nitrogen mustards (such as cyclophosphamide, dichloromethyldiethylamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine or trofosfamide), nitrosoureas (such as carmustine, streptozotocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine or semustine), alkyl sulfonates (such as busulfan, mannosulfuron or trooxsulfuron), aziridines (such as hexamethylmelamine (altretamine), triethylenemelamine, diamidophos (N,N',N'-triethylenethiophosphoramide), carbaquinone or triimidoquinone), hydrazines (such as procarbazine), triazenes (such as dacarbazine) or imidazotetrazines (such as temozolomide). The platinum coordination complex that can be used as an anticancer drug in combination with the compound of the present invention can be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin or triplatinum tetranitrate. The cytotoxic drug that can be used as an anticancer drug in combination with the compound of the present invention can be, for example, an antimetabolite, 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). The antimitotic agent that can be used as an anticancer drug in combination with the compounds of the present invention can be, for example, a taxane (e.g., docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel or nab-paclitaxel (e.g. ), vinca alkaloids (such as vinblastine, vincristine, vinflunine, vindesine or vinorelbine), epothilones (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E or epothilone F) or epothilone B analogs (such as ixabepilone / azaepothilone B). The antitumor antibiotics that can be used as anticancer drugs in combination with the compounds of the present invention may be, for example, anthracyclines (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin or daurubicin), anthraquinones (such as mitoxantrone or pixantrone) or antitumor antibiotics isolated from Streptomyces (such as actinomycins (including actinomycin D), bleomycin, mitomycins (including mitomycin C) or plicamycin). Tyrosine kinase inhibitors that can be used in combination with the compounds of the present invention as anticancer drugs can be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib, vemurafenib. Topoisomerase inhibitors that can be used in combination with the compounds of the present invention as anticancer drugs can be, for example, topoisomerase I inhibitors (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan or lamelliposide D) or topoisomerase II inhibitors (such as amsacrine, etoposide, etoposide phosphate, teniposide or doxorubicin). The PARP inhibitor that can be used as an anticancer drug in combination with the compound of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP 9722, MK4827, E7016 or 3-aminobenzamide. EGFR inhibitors / antagonists that can be used in combination with the compounds of the present invention as anticancer drugs can be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, 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 anticancer drugs can also be used in combination with the compounds of the present invention.Anticancer drugs may include biological or chemical molecules such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, ilofufen, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, iproxicam, porfibrin sodium, talaporin, temoporphin, vetiracetam, vinpoxetine ... Porofin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, colchicine, ilisimol, elsamitrucin, etogluconol, lonidamine, sulcanone, masopropol, dibromomannitol, mitoguanzone, mitotane, oblimersen sodium, homoharringtonine, sitimagene, ceradenovec, tegafur, testolactone, thiazofurine, tipifarnib, vorinostat, iniparib, or cupanisib.

[0280] The anticancer drug that can be used in combination with the compounds of the present invention can also be an immuno-oncology therapeutic agent (such as an antibody (e.g., a monoclonal antibody or a polyclonal antibody), an antibody fragment, an antibody construct (e.g., a single-chain construct), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a "fully human" antibody) that targets, for example, any of CTLA-4, PD-1, PD-L1, TIGIT, TIM3, LAG3, OX40, CSF1R, IDO, or CD40. Such immuno-oncology therapeutic agents include, for example, anti-CTLA-4 antibodies (particularly antagonistic or pathway-blocking anti-CTLA-4 antibodies; for example, ipilimumab or simumab), anti-PD-1 antibodies (particularly is an antagonist or pathway-blocking anti-PD-1 antibody; for example, nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab (CT-011), cemiprilimab, dotalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, sepalizumab, AMP-224, AMP-514 (or MEDI0680), JTX-4014, INCMGA00012 (or MGA012), or APE02058), an anti-PD-L1 antibody (particularly a pathway-blocking anti-PD-L1 antibody; for example, atezolizumab, avelumab, durvalumab, KN035 , CK-301, BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, MEDI6469 or Bitefup α), anti-TIGIT antibodies (e.g., tislelizumab, vebollimumab, dunalimab, ipilimumab, 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; for example, relalizumab ( or BMS-986016), elalimumab (or LAG525), ansalizumab (or TSR-033), tepolizumab (or MGD013), REGN3767 (or R3767), FS118, IMP701 or IMP731), an anti-OX40 antibody (particularly an agonistic anti-OX40 antibody; for example, MEDI0562), an anti-CSF1R antibody (particularly a pathway-blocking anti-CSF1R antibody; for example, IMC-CS4 or RG7155), an anti-IDO antibody (particularly a pathway-blocking anti-IDO antibody) or an anti-CD40 antibody (particularly an agonistic anti-CD40 antibody; for example, CP-870,893 or Chi Lob 7 / 4).Other examples of immuno-oncology therapeutics include anti-HER2 antibodies (eg, trastuzumab), anti-CD20 antibodies (eg, rituximab), anti-CD19 / CD3 constructs, and anti-TNF antibodies.

[0281] In particular, the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can be administered in combination with an immune checkpoint inhibitor, preferably in combination with an antibody (or an antigen-binding fragment thereof, or an antibody construct) against CTLA-4, PD-1, PD-L1, TIGIT or LAG3. Corresponding preferred examples include, but are not limited to, any of the anti-CTLA-4 antibodies ipilimumab or simumab, any of the anti-PD-1 antibodies nivolumab, pembrolizumab, pidilizumab, cemiplizumab, dotalizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalizumab, sepalizumab, AMP-224, AMP-514, JTX-4014, INCMGA00012 or APE02058, any of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MED Any of I4736, MPDL3280A, MDX-1105, MEDI6469 or Bitufupu α, any of the anti-TIGIT antibodies tislelizumab, vebollimumab, dunalizumab, etilizumab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939 or M6223, and / or any of the anti-LAG3 antibodies relarilimab, elaralimumab, ansarilimumab, tepolizumab, REGN3767, FS118, IMP701 or IMP731.Therefore, the present invention 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 treating or preventing cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more immune checkpoint inhibitors, wherein the 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, the one or more immune checkpoint inhibitors are selected from ipilimumab, simumab, nivolumab, pembrolizumab, pidilizumab, cemiprilimab, dotalimab, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, sepalimab, AMP -224, AMP-514, JTX-4014, INCMGA00012, APE02058, atezolizumab, avelumab, durvalumab, KN035, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, Bituximab alfa, tislelizumab, vebollimumab, duralizumab, etilizumab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, relalizumab, elaralimumab, ansarizumab, tepolizumab, REGN3767, FS118, IMP701, and IMP731.

[0282] The above combination can be conveniently provided for use in the form of pharmaceutical preparations. The individual components of this combination can be administered sequentially or simultaneously / concomitantly in the form of pharmaceutical preparations, either alone or in combination, by any convenient approach. When administered sequentially, the compound of the present invention (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or another therapeutic agent can be administered first. When administered simultaneously, the combination can be administered with the same pharmaceutical composition or with different pharmaceutical compositions. When combined in the same preparation, it should be understood that two or more compounds must be stable and compatible with each other and with other components of the preparation. When formulated separately, they can be provided in any convenient dosage form and can be administered by any convenient approach.

[0283] Formula (I) compound can also be co-administered with physical therapy such as radiotherapy. Radiotherapy can start before, after or simultaneously with the administration of the compounds of this invention. For example, radiotherapy can start about 1 minute to 10 minutes, about 1 hour to 10 hours or about 24 hours to 72 hours after the administration of the compounds of formula (I). Object / patient is exposed to radiation, preferably gamma radiation, thus can provide radiation in a single dose or in multiple doses administered in a few hours, a few days and / or a few weeks. Gamma radiation administration can be carried out using standard doses and protocols according to standard radiotherapy protocols.

[0284] Therefore, the present invention 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 treating or preventing cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more anticancer drugs (including any one or more than one specific anticancer drugs mentioned above) and / or in combination with radiotherapy.

[0285] However, the compounds of formula (I) can also be used in monotherapy, in particular in the treatment or prevention of cancer as a monotherapy (i.e., no other anticancer agent is administered before the end of treatment with the compound of formula (I)). Therefore, the present invention also 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 monotherapy or prevention of cancer.

[0286] In addition, the compounds of formula (I) can also be administered in combination with one or more than one other anticancer agent (including any of the exemplary anticancer agents described above) or without any other anticancer agent in combination with an antiemetic agent. The antiemetic agent is selected from, for example, alosetron, azasetron, bemisetron, cilansetron, clozapine, dazopril, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (e.g., palonosetron alone or in combination with netupitant), quetiapine, lamosetron, licarsetron, tropisetron, zatosetron, clozapine, cyproheptadine, hydroxyzine, olanzapine, risperidone, ziprasidone, dronabinol, nabilone, tetrahydrocannabinol, azanol, sirolimus ... Lispride, brompride, chlorpromazine, clebopride, domperidone, haloperidol, hydroxyzine, itopride, metoclopramide, metoprazine, prochlorperazine, ethioperazine, trimethobenzamide, cyclizine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, promethazine, atropine, diphenhydramine, scopolamine, scopolamine, aprepitant, casopitant, elopitant, fosaprepitant, maropitant, netupitant, rolapitant, vertipant, cerium oxalate, dexamethasone, lorazepam, midazolam, propofol, or a combination thereof. Preferably, the antiemetic drug is a 5-HT3 antagonist (or "setron"), such as alosetron, azasetron, bemisetron, cilansetron, clozapine, dazopril, dolasetron, granisetron, nerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (optionally in combination with netupitant), quetiapine, ramosetron, licarsetron, tropisetron, or zaltosetron.

[0287] The subject or patient to be treated according to the present invention can 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., male or female) 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, cattle, or pig). Most preferably, the subject / patient to be treated according to the present invention is a human.

[0288] As used herein, the term "treatment of a condition or disease" is well known in the art. "Treatment" of a condition or disease means that a patient / subject is suspected of or has been diagnosed with the condition or disease. A patient / subject suspected of having a condition or disease typically exhibits specific clinical and / or pathological symptoms that a skilled artisan can readily attribute to a specific pathological condition (i.e., diagnose the condition or disease).

[0289] "Treatment" of a disorder or disease can, for example, result in a cessation of the progression of the disorder or disease (e.g., no worsening of symptoms) or a delay in the progression of the disorder or disease (when the cessation of progression is only temporary). "Treatment" of a disorder or disease can also result in a partial response (e.g., an improvement in symptoms) or a complete response (e.g., the disappearance of symptoms) in the subject / patient suffering from the disorder or disease. Thus, "treatment" of a disorder or disease can also refer to an improvement in the disorder or disease, which can, for example, result in a cessation of the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such partial or complete remission may be followed by relapse. It should be understood that the subject / patient may experience a wide range of responses to treatment (such as the exemplary responses described above). Treatment of a disorder or disease can particularly include therapeutic treatment (preferably resulting in a complete response and ultimately resulting in healing of the disorder or disease) and palliative treatment (including symptomatic relief).

[0290] The term "prevention" used herein is also well known in the art. For example, patients / objects suspected of being susceptible to a disease or disease may particularly benefit from the prevention of a disease or disease. Objects / patients may have a susceptibility or susceptibility to disease, including but not limited to genetic susceptibility. This tendency can be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It should be understood that the disease or disease to be prevented according to the present invention has not yet been diagnosed or cannot be diagnosed in the patient / object (for example, the patient / object does not show any clinical or pathological symptoms). Therefore, the term "prevention" includes using the compounds of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0291] It should be understood that the present invention is specifically directed to each combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. Specifically, the present invention is specifically directed to each combination of the meanings (including general and / or preferred meanings) of the various groups and variables included in formula (I).

[0292] Throughout this specification, numerous references are cited, including patent applications and scientific literature. The disclosures of these references, while not considered relevant to the patentability of the present invention, are hereby incorporated by reference in their entirety. More specifically, all references are incorporated herein by reference to the same extent as if each individual reference were specifically and individually indicated to be incorporated herein by reference.

[0293] Reference in this specification to any prior disclosure (or information obtained therefrom) is not and should not be taken as an admission or acknowledgement or any form of suggestion that the corresponding prior disclosure (or information obtained therefrom) forms part of the common general knowledge in the technical field to which this specification relates.

[0294] The present invention is further illustrated by the following drawings:

[0295] Figure 1 : Western blot analysis results of NIK degradation in A375 cells treated with 10 μM of the compound of Example 3 for 72 hours (see Example 143).

[0296] The following examples further illustrate the present invention. The compounds of formula (I) described in the Examples are defined by their chemical formulas and their corresponding chemical names. In the event of a conflict between any chemical formula and the corresponding chemical name described herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and in particular to the compound defined by the chemical formula. Example

[0297] Introduction

[0298] The compounds of the present invention can be synthesized, for example, as shown with reference to the compounds of Examples 1 to 142 in Schemes 1 to 4 below:

[0299] Solution 1

[0300] Example 1 can be prepared according to the following reaction scheme 1:

[0301]

[0302] Compound 1 can be synthesized from 7-bromo-4-chloroquinoline and phenylboronic acid via a Suzuki coupling reaction, followed by coupling between compound 1 and 2-methoxy-4-(2-methoxyethoxy)aniline to give Example 1.

[0303] Option 2

[0304] Example 3, Example 9 to Example 10, Example 39 to Example 40, Example 46 to Example 55, Example 58 to Example 65, Example 71 to Example 72, Example 75 to Example 89, Example 103 to Example 110, Example 115, Example 119, Example 121, Example 126 to Example 130, Example 133 and Example 135 to Example 139 can be prepared according to the following reaction scheme 2:

[0305]

[0306] A mixture of the desired 4-chloroquinoline and the corresponding aniline was refluxed at 80°C.

[0307] Option 3

[0308] Example 2, Example 4 to Example 8, Example 11 to Example 44, Example 56 to Example 57, Example 66 to Example 70, Example 73 to Example 74, Example 101 to Example 102, Example 122 to Example 125 and Example 131 to Example 132 can be prepared according to the following reaction scheme 3:

[0309]

[0310]

[0311] 1: A mixture of the desired 4-chloroquinoline and 4-amino-3-methoxyphenol was stirred at 80°C overnight.

[0312] 2: A mixture of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol and 2-methoxyethyl-4-methylbenzenesulfonate or 1-bromo-2-(trifluoromethoxy)ethane is stirred at 60°C in the presence of cesium carbonate.

[0313] 3: The desired 7-bromoquinoline is coupled with the desired aryl-tributyltin group using a Stille coupling reaction.

[0314] 4: The desired 7-bromoquinoline is coupled with the desired boronic acid using a Suzuki coupling reaction.

[0315] 5: The desired 7-bromoquinoline is coupled with the desired amine using a Buchwald coupling reaction.

[0316] 6: The desired olefin was hydrogenated using Pd / C and H2 (5 bar).

[0317] 7: Deprotection of the desired Boc-protected amine under acidic conditions.

[0318] 8: The desired Boc-protected amine is reduced to the corresponding methylamine using lithium aluminum hydride.

[0319] Option 4

[0320] Examples 111 to 114, 116 to 118, 120, and 134 can be prepared according to the following reaction scheme 4:

[0321]

[0322] A mixture of the desired 4-chloroquinoline and the corresponding aniline was refluxed at 80 °C and then the corresponding bromo derivative and the desired boronic acid were coupled using Suzuki coupling conditions.

[0323] Experimental part

[0324] Several methods for preparing the compounds of the present invention are described in the following examples. Reagents were obtained from commercial sources and used without further purification. All temperatures are in °C. TLC was performed on aluminum-backed silica gel plates with a fluorescent indicator at 254 nM (median pore size). Flash column chromatography was performed using a Biotage Isolera One system using KP-Sil or Ultra silica gel columns, or an Isco CombiFlash Rf using FlashPure or RediSep Rf / RediSep Rf gold silica gel columns. NMR spectra were recorded on a 400 MHz or 500 MHz spectrometer at ambient probe temperature (nominal 298 K). Chemical shifts (δ) are expressed in ppm and were calibrated using the residual peak of the solvent as an internal standard (CDCl3, δ = 7.26 ppm; DMSO-d6, δ = 2.50 ppm). Coupling constants are expressed in Hertz (Hz). Analyses were performed using an Advion PlateExpress equipped with an APCI source. A compact mass spectrometer recorded the LRMS.

[0325] LCMS analysis was performed using a Waters Acquity UPLC equipped with a CSH C18 column or a BEH C18 column (2.1 x 30 mm) at 40°C with a flow rate of 0.77 mL / min and a linear 2% to 100% acetonitrile gradient appropriate to the lipophilicity of the compound over 3 minutes or 10 minutes. 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 between 210 nm and 400 nm using a Waters Acquity photodiode array detector. Mass spectra were recorded using a Waters Acquity QDa detector with ESI switched between positive and negative ion modes.

[0326] Method A

[0327] Instrument: Waters HClass; Quaternary solvent pump, SM-FTN, CMA, PDA: 210 nm to 400 nm, QDa: ACQ-QDaESI; Column: Waters CSH C18, 30 mm x 2.1 mm, 1.7 μm, Temperature: 40°C, Flow rate: 0.77 mL / min, Gradient: t0 = 2% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0328] Method B

[0329] Instrument: Waters HClass; binary solvent pump, SM-FTN, CMA, PDA: 210 nm to 400 nm, QDa: ACQ-QDaESI; column: Waters BEH C18, 30 mm x 2.1 mm, 1.7 μm, temperature: 40°C, flow rate: 0.77 mL / min, gradient: t0 = 2% B, t2.5 min = 100% B, t3.0 min = 100% B, eluent A: 0.1% NH3 in water, eluent B: acetonitrile.

[0330] Method C

[0331] Instrument: Waters HClass; Quaternary solvent pump, SM-FTN, CMA, PDA: 210 nm to 400 nm, QDa: ACQ-QDaESI; Column: Waters CSH C18, 30 mm x 2.1 mm, 1.7 μm, Temperature: 40°C, Flow rate: 0.77 mL / min, Gradient: t0 = 2% B, t9.5 min = 100% B, t10.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0332] Method D

[0333] Instrument: Waters HClass; binary solvent pump, SM-FTN, CMA, PDA: 210 nm to 400 nm, QDa: ACQ-QDaESI; column: Waters BEH C18, 30 mm x 2.1 mm, 1.7 μm, temperature: 40°C, flow rate: 0.77 mL / min, gradient: t0 = 2% B, t9.5 min = 100% B, t10.0 min = 100% B, eluent A: 0.1% NH3 in water, eluent B: acetonitrile.

[0334] Method E

[0335] Instrument: Agilent 1260; binary pump, HiP sampler, column compartment, DAD: 260+ / -90 nm, G6150 MSD: ESI; column: Waters Cortecs C18, 30 mm 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.

[0336] General steps

[0337] For substituted 4-chloroquinoline S N General Procedure A for Ar

[0338] A solution of the desired 4-chloroquinoline (1.0 equivalent) and 2-methoxy-4-(2-methoxyethoxy)aniline (1.2 equivalents) in EtOH (2 mL) was heated to 80° C. and stirred for 18 hours. 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.

[0339] Acid-catalyzed S-terminal catalysis of substituted 4-chloroquinolines N General Procedure B for Ar

[0340] To the solution of desired 4-chloroquinoline (1.0 equivalent) and desired aniline (1.2 equivalent) in IPA (0.3M), add HCl, 4.0M solution in dioxane (1.2 equivalent).Reaction mixture is heated to 80 DEG C, and stirred 18 hours.Evaporating solvent, residue is dissolved in acetone (5mL), then ultrasonically processed to form suspension.Precipitation is collected by vacuum filtration, washed with acetone (10mL x 3), then optionally by silica gel column chromatography or reversed-phase preparative HPLC purifying.If necessary, optionally using 4.0M HCl in dioxane, final product is converted into HCl salt, then dried at 50 DEG C in vacuum dessicator, obtain title compound.

[0341] General Procedure C for the Suzuki Reaction of 7-Bromoquinoline

[0342] To a stirred solution of the desired 7-bromoquinoline (1.0 equivalent) in 1,4-dioxane (2 mL) was added K2CO3 (3.0 equivalents) at room temperature. The reaction mixture was degassed by bubbling a stream of nitrogen through the reaction mixture for 10 minutes. To this mixture was added the desired boronic acid (2.0 equivalents) 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.

[0343] General Procedure D for the Buchwald Reaction of 7-Bromoquinoline

[0344] To a stirred solution of the desired 7-bromoquinoline in 1,4-dioxane (4 mL) was added the desired amine (2.0 equivalents) at room temperature. A stream of nitrogen was bubbled through the mixture for 10 minutes to degas the mixture. 2.0 M NaOt-Bu (5.0 equivalents) and RuPhos Pd G3 (10 mol %) in THF were added to the mixture. 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.

[0345] Step E of the Buchwald Reaction of 7-Bromoquinoline and Piperazin-2-one

[0346] To a reaction vessel was added 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, the reaction mixture was degassed with nitrogen, and heated to 120° C. under microwave irradiation for 2 hours. Aqueous workup (DCM-MeOH 9:1 / water) followed by preparative HPLC afforded the title compound.

[0347] General Procedure F for the Hydrogenation of Olefin and Nitro Intermediates

[0348] To a stirred solution of the olefin in a 4:1 mixture of EtOH and MeOH (5 mL) was added 10% Pd / C (50 wt% water, 0.1 eq) in EtOH (1 mL) at room temperature. The mixture was then hydrogenated with H (5 bar) for 24 h. The reaction mixture was filtered and the solution was concentrated in vacuo to afford the title compound.

[0349] General Procedure G for Stille Coupling of 7-Bromoquinoline

[0350] In a sealed tube, at room temperature, the desired 7-bromoquinoline (1 equivalent) was added to a degassed stirring solution in DMF (0.15 mole), lithium chloride (3.0 equivalents), tetrakis(triphenylphosphine)-palladium(0) (10 mol %), and then the desired aryl-tributyltin base (3.0 equivalents) was added. The reaction was heated to 110°C and stirred for 3 hours. The reaction was cooled to room temperature, and then MeCN (40mL) was added. The acetonitrile solution was extracted with heptane (5x10mL). Potassium fluoride (2g) and sodium sulfate (2g) were added to the acetonitrile phase, and then the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0.7M NH3 was dissolved in MeOH / DCM). The product was further purified by preparative HPLC to obtain the title compound.

[0351] General Procedure H for Deprotection of Boc-Protected Amines

[0352] A solution of the boc-protected amine (1 eq) and HCl (4 M in dioxane) (20 eq) in THF (1.00 mL) was stirred at 40° C. for 18 h. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (0.7 M NH in MeOH / DCM) to afford the title compound.

[0353] General Procedure I for the Reduction of Boc-Protected Amines to the Corresponding Methylamines

[0354] A solution of boc-protected amine (1 equivalent) in THF (0.05 mole) was cooled to 0°C and then 1.0M LiAlH (5.49 equivalents) in THF was added dropwise. The reaction was stirred at 0°C for 10 minutes, then at room temperature for 15 minutes, and then heated to 65°C and stirred for 3 hours. The reaction mixture was then cooled to 0°C and quenched with water (200 μL) and 2M NaOH solution (150 μL). The suspension was filtered and washed with THF (5mL), EtOAc (10mL) and DCM (20mL) in sequence. The filtrate was concentrated under reduced pressure. The crude product was further purified by trituration in cold EtO to obtain the title compound.

[0355] General Procedure J for the Alkylation of Phenol with Alkyl Tosylate

[0356] A mixture of desired phenol (1 equivalent), 2-(trifluoromethoxy)ethyl 4-toluenesulfonate (1.05 equivalents) and cesium carbonate (2.1 equivalents) in acetone (0.08 mole) was stirred at 60 ° C for 18 hours. The solvent was removed in vacuo, and the residue was ground in water (20ml), and the solid was collected by vacuum filtration. The crude product was purified by silica gel chromatography ([0.7M ammonia / MeOH] / DCM), and the resulting material was dissolved in 4M HCl in dioxane (2mL), and the solvent was removed in vacuo. The residue was dissolved in MeOH (2mL) and then concentrated (3 times). The residue was then ground in ether, the resulting solid was collected and dried to obtain the title compound.

[0357] General Procedure K for Suzuki Reaction with N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine

[0358] A solution of N-(4-bromo-2-methoxyphenyl)-7-methylquinolin-4-amine (1 equivalent), the desired boronic acid (2.0 equivalents) and K CO (3 equivalents) in a mixture of toluene / EtOH / H O (1 / 0.5 / 0.25) was degassed by bubbling 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 removed in vacuo. The crude product was purified by silica gel chromatography to give the title compound.

[0359] Preparation of synthetic intermediates

[0360] Preparation of compound 1 (4-chloro-7-phenylquinoline):

[0361] 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 micromoles) were added to the reaction vessel. The reaction vessel was evacuated and purged with nitrogen, and 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, and then stirred at 80 ° C for 18 hours. The reaction mixture was distributed between EtOAc (20 mL) and saturated NH4Cl (20 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (10 mL x 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 gel (40 g column, gradient elution 0% to 50% (10% MeOH in DCM) / isohexane) to afford 4-chloro-7-phenylquinoline (570 mg, 55%) as a white solid.

[0362] UPLC (Method A): m / z 240.3 [M+H] + , at 2.19 minutes.

[0363] 1 H NMR (400 MHz, chloroform-d) δ 8.81 (d, J = 4.7 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 7.94 (dd, J = 8.7, 1.8 Hz, 1H), 7.80-7.73 (m, 2H), 7.57-7.48 (m, 3H), 7.48-7.40 (m, 1H).

[0364] Preparation of compound 2 (4-chloro-7-(difluoromethyl)quinoline):

[0365] At room temperature, add 50% deoxyfluorine (deoxofluor) (420mg, 350 μ L, 50 weight %, 1.10 equivalents, 949 micromoles) that is dissolved in toluene to 4-chloroquinoline-7-formaldehyde (166mg, 1 equivalent, 866 micromoles) in the solution in dry DCM (2mL).Reaction mixture is stirred at room temperature and spend the night.Reaction mixture is at DCM (10mL) and saturated NaHCO Between (10mL), distribute, and separate each phase.Aqueous phase is extracted with DCM (10mL x 2), and the organic phase washed with salt water (20mL) that merges is used MgSO Drying, filter, remove solvent in vacuo.Crude product drying is supported on silicon dioxide, by silica gel chromatography (12g post, 0% to 50% MTBE / isohexane) purifying, obtain 4-chloro-7-(difluoromethyl) quinoline (119mg, 0.53 mmole, 61%, 95% purity) as white solid.

[0366] UPLC (Method A): m / z 214.1 [M+H]+ at 1.73 minutes.

[0367] 1H 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).

[0368] Preparation of compound 3 (4-chloro-7-(1-methyl-1H-pyrazol-4-yl)quinoline):

[0369] To a reaction vessel was added 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 reaction vessel was evacuated and purged with nitrogen, followed by the addition of a 4:1 mixture of 1,4-dioxane (0.3 M). 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). To 4-[ ...

[0370] UPLC (Method A): m / z 244.0 [M+H]+ at 1.38 minutes.

[0371] 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).

[0372] Preparation of compound 4 (2-(methoxy-d3)-4-(2-methoxyethoxy)-1-nitrobenzene):

[0373] In a sealed tube, K2CO3 (750 mg, 5.42 mmol) and iodomethane-d3 (1.0 g, 6.9 mmol) were added to a stirred solution of 5-(2-methoxyethoxy)-2-nitrophenol (771 mg, 3.62 mmol) in acetone (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 7 days. Saturated NaHCO3 aqueous solution (20 mL) was added to the reaction. The mixture was extracted with DCM (3 x 40 mL), and the combined organic phases were washed with brine (20 mL), dried by a separator, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (40 g column, 10% to 100% [1:4 MeOH was dissolved in EtOAc] / isohexane) to obtain 2-(methoxy-d3)-4-(2-methoxyethoxy)-1-nitrobenzene (237 mg, 1.03 mmol, 29%) as a light yellow powder.

[0374] LCMS (Method E): m / z 231.1 [M+H]+ at 1.23 min.

[0375] 1H 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).

[0376] Preparation of compound 5 (2-(methoxy-d3)-4-(2-methoxyethoxy)aniline:

[0377] General Procedure F was used to give the title compound as a dark red oil (134 mg, 68%).

[0378] UPLC (Method A): m / z 201.5 [M+H]+ at 0.46 min.

[0379] 1H 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(brs,2H),3.99-3.92(m,2H),3.63-3.56(m,2H),3.29(s,3H).

[0380] Preparation of compound 6 (4-(benzyloxy)-2-cyclopropyloxy-1-nitrobenzene):

[0381] To a suspension of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (1.0 equivalents) and CsCO (1.6 equivalents) in DMF (0.3M) was added cyclopropanol (1.5 equivalents) and the reaction mixture was heated to 80°C for 18 hours. The reaction mixture was cooled to room temperature and then distributed between EtOAc (40mL) and water (30mL). The phases were separated and the aqueous phase was extracted with EtOAc (30mL x 2). The combined organic phases were washed with salt water (30mL), dried with MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography eluting with 0% to 100% (25% EtOAc in isohexane) / isohexane to give the title compound (192mg, 81%) as a yellow oil.

[0382] UPLC (Method A): m / z [M+H]+ not observed at 2.13 min.

[0383] 1H 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).

[0384] Preparation of compound 7 (4-(benzyloxy)-2-cyclopropyloxy-1-nitrobenzene):

[0385] Using General Procedure F, the title compound was obtained as a black solid (91 mg, 78%).

[0386] UPLC (Method B): m / z 164.0 [M+H]+ at 0.74 min.

[0387] 1H NMR (400MHz, DMSO-d6)08.46(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).

[0388] Preparation of compound 8 (4-(benzyloxy)-2-(methoxy-d3)-1-nitrobenzene):

[0389] To a solution of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (1.0 equiv.) in THF (3 mL) was added methyl-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 evaporated in vacuo to afford the title compound (312 mg, 98%) as a light orange solid.

[0390] UPLC (Method A): m / z 263.2 [M+H]+ at 1.97 min.

[0391] 1H NMR(400MHz, DMSO-d6)67.96(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).

[0392] Preparation of compound 9 (4-amino-3-(methoxy-d3)phenol):

[0393] General Procedure F was used to afford the title compound as a dark brown solid (165 mg, 88%).

[0394] UPLC (Method B): m / z [M+H]+ not observed at 0.70 min.

[0395] 1H NMR (400MHz, DMSO-d6) 68.44(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).

[0396] Preparation of compound 10 (4-(cyclopentyloxy)-2-methoxy-1-nitrobenzene):

[0397] To 4-fluoro-2-methoxy-1-nitrobenzene (1.0 equivalents) and CsCO (3.0 equivalents) in MeCN (0.3M) solution, add cyclopentanol (2.5 equivalents).The reaction mixture is heated to 80 ℃, and stirred for 18 hours.The reaction mixture is cooled to room temperature, and distributed between EtOAc (40mL) and water (40mL).The aqueous phase is extracted with EtOAc (20mL x 3), and the organic phase merged is washed with salt water (30mL), uses MgSO4 drying, filters, and evaporates the solvent in vacuo.The crude product is purified by silica gel chromatography, eluted with 0% to 20% (25%EtOH in EtOAc) / isohexane, obtains the title compound (305mg, 73%) as a yellow oil.

[0398] UPLC (Method A): m / z 238.0 [M+H]+ at 2.00 min.

[0399] 1H NMR(400MHz, DMSO-d6)67.94(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).

[0400] Preparation of compound 11 (4-(cyclopentyloxy)-2-methoxyaniline):

[0401] Purify by silica gel chromatography using General Procedure F, eluting with 0% to 5% (0.7M NH3 / MeOH) / DCM, to give the title compound as a brown oil (229 mg, 86%).

[0402] UPLC (Method A): m / z 208.2 [M+H]+ at 0.83 min.

[0403] 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).

[0404] Preparation of compound 12 (4-(2-isopropoxyethoxy)-2-methoxy-1-nitrobenzene):

[0405] To a suspension of 4-fluoro-2-methoxy-1-nitrobenzene (1.0 equivalents) and 2-isopropoxy-1-ol (1.5 equivalents) at 0 DEG C of MeCN (0.4M) was added 2.0M NaOt-Bu (1.1 equivalents) in THF. The reaction mixture was slowly heated to room temperature and stirred for 18 hours. The reaction mixture was distributed between EtOAc (40mL) and water (40mL), and each phase was separated. The aqueous phase was extracted with EtOAc (30mL x 2), and the combined organic phases were washed with brine (30mL), dried with MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was dried and loaded on silica, then purified by silica gel chromatography, eluted with 0% to 100% (25% EtOAc in isohexane) / isohexane to give the title compound (578mg, 70%) as a light orange oil.

[0406] LCMS (Method E): m / z 256.2 [M+H]+ at 1.72 min.

[0407] 1H NMR(400MHz, DMSO-d6)67.94(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).

[0408] Preparation of compound 13 (4-(2-isopropoxyethoxy)-2-methoxyaniline):

[0409] Using General Procedure F, the title compound was obtained as a dark red / brown oil (358 mg, 97%).

[0410] LCMS (Method E): m / z 226.2 [M+H]+ at 0.41 min.

[0411] 1H 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).

[0412] Preparation of compound 14 (4-methoxy-2-(2-methoxyethoxy)-5-nitropyridine):

[0413] To a solution of 2-chloro-4-methoxy-5-nitropyridine (100 mg, 530 μmol) and CsCO (200 mg, 614 μmol) in MeCN (2 mL) at room temperature was added 2-methoxyethanol (50 μL, 0.63 mmol). The reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by silica gel chromatography (0% to 100% MTBE / isohexane) to give 4-methoxy-2-(2-methoxyethoxy)-5-nitropyridine (31 mg, 0.13 mmol, 24%) as an orange solid.

[0414] UPLC (Method A): m / z 229.1 [M+H]+ at 1.36 min.

[0415] 1H NMR (400 MHz, chloroform-d) 68.76 (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).

[0416] Preparation of compound 15 (4-methoxy-6-(2-methoxyethoxy)pyridin-3-amine):

[0417] General Procedure F was used to afford the title compound (24 mg, 0.12 mmol, 87%) as a dark orange oil.

[0418] UPLC (Method B): m / z 199.2 [M+H]+ at 0.65 min.

[0419] 1H NMR (400 MHz, chloroform-d) 67.53 (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).

[0420] Preparation of compound 16 (2-methoxy-6-(2-methoxyethoxy)-3-nitropyridine):

[0421] To a solution of 6-chloro-2-methoxy-3-nitropyridine (100 mg, 530 micromoles) and CsCO (200 mg, 614 micromoles) 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 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by silica gel chromatography (0% to 50% MTBE / isohexane) to give 2-methoxy-6-(2-methoxyethoxy)-3-nitropyridine (65 mg, 0.27 mmol, 51%) as an off-white solid.

[0422] UPLC (Method A): m / z [M+H]+ not observed at 1.48 min.

[0423] 1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 4.59-4.52 (m, 2H), 4.10 (s, 3H), 3.79-3.73 (m, 2H), 3.45 (s, 3H).

[0424] Preparation of compound 17 (2-methoxy-6-(2-methoxyethoxy)pyridin-3-amine):

[0425] General Procedure F was used to afford the title compound (55 mg, 0.26 mmol, 95%) as a dark red oil.

[0426] UPLC (Method B): m / z 199.2 [M+H]+ at 0.83 min.

[0427] 1H 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).

[0428] Preparation of compound 18 (4-methoxy-2-(2-methoxyethoxy)-5-nitropyrimidine):

[0429] At 0 ℃, to the solution of anhydrous THF (2mL) of 2-chloro-4-methoxy-5-nitropyrimidine (1.0 equivalent) and 2-methoxyethanol (1.1 equivalent), NaOt-Bu (1.2 equivalent) was added. The reaction mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was distributed between saturated NH4Cl (20mL) and dichloromethane (20mL). Each phase was separated and the aqueous phase was extracted with dichloromethane (10mL x 2). The combined organic phase was passed through a phase separator and the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography, eluting with 0% to 50% MTBE / isohexane to obtain the title compound (112mg, 71%) in the form of a light yellow gum.

[0430] UPLC (Method A): m / z 200.1 [M-OMe+H]+ at 0.79 min.

[0431] 1H 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).

[0432] Preparation of compound 19 (2-methoxy-6-(2-methoxyethoxy)pyrimidin-3-amine):

[0433] General Procedure F was used to afford the title compound as a light brown solid (149 mg, 91%).

[0434] UPLC (Method B): m / z 200.1 [M+H]+ at 0.79 min.

[0435] 1H 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).

[0436] Preparation of Compound 20 (2-methoxy-3-nitro-6-(2-(trifluoromethoxy)ethoxy)pyridine):

[0437] To 2-(trifluoromethoxy) second-1-alcohol (72.0mg, 554 micromoles) in THF (2mL) solution at 0 ℃, add NaOtBu (61.0mg, 635 micromoles) and 6-chloro-2-methoxy-3-nitropyridine (100mg, 530 micromoles).Reaction mixture is slowly heated to room temperature and stirred overnight.Reaction mixture is distributed between saturated NH4Cl (20mL) and DCM (20mL).Separate each phase, aqueous phase is extracted with DCM (10mL x 2).Filter the organic phase merged by phase separator, evaporate the solvent in vacuo.The crude product is purified by silica gel chromatography (0% to 100% DCM / isohexane) to obtain 2-methoxy-3-nitro-6-(2-(trifluoromethoxy) ethyoxy) pyridine (112mg, 0.38 mmol, 71%) in light yellow colloid form.

[0438] UPLC (Method A): m / z [M+H]+ not observed at 1.91 min.

[0439] 1H NMR (400 MHz, chloroform-d) δ 8.38 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 4.68-4.61 (m, 2H), 4.35-4.28 (m, 2H), 4.11 (s, 3H).

[0440] Preparation of Compound 21 (2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyridin-3-amine):

[0441] General Procedure F was used to afford the title compound (97 mg, 0.37 mmol, 95%) as a dark brown gum.

[0442] UPLC (Method A): m / z 253.1 [M+H]+ at 1.26 minutes.

[0443] 1H 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).

[0444] Preparation of compound 22 (2-methoxy-3-nitro-6-(2-(trifluoromethoxy)ethoxy)pyrimidine):

[0445] At 0 ℃, to 2-chloro-4-methoxy-5-nitropyrimidine (1.0 equivalents) and 2-(trifluoromethoxy) ethanol-1-ol (1.1 equivalents) in anhydrous THF (0.3M) solution, add NaOt-Bu (1.2 equivalents).The reaction mixture is slowly heated to room temperature and stirred for 18 hours.The reaction mixture is distributed between saturated NH4Cl (20mL) and dichloromethane (20mL).Separate each phase, the aqueous phase is extracted with dichloromethane (10mL x 2).The organic phase merged is passed through a phase separator, and the solvent is evaporated in vacuo.The crude product is purified by silica gel chromatography, eluting with 0% to 50% MTBE / isohexane to obtain the title compound (112mg, 71%) in the form of light yellow colloid.

[0446] UPLC (Method A): m / z [M+H]+ not observed at 1.36 min.

[0447] 1H NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 4.72-4.66 (m, 2H), 4.51-4.44 (m, 2H), 4.10 (s, 3H).

[0448] Preparation of compound 23 (2-methoxy-6-(2-(trifluoromethoxy)ethoxy)pyrimidin-3-amine):

[0449] General Procedure F was used to give the title compound as a dark brown oil (165 mg, 91%).

[0450] UPLC (Method B): m / z 254.2 [M+H]+ at 1.05 min.

[0451] 1H NMR (400MHz, DMSO-d6) δ7.64(s,1H),4.60-4.55(m,2H),4.46-4.32(m,4H),3.91(s,3H).

[0452] Preparation of compound 24 (4-(3-methoxy-4-nitrophenyl)-1H-pyrazole):

[0453] PdOAc2 (8 mg, 37 micromoles), tricyclohexylphosphine tetrafluoroborate (26 mg, 69.8 micromoles), 4-bromo-2-methoxy-1-nitrobenzene (200 mg, 863.3 micromoles), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (281 mg, 955 micromoles) and K2CO3 (476.7 mg, 3.449 mmoles) were added to a vial. Degassed with N2 for 5 minutes. 1,4-dioxane (4.0 mL) and water (0.20 mL) were added, and the suspension was degassed again with N2 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 celite pad. The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0% to 100% EtOAc in heptane) to afford 4-(3-methoxy-4-nitrophenyl)-1H-pyrazole (107 mg, 0.47 mmol, 54%) as a yellow solid.

[0454] UPLC (Method A): m / z 220.1 [M+H]+ at 1.32 minutes.

[0455] 1H 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).

[0456] Preparation of compound 25 (2-methoxy-4-(1H-pyrazol-4-yl)aniline):

[0457] General Procedure F was used to afford the title compound (88 mg, 393 μmol, 86%) as an off-white solid.

[0458] UPLC (Method B): m / z 190.2 [M+H]+ at 0.70 min.

[0459] 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).

[0460] Preparation of compound 26 (2-methoxy-3-nitro-6-(1H-pyrazol-4-yl)pyridine):

[0461] 6-chloro-2-methoxy-3-nitropyridine (1.0 equivalent), Pd(dppf)Cl2 (5 mol%) and K3PO4 (3.8 equivalents) were added to the reaction vessel. The mixture was evacuated and purged with nitrogen (nitroden), and then a 3:1 mixture of 1,4-dioxane / water was added. The reaction mixture was evacuated 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 obtain the title compound (193 mg, 78%) as a brown / grey solid.

[0462] LCMS (Method E): m / z 221.0 [M+H]+ at 1.30 min.

[0463] 1H NMR (400MHz, DMSO-d6) 613.35 (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).

[0464] Preparation of compound 27 (2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-amine):

[0465] Using General Procedure F, the title compound was obtained as a brown solid (134 mg, 91%).

[0466] LCMS (Method E): m / z 191.2 [M+H]+ at 0.35 min.

[0467] 1H NMR (400MHz, DMSO-d6) 612.76 (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).

[0468] Preparation of compound 28 (4-(2-(difluoromethoxy)ethoxy)-2-methoxy-1-nitrobenzene):

[0469] To a stirred solution of 2-(3-methoxy-4-nitrophenoxy)ethan-1-ol (884 mg, 4.06 mmol) in a mixture of DCM (3 mL) and water (3 mL) at 0° C. in a sealed tube was added KHF (3.17 g, 40.6 mmol), and the mixture was stirred for 10 minutes. (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 x 40 mL). The combined organic phases were washed with brine (20 mL), filtered through a phase separator, and the solvent removed in vacuo to afford 4-(2-(difluoromethoxy)ethoxy)-2-methoxy-1-nitrobenzene (1.05 g, 3.6 mmol, 88%) as a light brown powder.

[0470] UPLC (Method A): m / z 264.1 [M+H]+ at 1.74 min.

[0471] 1H NMR(400MHz, DMSO-d6)67.96(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).

[0472] Preparation of compound 29 (4-(2-(difluoromethoxy)ethoxy)-2-methoxyaniline):

[0473] Using General Procedure F, the title compound was obtained as a dark-red oil (893 mg, 3.83 mmol, 100%).

[0474] UPLC (Method B): m / z 234.2 [M+H]+ at 1.06 minutes.

[0475] 1H NMR(400MHz, DMSO-d6)66.94-6.51(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).

[0476] Preparation of compound 30 (2-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene):

[0477] To a solution of 3-fluoro-4-nitrophenol (2.00 g, 12.73 mmol) in DMF (20 mL) was added 1-bromo-2-methoxyethane (5.98 mL, 63.65 mmol) and KCO (3.52 mg, 25.46 mmol). The mixture was stirred at 70° C. for 4 hours. The solvent was evaporated and the product was extracted with EtOAc and washed with water (3 times) and brine (2 times). The organic phase was dried over MgSO, filtered and evaporated. The crude product was purified by flash column chromatography to give 2-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene (1.95 g, 71%) as a white powder.

[0478] 1 H NMR (400 MHz, chloroform-d) 68.14-8.05 (m, 1H), 6.84-6.73 (m, 2H), 4.23-4.16 (m, 2H), 3.81-3.74 (m, 2H), 3.45 (s, 3H).

[0479] Preparation of compound 31 (4-(5-(2-methoxyethoxy)-2-nitrophenyl)morpholine):

[0480] 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 and cooled to room temperature before adding a NaHCO solution. The product was extracted with DCM. The organic layer was washed with water and brine, dried over MgSO , filtered, and concentrated under reduced pressure to afford 4-(5-(2-methoxyethoxy)-2-nitrophenyl)morpholine (278 mg, 100%) as a yellow solid.

[0481] 1 H NMR(400MHz, chloroform-d)67.98(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,2H) ,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).

[0482] Preparation of compound 32 (4-(2-methoxyethoxy)-2-morpholinoaniline):

[0483] General Procedure F was used to give the title compound as a purple oil (176 mg, 98%).

[0484] 1H NMR(400MHz, chloroform-d)66.68(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).

[0485] Preparation of compound 33 (7-bromo-N-(2,4-dimethoxyphenyl)quinolin-4-amine, HCl):

[0486] To a solution of 7-bromo-4-chloroquinoline (100 mg, 412 micromoles) in EtOH (2.0 mL) was added 2,4-dimethoxyaniline (70.0 mg, 457 micromoles) at room temperature. The reaction mixture was stirred at 80°C overnight. The reaction mixture was diluted with acetone (10 mL), the precipitate was collected by filtration, and washed with acetone (10 mL x 3). The product was dried in a vacuum desiccator overnight to give 7-bromo-N-(2,4-dimethoxyphenyl)quinolin-4-amine, HCl (135 mg, 0.34 mmol, 82%) as a dark yellow solid.

[0487] UPLC (Method A): m / z 359.2 / 361.2 [M+H]+ at 0.84 min.

[0488] 1H NMR (400MHz, DMSO-d6) 614.23 (brs, 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).

[0489] Preparation of compound 34 (7-bromo-N-(2-methoxy-4-(2-methoxyethoxy)phenyl)quinolin-4-amine):

[0490] A mixture of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol, HCl (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 with water (50 mL), and the solid was collected by filtration. The solid was then triturated with isohexane (30 mL), then collected again 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.

[0491] UPLC (Method A): m / z 403.1 / 405.1 [M+H]+ at 1.18 minutes.

[0492] 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).

[0493] Preparation of compound 35 (7-bromo-N-(2-methoxy-4-(2-(trifluoromethoxy)ethoxy)phenyl)quinolin-4-amine, HCl):

[0494] To a stirred solution of 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol, HCl (750 mg, 1.97 mmol) in acetone (10.0 mL) was added CsCO (1.50 g, 4.60 mmol) and 1-bromo-2-(trifluoromethoxy)ethane (465 mg, 2.41 mmol) at room temperature. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resulting precipitate was collected by filtration, washed with water (3 x 20 mL), and then washed with isohexane (2 x 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 (725 mg, 77%) as a light yellow solid.

[0495] UPLC (Method A): m / z 457.1 / 459.1 [M+H]+ at 1.41 min.

[0496] 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).

[0497] Preparation of compound 36 (4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol, HCl):

[0498] 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 was evaporated, and the residue was triturated with acetone (30 ml), cooled to 0° C., and the precipitate was collected by filtration to give 4-((7-bromoquinolin-4-yl)amino)-3-methoxyphenol, HCl (1.87 g, 4.7 mmol, 81%) as a green solid.

[0499] UPLC (Method A): m / z 345.0 / 347.0 [M+H]+ at 1.05 min.

[0500] 1H 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).

[0501] Preparation of compound 37 (4-((7-methylquinolin-4-yl)amino)-3-methoxyphenol, HCl):

[0502] Purify by silica gel chromatography using general procedure A-2, eluting with 0% to 100% (10% 0.7M NH3 in DCM) / DCM to give the title compound (30 mg, 64%) as a pink / brown solid.

[0503] UPLC (Method A): m / z 284.2 [M+H]+ at 0.98 min.

[0504] 1H 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.

[0505] Preparation of compound 38 (3-(methoxy-d3)-4-((7-methylquinolin-4-yl)amino)phenol, HCl):

[0506] Purify by silica gel chromatography using General Procedure B, eluting with 0% to 100% (10% 0.7M NH3 in DCM) / DCM, to give the title compound as a pink / brown solid (30 mg, 64%).

[0507] UPLC (Method A): m / z 284.2 [M+H]+ at 0.98 min.

[0508] No NMR data were obtained.

[0509] Preparation of compound 39 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-methoxyphenol, HCl):

[0510] General Procedure B was used to afford the title compound as a dark yellow solid (26 mg, 69%).

[0511] UPLC (Method A): m / z 317.1 [M+H]+ at 1.64 min.

[0512] 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).

[0513] Preparation of Compound 40 (3-cyclopropyloxy-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol, HCl):

[0514] Purify by silica gel chromatography using General Procedure B, eluting with 0% to 10% (0.7M NH3 / MeOH) / DCM, to give the title compound as a dark brown solid (21 mg, 47%).

[0515] UPLC (Method A): m / z 343.2 [M+H]+ at 1.13 minutes.

[0516] No NMR data were obtained.

[0517] Preparation of compound 41 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-(methoxy-d3)phenol, HCl):

[0518] Purify by silica gel chromatography using General Procedure B, eluting with 0% to 10% (0.7M NH3 / MeOH) / DCM, to give the title compound as a light green solid (28 mg, 66%).

[0519] UPLC (Method A): m / z 320.2 [M+H]+ at 0.95 min.

[0520] No NMR data were obtained.

[0521] Preparation of compound 42 (3-cyclopropyloxy-4-((7-methylquinolin-4-yl)amino)phenol, HCl):

[0522] Purify by silica gel chromatography using General Procedure B, eluting with 0% to 10% (0.7M NH3 / MeOH) / DCM, to give the title compound as a dark brown solid (17 mg, 35%).

[0523] UPLC (Method A): m / z 307.2 [M+H]+ at 0.97 min.

[0524] No NMR data were obtained.

[0525] Preparation of compound 43 (4-((7-(difluoromethyl)quinolin-4-yl)amino)-3-fluorophenol, HCl):

[0526] Using General Procedure B, the title compound was obtained as a dark yellow solid (81 mg, 94%).

[0527] UPLC (Method A): m / z 317.1 [M+H]+ at 1.64 min.

[0528] 1H NMR (400MHz, DMSO) δ14.70 (brs, 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).

[0529] Preparation of Compound 44 (3-chloro-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol, HCl):

[0530] Using General Procedure B, the title compound was obtained as a yellow solid (80 mg, 89%).

[0531] UPLC (Method A): m / z 321.3 [M+H]+ at 1.04 minutes.

[0532] 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).

[0533] Preparation of Compound 45 (3-bromo-4-((7-(difluoromethyl)quinolin-4-yl)amino)phenol, HCl):

[0534] Using General Procedure B, the title compound was obtained as a light brown solid (87 mg, 88%).

[0535] UPLC (Method A): m / z 365.3 / 367.3 [M+H]+ at 1.04 min.

[0536] 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=55.1Hz1H),7.13(d,J=2.6Hz,1H),6.97(dd,J=8.6,2.7Hz,1H),6.38(d,J=6.9Hz,1H).

[0537] Preparation of compound 46 (3-chloro-4-((7-methylquinolin-4-yl)amino)phenol, HCl):

[0538] General Procedure B was used to afford the title compound as a dark beige solid (18 mg, 57%).

[0539] UPLC (Method A): m / z 285.0 / 287.0 [M+H]+ at 1.04 min.

[0540] 1H NMR (400MHz, DMSO) 14.14 (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).

[0541] Preparation of compound 47 (3-bromo-4-((7-methylquinolin-4-yl)amino)phenol, HCl):

[0542] Using General Procedure B, the title compound was obtained as a light tan solid (60 mg, 69%).

[0543] UPLC (Method A): m / z 329 / 331 [M+H]+ at 1.09 min.

[0544] 1H 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).

[0545] Preparation of Compound 48 (3-fluoro-4-((7-methylquinolin-4-yl)amino)phenol, HCl):

[0546] Using general procedure B, the title compound was obtained as a light brown solid (75 mg, 83%).

[0547] UPLC (Method A): m / z 269.2 [M+H]+ at 0.95 min.

[0548] 1H NMR (400MHz, DMSO) δ14.33 (brs, 1H), 10.56 (brs, 1H), 10.40 (s, 1H), 8.61 (d, J = 8.7Hz, 1H), 8.46 (d, J = 7.0Hz, 1H), 7.83-7.78 (m, 1H), 7.66 (dd, J=8.7, 1.6Hz, 1H), 7.34 (t, J=9.0Hz, 1H), 6.87 (dd, J=12.1, 2.6Hz, 1H), 6.83-6.79 (m, 1H), 6.40 (dd, J=7.0, 1.9Hz, 1H), 2.58 (s, 3H).

[0549] Preparation of Examples

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562] *Purified by preparative HPLC

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599] Pharmacology

[0600] Example 143: Evaluation of Pharmacological Activities of Inhibiting Proliferation, Inducing Senescence, and Degrading NIK

[0601] Proliferation and aging

[0602] A375 (American Type Culture Collection; CRL-1619) cells were seeded into 96-well plates (1200 cells / well; Perkin Elmer; 6005225) and cultured overnight at 37°C, 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 cultured at 37°C, 5% CO2 for 4 days. The culture medium was then aspirated from the cells, and freshly prepared compounds were added to the cells, which were then cultured for another 3 days at 37°C, 5% CO2. After 7 days of co-culture in the presence of compounds, the culture medium was removed and the cells were incubated at 37°C with Hoechst (1 / 1000; ThermoFisher; 62249), TOTO (1000), and 100 μg / ml of Hanks' balanced salt solution supplemented with 1.0 mM HEPES buffer. TM -3 (1 / 10000; Thermo Fisher; T3604) and SPiDERβGAL (1.0 μM; Sigma-Aldrich; 94433) were labeled for 20 minutes. Cells were imaged by confocal microscopy at 10× magnification using ImageXpress (Molecular Devices). Images were analyzed using MetaXpress software (Molecular Devices).

[0603] Western blot assay for NIK degradation

[0604] A375 cells were plated in 6-well culture dishes at a density of 2000 cells / cm 2 The cells were plated. The next day, the cells were treated with 10 μM of the compounds of the examples for 72 hours. During the last 4 hours of the treatment period, the cells were treated with 5 μM MG132 to inhibit proteasomal degradation. To isolate proteins, the cells were washed twice with PBS and then lysed with RIPA buffer (1X) containing protease and phosphatase inhibitors. After sonication, the lysate was centrifuged at 20,000 g for 10 minutes at 4°C, and the supernatant was collected and the protein concentration was determined using a BCA kit (Pierce).

[0605] Total protein (20 g) was separated by electrophoresis on a 10% SDS-polyacrylamide gel and transferred to a PVDF membrane (Millipore). Blocking was performed in Tris-buffered saline containing 3% BSA. The membrane was incubated with the appropriate primary antibody (NIK, CST#4994, 1 / 2000) and β-actin (Santa-Cruz, sc-47778, 1 / 5000) at 4°C overnight. After washing three times, the membrane was incubated with a horseradish peroxidase-conjugated secondary antibody for 1 hour. Bound antibodies were detected using an enhanced chemiluminescence plus kit (GE Healthcare).

[0606] The compounds of Examples 3, 4, 5, 6, 10 and 11 were tested and confirmed for NIK degradation (see corresponding tables below). Figure 1 Shown are the results of Western blot analysis of NIK degradation in cells treated with the compound of Example 3 (10 μM concentration for 72 hours).

[0607] Proliferative activity

[0608]

[0609] Aging activity

[0610]

[0611] NIK degradation

[0612] Example NIK degradation activity 3，4，5，6，10，11

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is an aromatic group selected from (A-1), (A-2), (A-3), (A-4), (A-5), (A-6) and (A-7): wherein the group (A-1) is a phenyl group or a 6-membered monocyclic heteroaryl group, wherein the phenyl group or the heteroaryl group is replaced by a group R at the indicated position. A1 and group R A2 substituted, and optionally also by one or more than one group R A3 replace; wherein the groups (A-2) and (A-3) are each a 5-membered monocyclic heteroaryl group which is replaced at the indicated position by a group R A1 and group R A2 substituted, and optionally also by one or more than one group R A3 replace; Wherein the group (A-4) is an 8-membered bicyclic heteroaryl group which is replaced by a group R at the indicated position A2 substituted, and optionally also by one or more than one group R A3 replace; wherein groups (A-5) and (A-6) are each a 9-membered bicyclic heteroaryl group which is replaced at the indicated position by a group R A2 substituted, and optionally also by one or more than one group R A3 replace; and wherein the group (A-7) is a naphthyl group or a 10-membered bicyclic heteroaryl group, wherein the naphthyl group or the heteroaryl group is replaced by a group R at the indicated position. A2 substituted, and optionally also by one or more than one group R A3 replace; R A1 Selected from -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 the -(C 0-3 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 The heterocycloalkyl groups in the alkylene)-heterocycloalkyl groups are each optionally substituted by one or more than one group R Cyc substituted, and wherein said -(C 0-3 Alkylene)-cycloalkyl or said-(C 0-3 One or more -CH2- units contained in the alkylene group in the alkylene group)-heterocycloalkyl group are optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- group replacement; R A2 Selected from 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 Halogenated alkyl), -CO(C 1-12 alkyl), -CO(C 1-12 Halogenated alkyl), -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)-heterocyclic group, wherein the 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 -SO2-(C 1-12 Alkyl) or the -SO2-(C 1-12 In the case of a haloalkyl group, one or more -CH2- units are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO- and -CH=CH-, wherein the -(C 0-5 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-5 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-5 Alkylene)-carbocyclic group or said-(C 0-5 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- group replacement; Each R A3 , if present, independently selected from 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)-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), -(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)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- group replacement; R N Selected from hydrogen, C 1-5 Alkyl and -CO-(C 1-5 alkyl); R 1 、R 4 and R 5 are each independently selected from 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 1-5 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 1-5 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)-carbocyclic group, -(C 0-3 alkylene)-heterocyclyl and -R 6 -R 7 wherein said-(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- group replacement; R 2 Selected from 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 1-5 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 1-5 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)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S- and -SO- group replacement; R 3 Selected from 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)-CH2F, -(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 1-5 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 and -(C 0-3 Alkylene)-heterocyclic group, wherein the -(C 0-3 Alkylene) -carbocyclic group and the carbocyclic group - (C 0-3 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc substituted, and wherein said -(C 0-3 Alkylene)-carbocyclic group or said-(C 0-3 The one or more -CH2- units contained in the alkylene group in the alkylene group)-heterocyclyl group are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-; provided that R 3 is not morpholin-4-yl or -NH-phenyl, wherein the phenyl group in the -NH-phenyl group is optionally replaced by one or more than one group R Cyc replace; Each R Cyc Independently selected from 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 Halogenated alkyl), -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 The cycloalkyl group in the alkylene)-cycloalkyl group and the -(C 0-3 Each of the heterocycloalkyl groups in the alkylene)-heterocycloalkyl group is optionally substituted by one or more than one independently selected group consisting of C 1-5 Alkyl group, 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(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 alkyl) group substitution; Each R 6 Independently selected from covalent bonds, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted by one or more than one 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 wherein the one or more -CH2- units contained in the alkylene, alkenylene or alkynylene are each optionally substituted by an independently selected -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2-; and Each R 7 Independently selected from -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 Halogenated alkyl), -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), aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein each of the aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more than one 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) groups.

2. The compound according to claim 1, wherein ring A is group (A-1): wherein the group (A-1) is a phenyl group or a pyridyl group, wherein the phenyl group or the pyridyl group is replaced by a group R at the indicated position A1 and group R A2 substituted, and wherein the phenyl or the pyridyl is optionally further substituted by one or more than one group R A3 replace.

3. The compound according to claim 1 or 2, wherein ring A is optionally substituted with one or more than one R A3 2-R substituted with a group A1 -4-R A2 -phenyl.

4. The compound according to any one of claims 1 to 3, wherein R A1 Selected from -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.

5. The compound according to any one of claims 1 to 4, wherein R A1 Yes-O(C 1-5 alkyl) or halogen.

6. The compound according to any one of claims 1 to 5, wherein R A2 Selected from 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), -SO2-(C 1-12 alkyl), -SO2-(C 1-12 haloalkyl), halogen, C 1-5 Haloalkyl, -(C 0-5 Alkylene)-carbocyclic group, -(C 0-5 Alkylene)-heterocyclic group, -O-(C 0-4 Alkylene)-carbocyclic group, -O-(C 0-4 Alkylene)-heterocyclic group, -(C 0-4 Alkylene)-O-carbocyclic group, -(C 0-4 Alkylene)-O-heterocyclic group, -CO-(C 0-4 Alkylene)-carbocyclyl and -CO-(C 0-4 Alkylene)-heterocyclic group, wherein the -(C 0-5 Alkylene)-carbocyclic group, the carbocyclic group in the -(C 0-5 Alkylene) -heterocyclic group, the heterocyclic group in the -O-(C 0-4 Alkylene)-carbocyclic group, the -O-(C 0-4 The heterocyclic group in the alkylene)-heterocyclic group, the -(C 0-4 Alkylene)-O-carbocyclic group in the carbocyclic group, the -(C 0-4 The heterocyclic group in the -CO-(C 0-4 Alkylene)-carbocyclic group and the carbocyclic group -CO-(C 0-4 The heterocyclyl groups in the alkylene)-heterocyclyl group are each optionally substituted by one or more than one radical R Cyc replace.

7. A compound according to any one of claims 1 to 6, wherein R 2 Selected from 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.

8. A compound according to any one of claims 1 to 7, wherein R 3 Selected from 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 each of the phenyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl and heterocycloalkenyl groups is optionally substituted by one or more than one radical R Cyc Replace, provided that R 3 Not morpholin-4-yl.

9. The compound according to claim 1, wherein the compound is selected from: 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-cyclopropyloxy-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-cyclopropyloxyethoxy)-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-cyclopropyloxy-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 of these compounds.

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

11. The compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 for use in treating or preventing cancer, inflammatory diseases or autoimmune diseases.

12. The compound for use according to claim 11 or the pharmaceutical composition for use according to claim 11, wherein the compound or the pharmaceutical composition is for treating or preventing cancer, and wherein 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 cancer, 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 cancer, bladder cancer, endometrial cancer, vaginal cancer, vulvar cancer, testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, epidermoid cancer, squamous cell carcinoma, fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, laryngeal cancer, oral cancer, thymoma, neuroendocrine cancer and multiple myeloma.

13. The compound for use according to claim 11 or the pharmaceutical composition for use according to claim 11, wherein the compound or the pharmaceutical composition is used to treat or prevent an inflammatory disease, and wherein the inflammatory disease is selected from arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, uric acid arthritis, gout, chronic polyarthritis, frozen shoulder, cervical arthritis, lumbosacral arthritis, enteropathic arthritis, ankylosing spondylitis, asthma, Dermatitis, psoriasis, scleroderma, polymyositis, dermatomyositis, juvenile dermatomyositis, primary biliary cirrhosis, fibrosis, cystic fibrosis, pulmonary fibrosis, cirrhosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic fibrosis, keloids, scleroderma, arthrofibrosis, late and / or chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, pemphigus, pemphigus vulgaris, pemphigus herpetiformis, proliferative pemphigus, IgA pemphigus, pemphigus erythematosus , bullous pemphigoid, pemphigoid gestationis, mucocutaneous disease, pemphigoid nodularis, linear IgA bullous dermatosis, bullous lichen planus, epidermolysis bullosa acquisita, autoimmune diabetes mellitus, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease, glomerulonephritis, Graves' disease, gastrointestinal irritability, conjunctivitis, atherosclerosis, coronary artery disease, angina pectoris, arteriolar disease , acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, systemic sclerosis, antiphospholipid syndrome, Sjögren's syndrome, autoimmune hemolytic anemia, colitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, embolism, pulmonary embolism, arterial embolism, venous embolism, allergic inflammation, cardiovascular disease, transplant-related disease, graft-versus-host disease, diseases related to transplant rejection, post-traumatic degeneration, stroke, transplant rejection, allergic disorders, hypersensitivity reactions, allergic rhinitis, allergic eczema, and skin / dermal inflammatory diseases.

14. The compound for use according to claim 11 or the pharmaceutical composition for use according to claim 11, wherein the compound or the pharmaceutical composition is used to treat or prevent an autoimmune disease, and wherein the autoimmune disease is selected from lupus, Hashimoto's thyroiditis, Wegener's granulomatosis, 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, ulcer Ulcerative colitis, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis, Sjögren'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. Use of a compound according to any one of claims 1 to 9 as a NIK inhibitor in vitro.

Images